Reimbursement Review

Clascoterone (Winlevi)

Sponsor: Sun Pharma Canada Inc.

Therapeutic area: Acne vulgaris

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Background Information on Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Acne is a chronic inflammatory skin condition of the pilosebaceous glands that typically begins during puberty and may continue through adulthood with flares often coinciding with increasing serum androgens.¹ Lesions occur primarily on the face, neck, upper back, and chest. When assessing the severity of acne, considerations include the distribution (back, chest, and upper arms), the type and number of lesions (comedones, papules, pustules, and nodules), and the presence or absence of scarring.^2,3 Acne is diagnosed by physicians in the community by visual assessment and no specific procedures are required. Acne is 1 of the most common dermatological disorders worldwide, affecting 5.6 million people living in Canada.⁴ Although it predominantly affects the adolescent population (approximately 80%), it can also affect preadolescents (aged 7 years to 12 years) and postadolescents.^4-6 Adolescent acne usually begins with the onset of puberty, with the increase in androgen hormone production, which affects acne development and severity. During adolescence, acne vulgaris is more common in males than in females.⁷ In adulthood, acne vulgaris is more common in females than in males.^7-9

Treatment for acne depends on the severity and type of acne, the age and treatment preferences of the patient, and adherence and response to previous therapy. Mild acne is typically treated with topical medications, particularly antimicrobials such as benzoyl peroxide, antibiotics, and topical retinoids such as tretinoin, adapalene, and tazarotene.^10,11 The main side effects of topical medications are local irritation and erythema. Most topical preparations require at least 6 weeks to 8 weeks before an improvement is experienced, with the exception of antimicrobials — they are fast-acting and a response can be expected in as soon as 5 days.^11,12 For topical retinoids, the optimal response is expected after 12 weeks.¹³ Moderate acne is treated with the same topical treatments with the addition of an oral antibiotic or an oral antiandrogen, such as a combined oral contraceptive or spironolactone. According to the updated 2024 American Academy of Dermatology guidelines for managing acne, clascoterone is conditionally recommended for acne treatment (with a conditional recommendation based on the current high cost of the drug) and is not restricted to first-line use or to moderate and severe acne.¹⁴ Systemic therapy, including oral antibiotic treatment, hormonal therapies, and isotretinoin, are the mainstay systemic therapies for acne when topical therapy is insufficient or not tolerated. However, a major concern for antibiotics is the development of resistance, given that 60% of Cutibacterium acnes isolates are resistant to at least 1 antibiotic.¹⁵ Hormonal drugs (e.g., estrogen-containing oral contraceptives, spironolactone) provide effective second-line treatment in females with acne, regardless of the presence or absence of hormonal abnormalities.¹⁵ However, possible side effects of spironolactone include hyperkalemia, menstrual irregularities, and the feminization of a male fetus. For severe acne (e.g., nodular and/or inflammatory acne, acne conglobata, recalcitrant acne that is treatment-resistant), the treatment of choice according to the clinical expert consulted for this review and Canadian practice guidelines is oral isotretinoin.¹⁰ As oral isotretinoin is indicated in specific forms of very severe acne, it is outside the treatment paradigm for the population included in the reimbursement request. For patients unwilling or unable to use oral isotretinoin and those with intolerance, systemic antibiotics in combination with topical benzoyl peroxide, with or without a topical retinoid, may be considered. For females, hormonal therapy with a combined oral contraceptive may also be considered.¹⁰ For males, current hormone therapies are not suitable. According to the clinical expert, nondrug treatments include diet — in particular, a low glycemic index diet and a diet that minimizes dairy products — as well as laser therapy. Treatment goals include clearing acne and preventing acne sequelae such as postinflammatory hyperpigmentation and scarring. The main therapies currently used for acne vulgaris are aimed at reducing severity and recurrences of skin lesions as well as improving appearance. According to the clinical expert, with the exception of oral isotretinoin, most treatments for acne control symptoms but they are not curative. Hence, patients must continue treatment to maintain benefit.

Clascoterone is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older.¹⁶ Clascoterone 10 mg/g is supplied in a 30 g tube.^16,17 The recommended dose per application is up to 1 g or to 2 fingertip units applied in a thin layer twice daily over the affected area. Patients should not spot-treat for optimal efficacy.¹⁶ Clascoterone is an androgen receptor inhibitor. Androgen receptor inhibitors may reduce sebaceous gland activity. The mechanism of action of clascoterone cream for the topical treatment of acne vulgaris is unknown.¹⁶

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of clascoterone, 1% topical cream, in the treatment of moderate to severe acne vulgaris in patients aged 12 years and older. While the Health Canada indication and reimbursement request is for the treatment of patients aged 12 years and older, the data reported in the Clinical Review Report are consistent with those in the pivotal trials, which included patients aged 9 years and older.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups that responded to the call for input and from the clinical expert consulted for the purpose of this review.

Patient Input

Two national, not-for-profit organizations, the Acne and Rosacea Society of Canada (ARSC) and the Canadian Skin Patient Alliance (CSPA), jointly conducted a survey in June 2022 with 154 patients living in Canada diagnosed with acne. The ARSC comprises dermatologists, patients, educators, and communicators providing information and raising awareness about the disease. The CSPA strives to improve the lives of people affected by skin, hair, and nail conditions through collaboration, advocacy, and education.

Patient groups emphasized that acne not only affects appearance but also impacts patients’ lives and mental health. Many patients reported having diminished self-image, self-esteem, self-confidence, and assertiveness. This emotional distress caused by unhappiness with appearance can lead to bad moods, anxiety (including in social situations), anger, loneliness, self-consciousness, shame, depression, and pain, generally making patients feel in poor health overall. Furthermore, patient groups said these factors impede their ability to be social and conduct daily activities (e.g., forming friendships and dating, having social interactions, being viewed on camera, swimming, changing in changerooms where patients’ acne on their body is exposed). Financial burden was cited as another challenge and some respondents reported paying out-of-pocket costs for prescription, over-the-counter, and self-care products, such as cleansers and makeup, which increase with acne severity (4% of patients with mild acne, 5% of patients with moderate acne, and 14% of the overall respondents were spending $100 or more per month). More than half of the patients had facials and peels (53% of patients, with 12% of them paying more than $500 for each session) and light or laser therapy (65% of patients, with 15% of them paying more than $500 for each session); these costs exacerbate financial burden on patients. As such, patients prioritize treatments that help them enjoy personal relationships and cause less scarring or changes in skin pigment. Other goals include clearer skin, better mental health, increased confidence, the ability to be social, and an improved overall quality of daily life.

To improve their lives, respondents want increased access to new treatment that is safe and effective, health care providers to be aware of all the new and existing treatment options for acne, and evaluation for depression and anxiety that could lead them to getting support.

Three individuals who had experience with clascoterone felt that their acne was well controlled with the drug (also resulting in greater confidence) and they did not experience the typical side effects associated with topicals for acne. However, it was noted that the medication was very expensive compared to other treatment options, with patients paying out of pocket or accessing treatment through insurance.

Clinician Input

Input From the Clinical Expert Consulted by CDA-AMC

According to the clinical expert, a major limitation of current acne therapy is that the most efficacious topical treatments, such as topical retinoids and benzoyl peroxide, tend to be irritative and exhibit a slow onset of effect, which may contribute to the issue of poor adherence to treatment. The clinical expert noted that as the majority of treatments are not curative, their continuation becomes imperative to sustain benefits. Moreover, acne severity exhibits variability over time, requiring potential modifications to the treatment regimen as time progresses.

According to the clinical expert, topical clascoterone will likely be used as a first-line topical for mild and moderate acne if it is effective and accessible. Clascoterone has a novel mechanism in that it is the first topical androgen receptor blocker and the first androgen blocker that can be used in males with acne. The clinical expert anticipated that clascoterone may be used alone or in combination with other topicals for mild acne and in combination with oral antibiotics for moderate acne. The clinical expert did not feel that clascoterone could be used as a first-line treatment for severe acne; however, it could be considered in combination with systemic treatment if a patient requested alternatives to first-line treatment for severe acne (i.e., isotretinoin).

According to the clinical expert, topical clascoterone is appropriate for use by any patient with mild to moderate acne. It is least suited for use in patients with severe or treatment-resistant moderate acne because oral retinoids are better suited for this patient population. However, the clinical expert noted that clascoterone 1% cream could be used in combination with other treatments if a patient requested alternatives to first-line treatment for severe acne. The clinical expert noted that clascoterone could potentially be used in combination with oral contraceptives or spironolactone in female patients to discover if there would be added benefit. It should not be used in patients who are pregnant, nursing, or contemplating pregnancy.

The clinical expert noted that treatment success should be determined at 3 months, apart from treatment with an oral contraceptive and spironolactone, which would require 4 months to 6 months to improve acne. Of note, some physicians elect to reevaluate their patients on treatment with isotretinoin monthly. The clinical expert noted that a physician will examine acne lesions and record acne as clear, minimal or almost clear, moderate, or severe; comment on acne sequalae, including pigmentation and scarring; and note how patients think they are doing with their treatment upon evaluation. The goal of treatment is minimal acne (1 to 2 lesions on examination) or no acne. Given that patients’ expectations can be variable, patient satisfaction is also an important factor in assessing treatment success. The clinical expert noted that both family physicians and dermatologists may prescribe clascoterone. According to the clinical expert, patients would discontinue treatment if there was a lack of response or a worsening of disease, adverse effects, or patient dissatisfaction with treatment. The clinical expert also noted that they would discontinue treatment in patients who are attempting to conceive or are pregnant or nursing.

Clinician Group Input

Two clinician groups submitted input: the Dermatology Association of Ontario (DAO), represented by 10 clinicians, and the Primary Care Dermatology Society of Canada (PCDSC), represented by 5 physicians who make up its board of directors. The clinician groups and clinical expert consulted by CDA-AMC agreed that clascoterone provides a novel mechanism of action as the first topical androgen blocker that can also be used in males with acne. Both clinician groups and the clinical expert consulted by CDA-AMC agreed that minimal or no acne (clear to almost clear skin) is a goal of acne treatment. PCDSC noted that patients using clascoterone should be advised that treatment effect may not be observed for several months. The clinician groups indicated that severe acne should be treated with isotretinoin, which is consistent with the feedback received from the clinical expert consulted by CDA-AMC. However, the clinician groups stated that clascoterone may be used as an adjunctive treatment to isotretinoin or in place of isotretinoin in the case of serious intolerance or contraindication, which differs from the input received from the clinical expert consulted by CDA-AMC, who stated that clascoterone would not be used for severe or treatment-resistant moderate acne. The clinical expert also mentioned that the benefit of adding clascoterone to oral contraceptives or off-label spironolactone is uncertain. A clinically meaningful response to treatment, according to DAO, would be a 30% reduction in lesion counts and a 2-point (or even 1-point) reduction in Investigator’s Global Assessment (IGA) scores. Additionally, DAO suggested that transmasculine patients, gender minority patients, mature patients with acne (aged 29 years to 40 years), or those with sensitive, eczema-prone skin may benefit from clascoterone. Overall, the input provided by the clinician groups and the clinical expert was consistent with regard to the unmet needs, treatment goals, patient population, assessment of response, and discontinuation of treatment.

Drug Program Input

Input was obtained from the drug programs that participate in the CDA-AMC reimbursement review process. The following were identified as key factors that could potentially impact the implementation of a CDA-AMC recommendation for clascoterone:

• relevant comparators

• consideration for the initiation of therapy

• consideration for the prescribing of therapy

• generalizability

• care provision issues.

The clinical expert consulted by CDA-AMC provided advice on the potential implementation issues raised by the drug programs. Refer to Table 4.

Clinical Evidence

Systematic Review

Description of Studies

Two identically designed, randomized, double-blind, vehicle-controlled, parallel-group trials (the CB-03-01/25 study [N = 708] and the CB-03-01/26 study [N = 732]) assessed the safety and efficacy of clascoterone 1% cream versus the vehicle cream (without active drug) applied twice daily for 12 weeks in patients with facial acne vulgaris.

The CB-03-01/25 study was conducted primarily in the US and the CB-03-01/26 study was conducted primarily in Europe. Neither trial had any study sites in Canada. In the CB-03-01/25 study, 708 patients were randomized to treatment with either clascoterone 1% cream (N = 353) or vehicle cream (N = 355). In the CB-03-01/26 study, 732 patients were randomized to treatment with either clascoterone 1% cream (N = 369) or vehicle cream (N = 363). In the CB-03-01/25 trial, the median age for both treatment groups was 18 years (range, 9 years to 58 years) and in the CB-03-01/26 trial, the median age for both treatment groups was 18 years (range, 10 years to 50 years). Block randomization was used for both studies. Patients were enrolled from January 21, 2016, to April 11, 2018, for the CB-03-01/25 trial and from November 16, 2015, to February 21, 2018, in the CB-03-01/26 trial.

Both studies are now complete. They consisted of the following study periods:

• screening phase — visit 1

• treatment phase — 12 weeks (consisting of 3 study visits at week 4, week 8, and week 12)

• follow-up phase — patients in both studies had the option to continue for up to 12 months in the long-term extension (LTE) study (the CB-03-01/27 trial).

Patients eligible for inclusion were required to have acne vulgaris of the face (which can include the nose) with an IGA score of 3 or 4, at least 30 inflammatory lesions to a maximum of 75 inflammatory lesions (papules, pustules, and nodules), and at least 30 noninflammatory lesions to a maximum of 100 noninflammatory lesions (open and closed comedones). Patients were excluded from the trials if they had nodulocystic acne, if they were pregnant, lactating, or planning to become pregnant during the study, if they were planning to be or needed to be exposed to artificial tanning devices or excessive sunlight during the trial, or if they had been using any topical antiacne preparations within 2 weeks to 6 weeks of treatment initiation or the systemic antiacne medications of corticosteroids, antibiotics, spironolactone, or retinoids within 1 week to 6 months of treatment initiation.

The demographic characteristics were similar between the treatment groups. With respect to acne severity, the majority of patients in the CB-03-01/25 study had an IGA rating of moderate (82.7% of patients in the clascoterone group and 82.0% of patients in the vehicle group) with the remainder of patients being rated severe. The mean inflammatory lesion count (ILC) was 42.4 lesions for the clascoterone group and 42.9 lesions for the vehicle group (range, 30 lesions to 83 lesions), the mean noninflammatory lesion count (NILC) was 59.1 lesions for the clascoterone group and 60.7 lesions for the vehicle group (range, 30 lesions to 144 lesions), and the mean total lesion count (TLC) was 101.5 lesions for the clascoterone group and 103.6 lesions for the vehicle group (range, 60 lesions to 196 lesions). In the CB-03-01/26 study, the majority of patients had an IGA rating of moderate (82.7% of patients in the clascoterone group and 86.2% of patients in the vehicle group) with the remainder of patients being rated severe. The mean ILC was 42.9 lesions for the clascoterone group and 41.3 lesions for the vehicle group (range, 30 lesions to 75 lesions), the mean NILC was 62.8 lesions and 63.3 lesions for the clascoterone group and vehicle group, respectively (range, 30 lesions to 177 lesions), and the mean TLC was 62.8 lesions and 63.3 lesions in the clascoterone group and vehicle group, respectively (range, 60 lesions to 241 lesions).

Efficacy Results

Global Success

Proportion of Patients Aged 12 Years or Older Achieving Improvement at Week 12

Improvement was defined as an IGA score of clear (0) or almost clear (1) and a 2-point or greater reduction in the IGA scale compared with baseline.

In the CB-03-01/25 study, the adjusted proportion of patients aged 12 years and older achieving improvement at week 12 was 18.8% in the clascoterone group versus 8.9% in the vehicle group (odds ratio [OR] = 2.36; 95% confidence interval [CI], 1.4 to 3.9; P = 0.0008). Similarly, in the CB-03-01/26 study, the adjusted proportion of patients aged 12 years and older achieving improvement at week 12 was 20.8% in the clascoterone group versus 6.5% in the vehicle group (OR = 3.8; 95% CI, 2.2 to 6.4; P < 0.0001). At week 12, the results of the pooled analysis were consistent across both studies.

Sensitivity analyses results in the intention-to-treat (ITT) population were consistent with the primary efficacy results in both trials, with the exception of the worst-case analysis. Results of the last observation carried forward (LOCF) and baseline observation carried forward (BOCF) analyses confirmed the robustness of the results obtained on the ITT set for the primary efficacy end points.

Lesion Counts

Absolute Change From Baseline in NILC at Week 12

In the CB-03-01/25 study, a greater absolute decrease from baseline in NILC was noted in patients treated with clascoterone (–19.4 lesions) compared to patients treated with vehicle cream (–13.1 lesions) at week 12 (difference between treatment groups = –6.3 lesions; 95% CI, –10.2 lesions to –2.4 lesions; P = 0.0016). Similarly, in the CB-03-01/26 study, the absolute change in NILC from baseline to week 12 was –19.4 lesions in the clascoterone group versus –10.9 lesions in the vehicle group (difference between treatment groups = −8.4 lesions; 95% CI, −12.4 lesions to −4.5 lesions; P < 0.0001).

The sensitivity analyses results in the ITT population were consistent with the primary efficacy results in both pivotal trials. However, the results of the worst-value and worst-case analyses were inconsistent with the results obtained on the ITT set for this outcome. Results of the LOCF and BOCF analyses confirmed the robustness of the results obtained on the ITT set for the primary efficacy end points.

Percentage Change in NILC From Baseline at Week 12

In the CB-03-01/25 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for NILC at −30.7% versus −21.6%, respectively (treatment group difference = −8.8%; 95% CI, −15.9% to −1.8%; P = 0.0141). In the CB-03-01/26 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for NILC at −29.3% versus −15.8%, respectively (treatment group difference = −13.5%; 95% CI, −19.8% to −7.1%; P < 0.0001).

Absolute Change From Baseline in ILC at Week 12

In the CB-03-01/25 study, the absolute change in ILC from baseline at week 12 was −19.4 lesions in the clascoterone group versus −15.5 lesions in the vehicle group (treatment group difference = −3.9 lesions; 95% CI, −6.5 lesions to −1.3 lesions; P = 0.0029). Similarly, in the CB-03-01/26 study, at week 12, the absolute change from baseline in ILC at week 12 was also −20.0 lesions in the clascoterone group versus −12.6 lesions in the vehicle group (treatment group difference = −7.4 lesions; 95% CI, −9.8 lesions to −5.0 lesions; P < 0.0001).

The sensitivity analyses results in the ITT population were consistent with the primary efficacy results in both pivotal trials. However, the results of the worst-value and worst-case analyses were inconsistent with the results obtained on the ITT set for this outcome in the CB-03-01/25 trial and the results of the worst-case analysis were inconsistent with results obtained on the ITT set for this outcome in the CB-03-01/26 trial.

Percentage Change in ILC From Baseline at Week 12

In the CB-03-01/25 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for ILC at −44.8% versus −36.6%, respectively (treatment group difference = −8.3%; 95% CI, −14.3% to −2.3%; P = 0.0070). In the CB-03-01/26 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for ILC at −47.0% versus −29.8%, respectively (treatment group difference = −17.2%; 95% CI, −22.9% to −11.5%; P < 0.0001).

Absolute Change From Baseline in TLC at Week 12

In the CB-03-01/25 study, the absolute change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −39.2 lesions versus −28.9 lesions, respectively (treatment group difference = −10.3 lesions; 95% CI, −15.7 lesions to −5.0 lesions; P = 0.0002). In the CB-03-01/26 study, the absolute change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −40.3 lesions versus −23.7 lesions, respectively (treatment group difference = −16.6 lesions; 95% CI, −22.0 lesions to −11.1 lesions; P < 0.0001).

Percentage Change in TLC From Baseline at Week 12

In the CB-03-01/25 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −37.1% versus 28.5%, respectively (treatment group difference = −8.7%; 95% CI, −14.0% to −3.3%; P = 0.0016). In the CB-03-01/26 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −37.7% versus −22.2%, respectively (treatment group difference = −15.6%; 95% CI, −20.9% to −10.3%, P < 0.0001).

Mental Health and Health-Related Quality of Life

Mental health and health-related quality of life (HRQoL) were not assessed in the CB-03-01/25 or CB-03-01/26 trial.

Harms Results

Treatment-Emergent Adverse Events

The safety profile of clascoterone was similar between the treatment groups for both pivotal trials. In the CB-03-01/25 and CB-03-01/26 studies, respectively, 40 (11.3%) patients and 42 (11.4%) patients who received clascoterone experienced treatment-emergent adverse events (TEAEs) compared to 41 (11.5%) patients and 50 (13.8%) patients who received the vehicle cream.

Serious Adverse Events

Overall, 1 patient each in the CB-03-01/25 trial and the CB-03-01/26 trial reported a serious adverse event (SAE). In the CB-03-01/25 study, 1 (0.3%) patient in the vehicle group had an SAE of pneumonia. In the CB-03-01/26 study, 1 (0.3%) patient in the vehicle group had an SAE of hematoma.

Withdrawals Due to Adverse Events

In the CB-03-01/25 study, there were 9 patients who experienced 9 TEAEs that led to study discontinuation: 3 (0.8%) patients in the clascoterone group and 6 (1.7%) patients in the vehicle group. In the CB-03-01/26 study, 10 (1.4%) patients discontinued due to adverse events (AEs), including 2 (0.5%) patients treated with clascoterone and 8 (2.2%) patients treated with vehicle cream.

Mortality

No deaths were reported in the CB-03-01/25 and CB-03-01/26 studies.

Notable Harms

In the CB-03-01/25 and CB-03-01/26 studies, the incidence of local skin reactions (LSRs) (i.e., telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling or dryness, stinging or burning, and pruritus) was similar across treatment groups. In the CB-03-01/25 trial, 52.6% of patients in the clascoterone group and 54.0% of patients in the vehicle group experienced LSRs. In the CB-03-01/26 trial, 55.3% of patients in the clascoterone group and 53.3% of patients in the vehicle group experienced LSRs. The most notable treatment-emergent LSRs in terms of frequency were erythema in both pivotal trials.

Critical Appraisal

There was no notable difference between treatment groups or baseline characteristics in either pivotal trial. Discontinuation was largely driven by patients who were lost to follow-up and who chose to withdraw. Missing data in the primary end points were imputed using a multiple imputation (MI) approach under the missing at random (MAR) assumption. The missing at worst-value analyses were not consistent with the primary analysis for absolute change in ILC and NILC. The amount of missing data was considered relatively high in both the clascoterone group and the vehicle group in both trials at week 12 (18% to 22%). The majority of patients who discontinued dropped out at the beginning of the study period (e.g., before visit 2) across both trials, and because patient dropout was likely driven by a lack of response, the MI approach to account for missing data in the primary analysis may not be sufficient to address this missing data mechanism. Therefore, there was potential for bias due to the amount of missing data in the efficacy results at week 12 and based on results from the sensitivity analysis, the true effect of clascoterone on NILC and ILC may have been overestimated in the primary analysis. Some secondary end points were not adjusted for multiple comparisons; hence, no definitive conclusions can be drawn due to the failure of statistical comparison in a prior end point in the testing hierarchy.

Clascoterone is indicated for patients aged 12 years and older, though the data reported in the Clinical Review Report are for patients aged 9 years and older. When comparing the 2 datasets (from the product monograph¹⁶ and the Clinical Study Reports for the pivotal trials^18,19), there were no changes to statistical significance that would meaningfully change conclusions on efficacy or harms. Moreover, the clinical expert consulted for this review highlighted that the number of patients aged 9 years to 11 years who were included in the trials was small and likely had a negligible effect on the study results. Clascoterone is indicated for patients with acne vulgaris and is not limited by severity of the condition. The pivotal trials for clascoterone included patients with moderate to severe acne vulgaris; however, the clinical expert felt that the results would still be generalizable to patients with mild acne. The clinical expert indicated that a treatment that is effective for moderate to severe acne would also be expected to show efficacy in patients with mild acne as well. Moreover, a notable group of patients with severe acne vulgaris (i.e., nodulocystic acne) was excluded from both trials. Hence, the sample population in the trials may not fully represent the general population of patients with severe acne vulgaris as noted in clinical practice in Canada. The clinical expert felt that 12 weeks of follow-up was a reasonable and standard time point across acne trials and would be considered the earliest time point at which a meaningful change in lesion numbers would be observed. However, the clinical expert noted that the optimal time point for follow-up for the end point of change in NILC would be 6 months. In addition, the clinical expert did note that lesion counts are not relevant to clinical practice as lesion counts are subjective, and it is not feasible for clinicians to be counting lesions. Instead, the clinical expert felt that the patient’s impression of change and the percentage change in lesion count was considered more clinically relevant.

GRADE Summary of Findings and Certainty of the Evidence

For the pivotal studies and randomized controlled trials (RCTs) identified in the sponsor’s systematic review, Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the certainty of the evidence for outcomes considered most relevant to inform deliberations of the CDA-AMC expert committee, and a final certainty rating was determined as outlined by the GRADE Working Group.^20,21

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for efficacy end points and notable harms (i.e., LSRs) was set according to the presence or absence of an important effect based on thresholds informed by the clinical expert.

For the GRADE assessments, findings from the CB-03-01/25 and CB-03-01/26 studies were considered together and summarized narratively per outcome because these studies were identical in population, interventions, design, and outcome measures.

The selection of outcomes for GRADE assessment was based on the sponsor’s summary of clinical evidence, consultation with the clinical expert, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• global success as measured by the proportion of patients aged 12 years or older achieving improvement, defined as an IGA score of clear (0) or almost clear (1) and a 2-point or greater reduction in the IGA scale compared with baseline

• lesion counts (absolute change from baseline in NILC, ILC, and TLC; percentage change from baseline in NILC, ILC, and TLC)

• mental health and HRQoL (change from baseline in mental health according to the Dermatology Life Quality Index and Cardiff Acne Disability Index)

• notable harms — LSRs, fertility issues, hypothalamic-pituitary-adrenal axis suppression.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for clascoterone 1% cream versus vehicle cream.

Table 2: Summary of Findings for Clascoterone Versus Vehicle Cream for Patients With Acne Vulgaris

CI = confidence interval; DLQI = Dermatology Life Quality Index; HRQoL = health-related quality of life; IGA = Investigator’s Global Assessment; ILC = inflammatory lesion count; LSR = local skin reaction; MID = minimal important difference; NA = not applicable; NILC = noninflammatory lesion count; NR = not reported; OR = odds ratio; RCT = randomized controlled trial; TLC = total lesion count.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level for serious indirectness as the treatment assessment scheduled was not reflective of clinical practice, based on clinical expert input noting that meaningful change is unlikely to be observed until at least 6 months — thus limiting generalizability to Canadian clinical practice.

^bRated down 1 level for serious study limitations. This was due to high rates of missing data with insufficient accounting for the likely missing data mechanism. Rated down 1 level for serious indirectness as the treatment assessment scheduled was not reflective of clinical practice, based on clinical expert input noting that meaningful change is unlikely to be observed until at least 6 months — thus limiting generalizability to Canadian clinical practice. Rated down 1 level for serious imprecision. The clinical expert identified that the MID threshold (10 lesions) had not been met; the CI for difference between groups included the possibility of no difference.

^cStatistical testing for this outcome was not adjusted for multiplicity. The results are considered as supportive evidence.

^dRated down 1 level for serious study limitations. This was due to high rates of missing data with insufficient accounting for the likely missing data mechanism. Rated down 1 level for serious indirectness as the treatment assessment scheduled was not reflective of clinical practice, based on clinical expert input noting that meaningful change is unlikely to be observed until at least 6 months — thus limiting generalizability to Canadian clinical practice. The outcome of percentage change in ILC and NILC was rated down 1 level for serious inconsistency. The 95% CI for the difference included the threshold for clinical meaningfulness (a reduction of lesions by 10%), which was compatible with both a benefit and little to no difference.

^eRated down 1 level for serious study limitations. This was due to high rates of missing data with insufficient accounting for the likely missing data mechanism. It was rated down 1 level for serious indirectness. This was due to limitations in generalizability to Canadian clinical practice.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ additional information request dated August 28, 2023.²² Details included in the table are from the sponsor’s summary of clinical evidence.²³

LTE Studies

Description of Studies

The CB-03-01/27 study was a multicentre, open-label, LTE study following the CB-03-01/25 and CB-03-01/26 parent studies. The primary objective was to determine the long-term safety of clascoterone cream, applied twice daily (morning and evening) for an additional 9 months in patients with acne vulgaris who participated in the phase III studies for a total treatment time of up to 12 months. For patients assigned to placebo in the parent trials, the total duration of treatment was 9 months. The end points for the primary objective were systemic and local TEAEs, including LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling or dryness, stinging or burning, and pruritus). The number of patients with each IGA severity score at each time point was the efficacy end point. The study consisted of a baseline visit, long-term follow-up (LTF) visits at month 1, month 3, month 6, and month 9, and follow-up phone calls at month 4.5 and month 7.5.

Efficacy Results

The majority of patients (83.1%) showed facial IGA scores that were mild or moderate in severity at baseline, with the overall proportion of patients whose skin was clear or almost clear increasing over time being greatest (ITT population = 181 of 609 [29.7%] patients) at the end of the study (day 274). The proportion of patients whose skin was clear or almost clear increased over time with clascoterone, from 9.9% at baseline to 29.7% at day 274. A similar proportion of patients originally assigned to the vehicle group (ITT population = 30.2%) and clascoterone group (ITT population = 29.3%) in the pivotal studies had clear or almost clear skin on the face at the end of the study at day 274. A similar trend was observed in patients whose trunks had been treated with clascoterone during the LTE period.

Harms Results

Of 607 patients in the safety set, 110 (18.1%) patients experienced at least 1 TEAE. The only TEAEs reported for at least 1.0% of patients were nasopharyngitis (2.6%) and upper respiratory tract infection (1.3%). Six patients experienced serious TEAEs; they consisted of coronary artery dissection, depression and suicide attempt, dizziness, eosinophilic gastroenteritis, fatigue, and induced abortion. Ten (1.7%) patients discontinued the study drug due to TEAEs and 9 of these patients discontinued the study due to the TEAEs. Overall, the most frequently reported LSRs were erythema (6.9% on the face and 1.2% on the trunk), scaling or dryness (4.0% on the face and 0.7% on the trunk), and pruritus (1.6% on the face and 0% on the trunk). According to the clinical expert consulted by CDA-AMC, atrophy (5% in the clascoterone group versus 1% in the vehicle group) was another noteworthy LSR.

Critical Appraisal

Based on the LTE results and discussion with the clinical expert consulted by CDA-AMC, clascoterone 1% cream appears to be safe when used for up to 1 year of treatment. According to the clinical expert, among AEs that occurred more frequently in the clascoterone cohort compared to the vehicle cohort, skin atrophy (5% in the clascoterone group versus 1% in the vehicle group) seems to be the most noteworthy event. Even though the effectiveness of clascoterone 1% cream seems to be maintained long term, the long-term study was not randomized and no formal statistical testing for efficacy outcomes (which were not primary objectives) was conducted. Furthermore, no true comparator was tested during the LTE period. There may also have been a selection bias as those who benefited from clascoterone treatment during the 12-week pivotal trials were more likely to continue and a high compliance rate (greater than 80%) was an inclusion criterion for the LTE study; this could overestimate the treatment effect. Another concern was a high attrition rate. For example, at 9 months, about 20% of patients remained in the LTE study. It is uncertain how this attrition rate affects the long-term results of safety and/or effectiveness of clascoterone treatment. Lastly, treatment effects on patients’ HRQoL were not assessed, even though the impact of acne vulgaris on HRQoL seems to be significant based on patient group input. As for external validity, because patients were rolled over from the pivotal trials, the same generalizability concerns as those in the main trials applied to the LTE population.

Indirect Comparisons

Description of Studies

CDA-AMC appraised a systematic review and network meta-analysis (NMA) submitted by the sponsor. The reference-case NMAs compared clascoterone with benzoyl peroxide (2.5% cream or 3.1% gel or 5% cream, applied once daily), tretinoin (0.025% cream or 0.04% gel or 0.05% cream, applied once daily), tazarotene (0.045% gel or 0.1% cream, applied once daily), adapalene (0.1% cream or 0.15% gel or 0.3% cream, applied once daily), and trifarotene (0.005% cream, applied once daily). Sensitivity and scenario analyses considered additional comparators (i.e., oral contraceptives, topical or oral spironolactone, clindamycin phosphate 1.2% gel and clindamycin 1% cream, erythromycin 1.5% cream, and combinations) in terms of effects at 12 weeks on inflammatory lesions, noninflammatory lesions, and study discontinuations for any reason. Scenario analyses were also presented as sensitivity analyses that considered additional treatments (combination therapies, spironolactone, and oral contraceptives).

Efficacy Results

Reference-case NMAs for changes in ILCs and NILCs at 12 weeks consisted of 8 treatment nodes,19 RCTs, and 12,226 patients. Findings from Bayesian random-effects (RE) NMAs regarding inflammatory lesions found clascoterone (ILC = –5.2; 95% credible interval [CrI], –7.2 to –3.2) and all other active treatments in the network to be associated with a greater impact on the reduction of inflammatory lesions compared to placebo, while comparisons between active treatments showed no treatment was favoured based on the inspection of 95% CrIs. Interpretations from an RE NMA investigating changes in noninflammatory lesions were similar.

Harms Results

A comparison of study discontinuations for any reason at 12 weeks after randomization was also performed using a Bayesian RE NMA. Clascoterone displayed a similar frequency of discontinuation compared to placebo (risk ratio [RR] = 0.90; 95% CrI, 0.72 to 1.10), as did most active treatments. Comparisons of clascoterone with other active treatments found no important differences with the exception of a reduced frequency of discontinuation when compared to tazarotene 1% (RR = 0.71; 95% CrI, 0.53 to 0.94).

Critical Appraisal

The sponsor’s submitted NMA used recommended methods for the conduct and reporting of NMAs and demonstrated similar benefits relative to other available treatments, though certain limitations were noted. The NMAs appeared to include study populations that ranged broadly from mild to severe based on mean baseline lesion counts. This introduced challenges to the interpretation of findings from the NMA as well as concerns that the validity of treatment effects measuring absolute changes in lesion count could be impacted. The variability of placebo or vehicle group responses across trials was not described in detail and thus the appropriateness of combining these groups for the purposes of the NMA was unclear. Methods to identify effect modifiers of interest to judge the appropriateness of the transitivity assumption were unclear, and the effects of differences between study populations for specific effect modifiers (the duration of acne, the severity of acne, and previous treatments) could not be addressed due to limited reporting from the included trials. Input from the clinical expert suggested that certain additional treatments (oral antibiotics, isotretinoin, topical dapsone, and combination treatments) could have been included in reference-case analyses. Findings from NMAs should thus be interpreted with some degree of caution.

Conclusions

The evidence in this review includes 2 sponsor-submitted, phase III, randomized, double-blind, vehicle-controlled trials, the CB-03-01/25 study (N = 708) and the CB-03-01/26 study (N = 732). The CB-03-01/25 and CB-03-01/26 trials assessed the safety and efficacy of treatment with clascoterone 1% cream compared to vehicle cream in patients with moderate to severe acne vulgaris. The 2 trials demonstrated that 12 weeks of treatment with clascoterone 1% cream applied twice daily likely results in a clinically important improvement in achieving treatment success as defined by an IGA score of 0 or 1 and a 2-point or greater reduction from baseline when compared with vehicle cream. However, the evidence was uncertain with regard to the ability of clascoterone to reduce the number and percentage of lesions (NILC, ILC, and TLC) at week 12. There is no evidence for the effect of clascoterone on mental health and HRQoL, which was identified as a clinically important outcome by the clinical experts and patient groups. Most efficacy outcomes were affected by concerns for imprecision (i.e., CIs included the potential for little to no difference versus placebo). All outcomes were impacted by the risk of bias due to missing data and indirectness due to concerns with generalizability to patients with severe acne vulgaris in clinical practice in Canada.

Because there was no direct evidence comparing clascoterone to other treatments for acne vulgaris, the sponsor provided an NMA that assessed short-term efficacy versus multiple comparators. For comparisons between clascoterone and active treatments, the results of the NMA did not favour either treatment in terms of a reduction in inflammatory lesions. Higher baseline lesion counts in trials of clascoterone may also provide rationale to interpret treatment effects relative to other treatments in terms of changes from baseline with caution.

Regarding safety, clascoterone resulted in little to no clinically important difference in LSRs. Of note, few to no events were observed during follow-up for these notable harms. Based on the harms observed at week 12 and LTF at 12 months, the clinical expert suggested that there were no concerns for the overall safety of clascoterone that would be expected to have an impact on clinical decision-making. In addition, the NMA found no important differences in safety outcomes between clascoterone, placebo, and active comparators.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of clascoterone (Winlevi), 1% topical cream, in the treatment of acne vulgaris in patients aged 12 years and older.

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CDA-AMC review team.

Acne is a chronic inflammatory skin condition of the pilosebaceous glands that typically begins during puberty and may continue through adulthood, with flares often coinciding with increasing serum androgens.¹ Lesions occur primarily on the face, neck, upper back, and chest. When assessing the severity of acne, considerations include the distribution (back, chest, and upper arms), the type and number of lesions (comedones, papules, pustules, and nodules), and the presence or absence of scarring.^2,3 Acne is diagnosed by physicians in the community by visual assessment and no procedures are required.

Acne vulgaris is characterized by noninflammatory open or closed comedones (blackheads or whiteheads) and by inflammatory papules, pustules, and nodules. The basic acne lesion is a comedone (clogged hair follicle in the skin), which is considered noninflammatory. A comedone forms when keratin combines with oil to block the follicle. A comedone can be open or closed by skin and can occur with or without acne. It is a microscopic lesion that is the direct result of abnormal keratinization in the follicle of the pilosebaceous unit. When acne lesions become red and/or tender bumps, they are termed papules. These papules can fill with purulent material, forming pustules. Acne lesions that become large red bumps are called nodules.^24,25 Lesions are defined in Appendix 1, Table 27.

Acne is 1 of the most common dermatological disorders worldwide. The incidence and severity of acne are influenced by genetics (i.e., hereditary) and environment (i.e., diet, cosmetics, pollutants, heat, and humidity).^1,3,26 Endogenous androgens, particularly testosterone and dihydrotestosterone, mediate excess sebum production in the skin and stimulate abnormal keratinization and desquamation, leading to obstruction of the pilosebaceous duct that allows C. acnes to proliferate.^3,26,27 Proinflammatory mediators are released in response, triggering localized inflammation and exacerbation of acne lesion eruption.²⁷

Acne affects 5.6 million people living in Canada.⁴ Although it predominantly affects the adolescent population (approximately 80%), it can also affect preadolescents (aged 7 years to 12 years) and postadolescents.^4-6 Starting around puberty and lasting until adulthood, acne can persist for many years, regardless of age. Adolescent acne usually begins with the onset of puberty, with the increase in androgen hormone production, which affects acne development and severity. Approximately 85% of people aged between 12 years and 24 years’ experience at least minor acne. Acne occurring in adults is increasing, and at age 50 years or older, more than 7% of men and 15% of women still have acne.⁸ During adolescence, acne vulgaris is more common in males than in females,⁷ while in adulthood, acne vulgaris is more common in females than in males.^7-9

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CDA-AMC review team.

The treatment of acne depends on the severity and type of acne, the age and treatment preferences of the patient, and adherence and response to previous therapy. Mild acne is typically treated with topical medications, particularly antimicrobials such as benzoyl peroxide, antibiotics, and topical retinoids such as tretinoin, adapalene, and tazarotene.^10,11 The main side effects of topical medications are local irritation and erythema. Most topical preparations require at least 6 weeks to 8 weeks before an improvement is experienced, with the exception of antimicrobials — they are fast-acting and a response can be experienced in as soon as 5 days.^11,12 For topical retinoids, the optimal response is expected after 12 weeks.¹³ Moderate acne is treated with the same topical treatments with the addition of an oral antibiotic or an oral antiandrogen for females, such as a combined oral contraceptive or spironolactone. According to the updated 2024 American Academy of Dermatology guidelines for managing acne, clascoterone is conditionally recommended for acne treatment (with a conditional recommendation based on the current high cost of the drug) and is not restricted to first-line use or to moderate and severe acne.¹⁴ Systemic therapy, including oral antibiotic treatment, hormonal therapies, and isotretinoin, are the main therapies for acne when topical therapy is insufficient or not tolerated. However, a major concern for antibiotics is the development of resistance, given that 60% of C. acnes isolates are resistant to at least 1 antibiotic.¹⁵ Hormonal drugs (e.g., estrogen-containing oral contraceptives, spironolactone) provide effective second-line treatment in women with acne regardless of the presence or absence of any underlying hormonal abnormalities.¹⁵ However, possible side effects of spironolactone include hyperkalemia, menstrual irregularities, and the feminization of a male fetus. For severe acne (e.g., nodular and/or inflammatory acne, acne conglobata, recalcitrant acne that is treatment-resistant), the treatment of choice according to the clinical expert consulted by CDA-AMC and Canadian practice guidelines is oral isotretinoin.¹⁰ Because oral isotretinoin is indicated in specific forms of very severe acne, it is outside the treatment paradigm for the population included in the reimbursement request. For patients unwilling or unable to use oral isotretinoin and those with intolerance, systemic antibiotics in combination with topical benzoyl peroxide, with or without a topical retinoid, may be considered. For females, hormonal therapy with a combined oral contraceptive may also be considered.¹⁰ For males, current hormone therapies are not suitable. According to the clinical expert, nondrug treatments include diet — in particular, a low glycemic index diet and a diet that minimizes dairy products — as well as laser therapy. Treatment goals include clearing acne and preventing acne sequelae such as postinflammatory hyperpigmentation and scarring. The main therapies currently used for acne vulgaris are aimed at reducing the severity and recurrences of skin lesions as well as improving appearance. According to the clinical expert consulted by CDA-AMC, with the exception of oral isotretinoin, most treatments for acne control symptoms but are not curative. Hence, patients must continue treatment to maintain benefit.

Drug Under Review

Key characteristics of clascoterone are summarized in Table 3 with other treatments available for acne vulgaris.

Clascoterone 10 mg/g is supplied in a 30 g tube.^16,17 The recommended dose per application is up to 1 g or to 2 fingertip units applied in a thin layer twice daily over the affected area. Patients should not spot-treat for optimal efficacy.¹⁶

Clascoterone is an androgen receptor inhibitor. Androgen receptor inhibitors may reduce sebaceous gland activity. The mechanism of action of clascoterone cream for the topical treatment of acne vulgaris is unknown.¹⁶ On June 15, 2023, clascoterone was approved by Health Canada for the topical treatment of acne vulgaris in patients aged 12 years and older.¹⁶ The sponsor-requested reimbursement indication is for the first-line prescription topical treatment of moderate to severe acne vulgaris in patients aged 12 years and older. While the indication states that clascoterone is for the treatment of patients aged 12 years and older, the data reported in the Clinical Review Report are consistent with those in the trials (i.e., for patients aged 9 years and older). Clascoterone has not been reviewed by CDA-AMC.

Table 3: Key Characteristics of Clascoterone, Topical Antibiotics, Topical Retinoids, Oral Hormonal Therapy, and Spironolactone

BP = benzoyl peroxide; MI = myocardial infarction; NA = not applicable; NR = not reported; P. acnes = Propionibacterium acnes; TE = thromboembolism.

^aAvailable in many different forms, such as cream, gel, solution, powder, and pads. Combinations of BP and clindamycin as well as BP and erythromycin are also available.

^bHealth Canada–approved indication.

^cAdapalene and trifarotene are indicated for acne vulgaris in patients 12 years and older.

^dYaz and Alesse are indicated for females aged 14 years and older, Yasmin is indicated for patients aged 16 years and older, Tri-Cyclen is indicated for patients aged 15 years and older, and Diane-35 does not have a patient age restriction.

Sources: Sponsor’s clinical evidence summary²³ and Health Canada product monographs for clascoterone, Benzamycin, BenzaClin, Differin, Altreno, Tazorac, Aklief, isotretinoin, Aldactone, Yaz, Yasmin, Tri-Cyclen, Diane-35, and Alesse.^{16, 28-42,43}

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received by CDA-AMC are available in the consolidated patient and clinician group input document for this review on the project website: Clascoterone: Patient and Clinician Group Input.

Patient Group Input

This section was prepared by the CDA-AMC review team based on the input provided by patient groups. Two national, not-for-profit organizations, the ARSC and the CSPA, jointly conducted a survey in June 2022 with 154 patients living in Canada diagnosed with acne. The ARSC comprises dermatologists, patients, educators, and communicators providing information and raising awareness about the disease. The CSPA strives to improve the lives of people affected by skin, hair, and nail conditions through collaboration, advocacy, and education.

Patient groups reported that as acne appears on the face, it not only affects appearance, but has great psychological impact on patients’ lives. Many patients reported experiencing diminished self-image, self-esteem, self-confidence, and assertiveness. This emotional distress caused by unhappiness with appearance can lead to bad moods, anxiety (including in social situations), anger, loneliness, self-consciousness, shame, depression, and pain, generally making patients feel in poor health overall. Furthermore, patient groups said these factors impede their ability to be social and conduct daily activities (e.g., forming friendships and dating, having social interactions, being viewed on camera, swimming, changing in change rooms where patients’ acne on their body is exposed). According to the input received, acne does not just leave physical scars (affecting 71% of patients with mild acne, 84% of patients with moderate acne, and 100% of patients with severe acne) and pigmentation changes (affecting 86% of patients with mild acne, 94% of patients with moderate acne, and 100% of those with severe acne), it also leaves “emotional scarring.” Another aspect of acne that affects patients’ HRQoL is stigmatizing “myth,” such as acne being self-caused by fatty or high carb foods, unhygienic daily self-care, or a dismissive attitude (e.g., “it’s just pimples”) with little empathy or understanding of patients’ emotional distress. Financial burden was cited as another challenge; some respondents have to pay out-of-pocket costs for prescription, over-the-counter, and self-care products, such as cleansers and makeup, which increase with acne severity (with 4% of patients with mild acne, 5% of patients with moderate acne, and 14% of overall respondents spending $100 or more per month). More than half of patients had facials and peels (53% of patients, with 12% of them paying more than $500 per session) and light or laser therapy (65% of patients, with 15% of them paying more than $500 per session) that exacerbate financial burden on patients. As such, patients prioritize treatments that help them enjoy personal relationships and cause less scarring or changes in skin pigment. Other goals include clearer skin, better mental health, increased confidence, the ability to be social, and an improved overall quality of daily life.

Three individuals who had experience with clascoterone felt that their acne was well controlled with the drug (also resulting in greater confidence) and did not experience the typical side effects associated with topicals for acne. However, it was noted that the medication was very expensive compared to other treatment options, with patients paying out of pocket or accessing treatment through insurance.

According to the input, acne is underdiagnosed and undertreated in Canadian health care settings. Almost half of respondents (42%) answered that they were diagnosed after 2 to 5 health care visits, with 30% having visited more than 5 times. To improve their lives, respondents want increased access to new treatments that is safe and effective, health care providers to be aware of all the new and existing treatment options for acne, and evaluation for depression and anxiety that could lead them to getting support.

Clinician Input

Input From the Clinical Expert Consulted by CDA-AMC

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, providing guidance on the potential place in therapy). The following input was provided by 1 clinical specialist with expertise in the diagnosis and management of acne vulgaris.

Unmet Needs

According to the clinical expert, a major limitation of current acne therapy is that the most efficacious topical treatments, such as topical retinoids and benzoyl peroxide, tend to be irritative and exhibit a slow onset of effect, which may contribute to the issue of adherence to treatment. As mentioned by the clinical expert, a study reported that 46% of patients prescribed topical treatment did not adhere to their prescribed regimen due to the lack of desired response and adverse effects.⁴⁴ The clinical expert noted that as the majority of treatments are not curative, their continuation becomes imperative to sustain benefits. Moreover, acne severity exhibits variability over time, requiring potential modifications to the treatment regimen as time progresses.

Place in Therapy

According to the clinical expert, topical clascoterone will likely be used as a first-line topical for mild and moderate acne as it appears to be well tolerated if it is effective and accessible. Clascoterone has a novel mechanism in that it is the first topical androgen receptor blocker and the first androgen blocker that can be used in males with acne. The clinical expert anticipated that clascoterone may be used alone or in combination with other topicals for mild acne and in combination with oral antibiotics for moderate acne. The clinical expert did not feel that clascoterone could be used as first-line treatment for severe acne; however, it could be considered in combination with systemic treatment if a patient requested alternatives to first-line treatment for severe acne (i.e., isotretinoin).

Patient Population

According to the clinical expert, topical clascoterone is appropriate for use by any patient with mild to moderate acne. It is least suited for use in patients with severe or treatment-resistant moderate acne because oral retinoids are still preferred for this patient population. However, the clinical expert noted that clascoterone 1% cream could be used in combination with other treatments if a patient requested alternatives to first-line treatment for severe acne. The clinical expert noted that clascoterone could potentially be used in combination with oral contraceptives or spironolactone in women to determine if there would be added benefit. However, they highlighted that it should not be used in patients who are pregnant, nursing, or contemplating pregnancy.

Assessing the Response Treatment

The clinical expert noted that patients are typically assessed every 3 months to determine treatment response with the exception of treatment with isotretinoin, which is assessed every 2 months and, in some instances, assessed monthly given the need for monthly pregnancy testing in patients of childbearing potential. The clinical expert noted that a clinician would examine acne lesions and record acne as clear, minimal or almost clear, moderate, or severe; comment on acne sequalae, including pigmentation and scarring; and also note a patient’s self-reported assessment of treatment experience upon evaluation. The goal of treatment is minimal acne (1 to 2 lesions on examination) or no acne. Given that patients’ expectations can be highly variable, patient satisfaction is also an important factor in assessing treatment success.

Discontinuing Treatment

According to the clinical expert, patients would discontinue treatment if there was a lack of response or a worsening of disease, adverse effects, or patient dissatisfaction with treatment. The clinical expert also noted that they would discontinue treatment in patients who are attempting to conceive, are pregnant, or nursing.

Prescribing Considerations

Family physicians may prescribe clascoterone.

Clinician Group Input

This section was prepared by the CDA-AMC review team based on the input provided by 2 clinician groups.

Two clinician groups submitted input: DAO, represented by 10 clinicians, and PCDSC, represented by 5 physicians who make up its board of directors. Both clinician groups and the clinical expert consulted by CDA-AMC agreed that patients with acne vulgaris are not being treated effectively for various reasons. First, many patients do not adhere to prescribed medications due to intolerance (e.g., irritation or photosensitivity caused by topical drugs), even though acne vulgaris typically requires long-term topical therapy. Even if patients are adherent, not all patients respond to currently available treatments, which only control symptoms and do not induce remission (except for isotretinoin). Second, male patients are reluctant to use off-label spironolactone (e.g., due to side effects such as gynecomastia) and cannot take antiandrogenic combined oral contraceptives. Third, none of the topicals available target the 4 key factors of acne pathogenesis (desquamation, sebum production, C. acnes, and androgen — all related to inflammation). Also, no antiandrogen topical is available.

According to PCDSC, acneiform scarring is another unmet need that requires treatment. DAO stated that a quarter of patients are strongly dissatisfied with the medical care that they received for acne.⁴⁵ Both clinician groups and the clinical expert agreed that clascoterone would be used as the first-line monotherapy for uncomplicated cases (or mild acne) and in combination with other topical or systemic drugs for complex cases (moderate acne). The clinician groups stated that clascoterone may decrease antibiotic prescribing for acne, and shift or delay the use of isotretinoin. Both clinician groups and the clinical expert consulted by CDA-AMC said patients with mild to moderate acne are best suited for treatment with clascoterone. Furthermore, PCDSC added that patients who are more likely to experience adverse effects with available topical therapies, such as those with sensitive skin, those spending significant time outdoors, or those who are likely to be affected negatively by systemic hormonal therapies (such as teenagers, perimenopausal women with acne, or patients with metabolic syndrome) may benefit from clascoterone. Additionally, DAO suggested that transmasculine patients, gender minority patients, mature patients with acne (aged 29 years to 40 years), and those with sensitive, eczema-prone skin may benefit from clascoterone.

The clinician groups indicated that severe acne should be treated with isotretinoin, which is consistent with the feedback received from the clinical expert consulted by CDA-AMC. However, the clinician groups stated that clascoterone may be used as adjunctive treatment to isotretinoin or in place of isotretinoin in the case of serious intolerance or contraindication. Also, DAO mentioned that clascoterone is the least suitable option in older people (aged 65 years or older), pediatric (aged 12 years or younger), pregnant, or nursing populations. The clinical expert consulted by CDA-AMC mentioned that the benefit of adding clascoterone to oral contraceptives or off-label spironolactone is uncertain.

Both clinician groups and the clinical expert consulted by CDA-AMC agreed that minimal or no acne (clear to almost clear skin) is a goal of acne treatment. DAO and PCDSC added that instead of structured criteria such as IGA scores, other ways to measure response to treatment are descriptive assessment, improvement as viewed on photos taken before and after treatment, reduced lesion counts, patient satisfaction, and improved function. According to DAO, a 30% reduction in lesion counts and a 2-point (or even 1-point) reduction in IGA scores are considered clinically meaningful.

PCDSC noted that patients using clascoterone should be advised that treatment effect may not be observed for several months. The clinician groups relayed that the time to assess treatment may vary between clinicians, but typically 4 months to 6 months following the initiation of treatment is an appropriate time in which to assess response. Both the clinician groups and the clinical expert agreed that they would consider discontinuing clascoterone if no response was observed in 3 months to 6 months, or if a patient experienced worsening acne or intolerance to treatment. PCDSC also added that if patients were planning to get pregnant, already pregnant, or nursing, then they would discontinue clascoterone treatment, which is consistent with the feedback received from the clinical expert consulted by CDA-AMC. DAO mentioned that poor adherence is another reason to discontinue clascoterone treatment.

The clinician groups submitting input for this review agreed that dermatologists and general practitioners (e.g., family physicians, nurse practitioners) can prescribe clascoterone to treat acne.

One clinician group, DAO, had experience with clascoterone and indicated that the drug is well tolerated, which is important for those with sensitive skin and for maintaining treatment adherence. Of note, PCDSC felt that acne is likely underdiagnosed and that access to dermatological care is seriously limited in Canadian practice settings.

Drug Program Input

The drug programs provide input on each drug being reviewed through CDA-AMC reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical expert consulted by CDA-AMC are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CDEC = Canadian Drug Expert Committee; HPA = hypothalamic-pituitary-adrenal; IGA = Investigator’s Global Assessment.

Clinical Evidence

The objective of the CDA-AMC Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of clascoterone 1% cream in the treatment of acne vulgaris in patients aged 12 years and older. The focus has been placed on comparing clascoterone 1% cream to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of clascoterone is presented in 3 sections with the CDA-AMC critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and RCTs that were selected according to the sponsor’s systematic review protocol. The CDA-AMC assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes sponsor-submitted LTE studies. The third section includes indirect evidence from the sponsor.

Included Studies

Clinical evidence from the following is included in the CDA-AMC review and appraised in this document:

• 2 pivotal studies identified in the systematic review

• 1 LTE study

• 1 indirect treatment comparison.

Systematic Review

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CDA-AMC review team.

Description of Studies

Two randomized, double-blind, vehicle-controlled, parallel-group trials (the CB-03-01/25 and CB-03-01/26 studies) met the inclusion criteria for the systematic review conducted by the sponsor. Both trials were considered pivotal and were conducted with an identical study design with patients randomized 1:1 to either clascoterone 1% or vehicle cream for 12 weeks of treatment.

The primary objective of both pivotal trials was to determine the safety and efficacy of clascoterone 1% cream versus the vehicle cream applied twice daily for 12 weeks in patients with facial acne vulgaris.

The CB-03-01/25 study (N = 708) was conducted primarily in the US and the CB-03-01/26 study (N = 732) was conducted primarily in Europe. Neither trial had any study sites in Canada. In the CB-03-01/25 study, 708 patients were randomized to treatment with either clascoterone 1% cream (N = 353) or vehicle cream (N = 355). In the CB-03-01/26 study, 732 patients were randomized to treatment with either clascoterone 1% cream (N = 369) or vehicle cream (N = 363). In the CB-03-01/25 study, the median age for both treatment groups was 18 years (range, 9 years to 58 years) and in the CB-03-01/26 study, the median age for both treatment groups was 18 years (range, 10 years to 50 years). Block randomization was used for both studies. Patients were enrolled from January 21, 2016, to April 11, 2018, for the CB-03-01/25 study and from November 16, 2015, to February 21, 2018, in the CB-03-01/26 study. The dates of the database lock for the CB-03-01/25 trial was June 25, 2018, and for the CB-03-01/26 trial was June 27, 2018. Data were unblinded on June 27, 2018, for both studies.

Both studies are now complete. They consisted of the following study periods:

• screening phase — visit 1

• treatment phase — 12 weeks (consisting of 3 study visits at week 4, week 8, and week 12)

• follow-up phase — patients in both studies had the option to continue for up to 12 months in the LTE trial (the CB-03-01/27 study).

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

AE = adverse event; ECG = electrocardiogram; IGA = Investigator’s Global Assessment; ILC = inflammatory lesion count; LSR = local skin reaction; LTE = long-term extension; NILC = noninflammatory lesion count; OTC = over the counter; TLC = total lesion count; UPT = urine pregnancy tests.

^aThe number of patients reported included patients aged 9 years or older. The sample sizes for the approved population (patients aged 12 years or older) were N of 692 patients (clascoterone [N = 352 patients] and vehicle [N = 350 patients]) and N of 729 patients (clascoterone [N = 367 patients] and vehicle [N = 362 patients]) in the CB-03-01/25 and CB-03-01/26 studies, respectively.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial.¹⁹ Details included in the table are from and the sponsor’s summary of clinical evidence.²³

Populations

Inclusion and Exclusion Criteria

At least 700 patients per study were enrolled at approximately 38 sites for the CB-03-01/25 study and 40 sites for the CB-03-01/26 study. Patients eligible for inclusion were required to have acne vulgaris of the face (which can include the nose) with an IGA score of 3 or 4, at least 30 inflammatory lesions to a maximum of 75 inflammatory lesions (papules, pustules, and nodules), and at least 30 noninflammatory lesions to a maximum of 100 noninflammatory lesions (open and closed comedones). Patients were excluded from the trials if they had nodulocystic acne, if they were pregnant, lactating, or planning to become pregnant during the study, if they were planning to be or needed to be exposed to artificial tanning devices or excessive sunlight during the trial, or if they had been using any topical antiacne preparations within 2 weeks to 6 weeks of treatment initiation or the systemic antiacne medications of corticosteroids, antibiotics spironolactone, or retinoids within 1 week to 6 months of the initiation of treatment. Before entry into the study, patients must not have used the medications and/or procedures on the face as specified in the exclusion criteria. During the study, patients must not have used the following products and/or procedures on the face:

• topical antiacne treatments, including but not limited to over-the-counter acne cleansers or treatments, benzoyl peroxide, antibiotics, azelaic acid, sulfa-based products, corticosteroids, and salicylic acid

• retinoids, including tazarotene, adapalene, and tretinoin

• light treatments (including artificial tanning devices), microdermabrasion, or chemical peels

• any other investigational drug or the use of any investigational device

• systemic medications with potential antiacne effects, including:

  • corticosteroids, including intramuscular and intralesional injections (inhaled, intranasal, or ocular corticosteroids were allowed)

  • antibiotics

  • spironolactone

  • retinoid therapy

  • the addition of a hormonal contraception

  • change to a pre-existing hormonal contraception

  • other systemic therapy that may have materially affected the patient’s acne in the opinion of the investigator.

Other chronic medications being used at the time of the baseline visit were allowed to be continued at the discretion of the investigator.

Interventions

Patients were randomized 1:1 to clascoterone (cortexolone 17alpha-propionate) 1% cream or the vehicle cream. Clascoterone 1% cream was applied topically twice daily for 12 weeks in patients with facial acne vulgaris. The control group featured a vehicle cream, which was similarly applied topically twice daily for 12 weeks in patients with facial acne vulgaris. Applications typically occurred in the morning and in the evening.

At the first visit, the patients were instructed to wash their entire face (the area to be treated) with mild soap and water and then dry the area gently. The study staff then instructed the patient and parent or guardian (if applicable) on how to dispense the cream, how much to use, and where to apply it. The first application of cream was to be applied in the office at visit 1 under supervision of the study staff after the patient was deemed eligible and the remainder of applications occurred at home and at each study visit. Before the patient left, the medication was weighed and dispensed to the patient. About 1 g of the cream was dispensed onto a fingertip and applied to the face by dabbing small amounts gently on multiple regions of the face (e.g., forehead, nose, cheeks, chin). Using a fingertip, the cream was spread to provide a thin, uniform layer of the cream over the entire face. Patients and parents or guardians (if applicable) were instructed to apply the cream to the whole face twice daily (in the morning and evening) for 12 weeks; hence, a total of 2 g of product was used per day. Patients were provided with a diary where they were instructed to record the date and time of each application for the 12 weeks of therapy. Unused medication tubes were to be returned at each visit.

Concomitant Medications and Cointerventions

There were no other protocol-required drugs included in the trials. Therapies (medication and nonmedication therapies) not restricted by the protocol were used during the study for the treatment or prevention of disease or to maintain good health. Vitamins and mineral supplements were permitted at dosages considered by the investigator as reasonable for maintaining good health. Nonprohibited chronic therapies being used at visit 1 were allowed to be continued. Any changes in concomitant therapies during the study were recorded. Other chronic medications being used at the time of the baseline visit were allowed to be continued at the discretion of the investigator.

In the CB-03-01/25 study, the most common concomitant medications by medication class (more than 2%) were propionic acid derivatives (4.0%), progestogens and estrogens or fixed combinations (3.1%), centrally acting sympathomimetics (2.4%), progestogens (2.3%), anilide (2.1%), intrauterine contraceptives (2.0%), and selective serotonin reuptake inhibitors (2.0%).

In the CB-03-01/26 study, the most common concomitant medications were progestogens and estrogens that were fixed combinations used as contraceptives (1.6% in the clascoterone group and 2.5% in the vehicle group) and thyroid hormones (1.1% in the clascoterone group and 2.2% in the vehicle group).

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s summary of clinical evidence as well as any outcomes identified as important to this review according to the clinical expert consulted by CDA-AMC and input from patient and clinician groups and public drug plans. Using the same considerations, the review team selected end points that were considered to be most relevant to inform deliberations of the CDA-AMC expert committee and finalized this list of end points in consultation with members of the expert committee. All summarized efficacy end points were assessed using GRADE. Select notable harms outcomes considered important for informing deliberations of the CDA-AMC expert committee were also assessed using GRADE.

The efficacy measures and end points were consistent with the 2005 FDA guidance Acne Vulgaris: Developing Drugs for Treatment⁴⁸ and the subsequent 2018 FDA guidance Acne Vulgaris: Establishing Effectiveness of Drugs Intended for Treatment.⁴⁹

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

AE = adverse event; DLQI = Dermatology Life Quality Index; HRQoL = health-related quality of life; IGA = Investigator’s Global Assessment; ILC = inflammatory lesion count; LSR = local skin reaction; NILC = noninflammatory lesion count; NR = not reported; TLC = total lesion count.

^aStatistical testing for these end points was adjusted for multiple comparisons (e.g., hierarchical testing).

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Global Success

Proportion of Patients Aged 12 Years or Older Achieving Improvement at Week 12

Treatment success was a coprimary end point and assessed at week 12 in both pivotal trials. Treatment success was defined as a 2-point or greater reduction in IGA score from baseline and a score of clear (0) or almost clear (1). The IGA is a static, investigator-reported measure of overall (qualitative and quantitative) acne severity. It uses an ordinal scale with 5 severity grades from 0 (clear skin) to 4 (severe) based on morphologic descriptions. Patients received an IGA score at baseline from the investigator. At week 12, the IGA score was reassessed.

Lesion Counts

Absolute Change From Baseline in NILC at Week 12

The absolute change in NILC from baseline to week 12 was a coprimary end point in both pivotal trials. At baseline, the number of noninflammatory lesions (open and closed comedones) on the face vertically from the hairline to mandible room and horizontally from ear to ear, including those on the nose, were counted. At baseline, patients must have had at least 30 noninflammatory lesions to a maximum of 100 noninflammatory lesions on the face at baseline to be eligible for enrolment. Noninflammatory lesions were counted again at week 12 and the change in lesion counts was documented. Photographs were taken to document clinical status of the patient but were not used for counting lesions. According to the clinical expert, a minimally important difference would be 0 or minimal lesions present.

Lesions were defined as follows:

• comedones — open (blackheads) and closed (whiteheads)

• papules — raised inflammatory lesions with no visible purulent material

• pustules — raised inflammatory lesions with visible purulent material

• nodules — any circumscribed, inflammatory mass greater or equal to 5 mm in diameter with or without cystic changes.

Absolute Change From Baseline in ILC at Week 12

The absolute change in ILC from baseline to week 12 was a coprimary end point in both pivotal trials. At baseline, the number of inflammatory lesions (papules, pustules, and nodules) on the face vertically from the hairline to mandible room and horizontally from ear to ear, including those on the nose, were counted. At baseline, patients must have had at least 30 inflammatory lesions to a maximum of 75 inflammatory lesions to be eligible for enrolment. Inflammatory lesions were counted again at week 12 and the change in lesion counts was documented. According to the clinical expert, a minimal important difference would be 0 or minimal lesions present.

Absolute Change From Baseline in TLC at Week 12

The absolute change in TLC (including inflammatory and noninflammatory lesions) from baseline to week 12 was a secondary end point in both pivotal trials. At baseline, the number of inflammatory lesions (papules, pustules, and nodules) and noninflammatory lesions (open and closed comedones) on the face vertically from the hairline to mandible room and horizontally from ear to ear, including those on the nose, were counted. Inflammatory lesions and noninflammatory lesions were counted again at week 12 and summed as a total. The change in TLCs was documented. According to the clinical expert, a minimal important difference would be 0 or minimal lesions present.

Percentage Change From Baseline in NILC, ILC, and TLC at Week 12

The percentage change from baseline to week 12 in NILC, ILC, and TLC were secondary end points in both pivotal trials. The mean percentage change from baseline of NILC, ILC, and TLC at week 12 was calculated for each treatment group. The clinical expert considered the percentage change in NILC, ILC, and TLC from baseline to week 12 to be a clinically important outcome.

Mental Health and HRQoL

HRQoL and mental health were considered to be important outcomes by patient groups but were not assessed in either trial.

Table 7: Summary of Outcome Measures and Their Measurement Properties

CADI = Cardiff Acne Disability Index; CI = confidence interval; DLQI = Dermatology Life Quality Index; ICC = intraclass correlation coefficient; IGA = Investigator’s Global Assessment; MID = minimal important difference.

Sources: FDA^48,49 and Alsulaimani et al. (2020).⁵⁰

Harms

AEs were classified as TEAEs, according to the period of occurrence. TEAEs were all AEs occurring or worsening after the first dose of the drug. TEAEs were summarized by treatment group and overall. The number and proportion of patients with any TEAE and the number of TEAEs were tabulated by Medical Dictionary for Regulatory Activities version 18.1 system organ class and preferred term and seriousness.

The number and percentage of patients with any serious TEAE and the number of serious TEAEs were presented overall and were tabulated.

All serious TEAEs were listed and all TEAEs leading to discontinuation were listed. LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling or dryness, stinging or burning, and pruritus) were listed separately for face and trunk and summarized separately for face and trunk by the frequency of each individual LSR and severity at each visit.

At every study visit, the investigator or designee documented the severity of the following LSRs known to be associated with the application of topical steroids: telangiectasia, skin atrophy, and striae rubrae. In addition, the investigator or designee evaluated the severity of LSRs known to be associated with acne vulgaris (erythema, edema, and scaling or dryness), using ordinal scales. A 5-point ordinal scale was used to assess the severity of these reactions (0 = none, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe). A 4-point ordinal scale was used by patients to assess LSR severity (0 = none, 1 = minimal, 2 = moderate, 3 = severe).

All patients were actively graded by the investigator for LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling or dryness, stinging or burning, and pruritus) that may have occurred within the treatment area. LSRs were summarized by the frequency of each individual LSR by treatment group and severity at each visit.

The following harms outcomes were selected for GRADE assessment: LSRs, nasopharyngitis, and fertility disruption. These notable harms were identified using the product monograph approved by Health Canada.

Statistical Analysis

Sample Size and Power Calculation

Based on assumptions estimated from the phase II dose escalation study (the NCT01631474 trial),⁵¹ at least 350 patients in each treatment group in each study were required to provide sufficient power (90%) with the selected primary end points. In the CB-03-01/25 study, 692 patients aged 12 years and older were randomized to 2 groups (clascoterone [n = 342] and vehicle [n = 350]). In the CB-03-01/26 study, 729 patients aged 12 years and older were randomized to 2 groups (clascoterone [n = 367] and vehicle [n = 362]).

Primary Efficacy End Point: Statistical Test and Model

Hypothesis tests on the coprimary efficacy end points were conducted using a hierarchical testing approach in the following order: the proportion of patients achieving treatment improvement at week 12, absolute change from baseline in NILC, and absolute change from baseline in ILC at week 12. All the hypothesis tests for the primary efficacy end points were performed at the same significance level, a 2-sided alpha of 0.05, and the failure to reject a null hypothesis implied the failure of rejecting all the subsequent null hypotheses.

A logistic regression model with treatment and analysis centre as fixed effects was used to compare the proportion of patients achieving improvement in each treatment group at week 12, where improvement was defined as an IGA score of clear (0) or almost clear (1) and at least a 2-point improvement in the IGA score compared with baseline.

An analysis of covariance (ANCOVA) was used to compare the absolute change from baseline in NILC in each treatment group at week 12, with treatment and analysis centre as fixed effects and the baseline NILC as the covariate. The same method was applied to absolute change from baseline in ILC, with the baseline ILC as the covariate.

Data Imputations for Missing Values

Missing values for the primary end point in the ITT analyses were imputed by the MI method under the MAR assumption. For each end point, data from visit 1 (baseline), visit 2, visit 3, and visit 4 (primary end point) were included in the MI approach. Thus, the MI approach uses a MAR assumption where missing values for each end point can be explained by observed values of that end point across the 4 visits in the study.

Primary Efficacy End Point: Sensitivity Analyses

Sensitivity analyses were performed to investigate the robustness of the results obtained on the ITT set for the primary efficacy end points (proportion of patients with IGA success, and change from baseline in NILC, and ILC). Four sensitivity analyses were performed using different methods of imputation on the ITT set. On a per-patient basis, missing values for the primary efficacy end points were imputed with the following sensitivity analyses.

• Missing at worst value: For each patient, missing values of a variable were replaced with the worst value of that variable (failure in the case of dichotomous variables or the higher value collected in the study for lesions counting) regardless of the treatment group.

• Worst case: For each patient, missing values of a variable were to be replaced with the worst value of that variable (failure in the case of dichotomous variables or the higher value collected in the study for lesions counting) if the patient was assigned to the clascoterone group and with the best value of that variable (success in the case of dichotomous variables or the lower value collected in the study for lesions counting) if the patient was assigned to the vehicle group.

• LOCF: Missing values of a variable were replaced by the last observed value of that variable.

• BOCF: Missing values of a variable were replaced by the baseline observed value of that variable.

The MI using the MAR assumption was adopted from the individual studies on the integrated summary of efficacy analysis. The imputation was performed on the ITT analyses set. One per-protocol (PP) analysis was done on the PP set.

Secondary Efficacy End Points: Statistical Test and Model

An ANCOVA model was used to compare the absolute change from baseline in TLC in each treatment group at week 12, with treatment and analysis centre as fixed effects and the baseline TLC as covariate. The adjusted mean difference of the comparison between groups and its 95% CI were derived from the regression model.

An ANCOVA model was used to compare the percentage change from baseline in all secondary end points in each treatment group at week 12, with treatment and analysis centre as fixed effects and the baseline outcome as a covariate. The adjusted mean difference of the comparison between groups and its 95% CI were derived from the regression model.

Given that both pivotal trials had the same study design, end points, and hypotheses, the sponsor felt it was justifiable to pool the efficacy data for a comprehensive evaluation on pooled treatment effect and treatment-by-subgroup analyses. The analysis populations, coprimary end points, and secondary end points for the pooled analyses were the same as for the individual study analyses.

Secondary Efficacy End Points: Multiple Testing Procedure

The key secondary outcomes were included in the multiplicity adjustment of the type I error to control the familywise error rate at a 2-sided significance level of 0.05 in the hierarchical order. For the secondary efficacy end points, hypothesis tests on the secondary efficacy end points were conducted in hierarchical order for secondary end points 1 through 4 in the following order: absolute change from baseline in TLC at week 12, percentage change from baseline in TLC at week 12, percentage change from baseline in NILC at week 12, and percentage change from baseline in ILC at week 12.

Secondary Efficacy End Points: Sensitivity Analysis

No sensitivity analyses were conducted for secondary end points.

Subgroup Analyses

No prespecified subgroup analyses were conducted for either trial.

Safety End Points

Safety outcomes were compared between treatment groups using descriptive statistics and no hypothesis testing was performed. Formal statistical analyses of AEs and LSRs to determine treatment group differences or to determine changes from baseline were neither planned nor performed.

Table 8: Statistical Analysis of Efficacy End Points

ANCOVA = analysis of covariance; BOCF = baseline observation carried forward; ILC = inflammatory lesion count; ITT = intention to treat; LOCF = last observation carried forward; MAR = missing at random; MI = multiple imputation; NILC = noninflammatory lesion count; PP = per protocol; TLC = total lesion count.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Analysis Populations

Analysis populations are described in Table 9.

Table 9: Analysis Populations of CB-03-01/25 and CB-03-01/26 Studies

ITT = intention to treat; PP = per protocol.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Results

Patient Disposition

There were 825 patients screened for the CB-03-01/25 study; 708 (85.8%) patients were enrolled, and 117 (14.2%) patients were screened out. Reasons for not advancing past screening included not meeting all inclusion criteria (85 [10.3%] patients), withdrawal by patient (16 [1.9%] patients), meeting at least 1 exclusion criterion (10 [1.2%] patients), and other reasons (6 [0.7%] patients). Of the 708 enrolled patients, 353 patients were randomized to treatment with clascoterone and 355 patients were randomized to treatment with vehicle cream. Overall, 577 of 708 (81.5%) patients completed the study (287 patients in the clascoterone group and 290 patients in the vehicle group).

For the CB-03-01/26 study, a total of 756 patients were screened and 732 of them were randomized (369 patients were randomized to the clascoterone group and 363 patients were randomized to the vehicle group), whereas 24 (3.2%) patients were screened out. A total of 584 (79.8%) patients overall — 302 (81.8%) of those in the clascoterone group and 282 (77.7%) of those in the vehicle group — completed the study according to protocol, while 148 (20.2%) patients in total — 67 (18.2%) of those in the clascoterone group and 81 (22.3%) of those in the vehicle group — prematurely discontinued the study. In the CB-03-01/25 study, the most common reason for treatment discontinuation was loss to follow-up in both the treatment group (11.0%) and the vehicle group (9.0%), followed by patient withdrawal (6.5% and 5.1% in the clascoterone and vehicle groups, respectively). In the CB-03-01/26 study, the most common reason for treatment discontinuation was patient withdrawal in both the clascoterone group (9.5%) and the vehicle group (11.3%), followed by loss to follow-up (6.5% and 6.6% in the clascoterone and vehicle group, respectively).

Table 10: Summary of Patient Disposition From Studies Included in the Systematic Review

ITT = intention to treat; PP = per protocol.

^aIn the Clinical Study Reports of the CB-03-01/25 and CB-03-01/26 trials, 1 of these patients was counted as discontinuing for progressive disease.

^bOther reasons for discontinuation included the following: due to investigational product liquification, due to the site being instructed by the sponsor to roll the patient over into the CB-03-01/27 study, and due to nonresponse.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Baseline Characteristics

A summary of baseline patient demographics and disease characteristics are presented in Table 11. The baseline characteristics outlined in this table are limited to those that are most relevant to this review or were felt to affect the outcomes or interpretation of the study results.

The demographic characteristics were similar between the treatment groups. More patients were female (61.6%) than male (38.4%) in the CB-03-01/25 trial. The mean age of patients was 19.9 years (range, 9 years to 58 years) and the mean body mass index (BMI) was 24.6 kg/m² (range, 11.9 kg/m² to 77.1kg/m²). With respect to acne severity, the majority of patients had an IGA rating of moderate (82.7% for the clascoterone group and 82.0% for the vehicle group) with the remainder rated severe. The mean ILC was 42.4 lesions for the clascoterone group and 42.9 lesions for the vehicle group (range, 30 lesions to 83 lesions), the mean NILC was 59.1 lesions for the clascoterone group and 60.7 lesions for the vehicle group (range, 30 lesions to 144 lesions), and the mean TLC was 101.5 lesions for the clascoterone group and 103.6 lesions for the vehicle group (range, 60 lesions to 196 lesions).

In the CB-03-01/26 trial, more patients were female (63.4%) than male (36.6%). The mean age of patients was 19.2 years (range, 10 years to 50 years) and the mean BMI was 22.1 kg/m² (range, 13.2 kg/m² to 40.6 kg/m²). With respect to acne severity, the majority of patients had an IGA rating of moderate (82.7% in the clascoterone group and 86.2% in the vehicle group), with the remainder of patients rated severe. The mean ILC was 42.9 lesions for the clascoterone group and 41.3 lesions in the vehicle group (range, 30 lesions to 75 lesions), the mean NILC was 62.8 lesions and 63.3 lesions for the clascoterone group and vehicle group, respectively (range, 30 lesions to 177 lesions) and the mean TLC was 105.7 lesions (range, 60 lesions to 241 lesions) and 104.6 lesions (range, 60 lesions to 170 lesions) in the clascoterone group and vehicle group, respectively.

Table 11: Summary of Baseline Characteristics From Studies Included in the Systematic Review (ITT Set)

BMI = body mass index; IGA = Investigator’s Global Assessment; ILC = inflammatory lesion count; NILC = noninflammatory lesion count; SD = standard deviation; TLC = total lesion count.

^a“Other” defined as American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, other, and multiple races.

^bDefinitions for the Fitzpatrick skin type scale: type I means always burns easily, never tans (sensitive); type II means always burns easily, tans minimally (sensitive); type III means burns moderately, tans gradually (light brown) (normal); type IV means burns minimally, always tans well (moderate brown) (normal); type V means rarely burns minimally, tans profusely (dark brown) (insensitive); and type VI means never burns, deeply pigmented (insensitive).

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Exposure to Study Treatments

Patients who adhered to treatment had at least 80% of the expected cream applications at the study visits. Nonadherence was defined as adherence of less than 80%. In the ITT set, 89.5% (316 of 353) of patients and 87.3% (310 of 355) of patients treated with clascoterone and vehicle cream, respectively, adhered to treatment with at least 81% of patients who adhered at each time point throughout the CB-03-01/25 trial. In addition, the mean daily amount of drug applied (the total amount of drug used divided by the number of days of treatment) was calculated for each patient. In the ITT set, the mean daily amount of product was 1.96 g of clascoterone and 1.96 g of vehicle cream in the CB-03-01/25 trial.

Table 12: Summary of Patient Exposure From Studies Included in the Systematic Review (ITT Population)

ITT = intention to treat; SD = standard deviation.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

In the ITT population of the CB-03-01/26 study, the mean overall adherence was 95.7% in patients in the clascoterone group and 95.0% in the vehicle group. The mean daily amount of product was 1.97 g and 1.98 g in the clascoterone and vehicle groups, respectively, in the CB-03-01/26 study.

Protocol Deviations

Protocol deviations in the pivotal trials are summarized in Table 13. The most common category of protocol deviations was related to the use of prohibited concomitant medications, which occurred in 2.5% of patients in both in the clascoterone and vehicle groups of the CB-03-01/25 study and in 4.1% and 3.0% of patients in the clascoterone and vehicle groups, respectively, in the CB-03-01/26 study.

Table 13: Major Protocol Deviations in the Pivotal Trials (ITT Set)

ITT = intention to treat.

Sources: Clinical Study Report for the CB-03-01/25 trial¹⁸ and Clinical Study Report for the CB-03-01/26 trial.¹⁹

Efficacy

Global Success

Proportion of Patients Aged 12 Years or Older Achieving Improvement at Week 12

In the CB-03-01/25 study, the adjusted proportion of patients aged 12 years and older achieving improvement at week 12 was 18.8% in the clascoterone group versus 8.9% in the vehicle group (OR = 2.36; 95% CI, 1.4 to 3.9; P = 0.0008). Similarly, in the CB-03-01/26 study, at week 12, the adjusted proportion of patients aged 12 years and older achieving improvement at week 12 was 20.8% in the clascoterone group versus 6.5% in the vehicle group (OR = 3.8; 95% CI, 2.2 to 6.4; P < 0.0001). At week 12, the results of the pooled analysis were consistent across both studies.

Sensitivity analyses results in the ITT population were consistent with the primary efficacy results in both trials, with the exception of the worst-case analysis.

Lesion Counts

Absolute Change From Baseline in NILC at Week 12

In the CB-03-01/25 study, a greater absolute decrease from baseline in NILC was noted in patients treated with clascoterone (−19.4 lesions) compared to patients treated with vehicle cream (−13.1 lesions) at week 12 (treatment group difference = −6.3 lesions; 95% CI, −10.2 lesions to −2.4 lesions; P = 0.0016). Similarly, in the CB-03-01/26 study, at week 12, the absolute change in NILC from baseline to week 12 was −19.4 lesions in the clascoterone group versus −10.9 lesions in the vehicle group (treatment group difference = −8.4 lesions; 95% CI, −12.4 lesions to −4.5 lesions; P < 0.0001).

Results of the worst-value and worst-case analyses were inconsistent with the results obtained on the ITT set for this outcome while results from sensitivity analyses using LOCF and BOCF were consistent with the primary result from the pivotal trials.

Percentage Change in NILC From Baseline at Week 12

In the CB-03-01/25 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for NILC at −30.7% versus −21.6%, respectively (treatment group difference = −8.8%; 95% CI, −15.9% to −1.8%; P = 0.0141). In the CB-03-01/26 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for NILC at −29.3% versus −15.8%, respectively (treatment group difference = −13.5%; 95% CI, −19.8% to −7.1%; P < 0.0001).

Absolute Change From Baseline in ILC at Week 12

In the CB-03-01/25 study, the absolute change in ILC from baseline at week 12 was −19.4 lesions in the clascoterone group versus −15.5 lesions in the vehicle group (treatment group difference = −3.9 lesions; 95% CI, −6.5 lesions to −1.3 lesions; P = 0.0029). Similarly, in the CB-03-01/26 study, at week 12, the absolute change from baseline in ILC at week 12 was also −20.0 lesions in the clascoterone group versus −12.6 lesions in the vehicle group (treatment group difference = −7.4 lesions; 95% CI, −9.8 lesions to −5.0 lesions; P < 0.0001).

Results of the worst-value and worst-case analyses were inconsistent with the results obtained on the ITT set for this outcome in the CB-03-01/25 trial and the results of the worst-case analysis were inconsistent with results obtained on the ITT set for this outcome in the CB-03-01/26 trial.

Percentage Change in ILC From Baseline at Week 12

In the CB-03-01/25 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for ILC at −44.8% versus −36.6%, respectively (treatment group difference = −8.3%; 95% CI, −14.3% to −2.3%; P = 0.0070). In the CB-03-01/26 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for ILC at −47.0% versus −29.8%, respectively (treatment group difference = −17.2%; 95% CI, −22.9% to −11.5%; P < 0.0001).

Absolute Change From Baseline in TLC at Week 12

In the CB-03-01/25 study, the absolute change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −39.2 lesions versus −28.9 lesions, respectively (treatment group difference = −10.3 lesions; 95% CI, −15.7 lesions to −5.0 lesions; P = 0.0002). In the CB-03-01/26 study, the absolute change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −40.3 lesions versus −23.7 lesions, respectively (treatment group difference = −16.6 lesions; 95% CI, −22.0 lesions to −11.1 lesions; P < 0.0001).

Percentage Change in TLC From Baseline at Week 12

In the CB-03-01/25 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −37.1% versus −28.5%, respectively (treatment group difference = −8.7%; 95% CI, −14.0% to −3.3%; P = 0.0016). In the CB-03-01/26 study, the percentage change from baseline to week 12 was greater in the clascoterone group than the vehicle group for TLC at −37.7% versus −22.2%, respectively (treatment group difference = −15.6%; 95% CI, −20.9% to −10.3%; P < 0.0001).

Mental Health and HRQoL

Mental health and HRQoL were not assessed in either the CB-03-01/25 trial or the CB-03-01/26 trial.

Table 14: Summary of Key Efficacy Results From Studies Included in the Systematic Review (ITT Set)

CI = confidence interval; ILC = inflammatory lesion count; ITT = intention to treat; LSM = least squares mean; NILC = noninflammatory lesion count; OR = odds ratio; SD = standard deviation; TLC = total lesion count; vs. = versus.

Note: Treatment success was defined as an IGA deduction of at least 2 points from baseline and an IGA score of 0 or 1 at week 12.

^aTests were included in the hierarchical testing structure to control the global type I error rate. The threshold for significance was an alpha of less than 0.05.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Harms

Refer to Table 15 for harms data.

Adverse Events

The safety profile was similar between the treatment groups for both pivotal trials. In the CB-03-01/25 study and the CB-03-01/26 study, respectively, 40 (11.3%) patients and 42 (11.4%) patients who received clascoterone experienced TEAEs compared to 41 (11.5%) patients and 50 (13.8%) patients who received vehicle cream.

Serious Adverse Events

In the CB-03-01/25 study, 1 (0.3%) patient in the vehicle group had an SAE of pneumonia. In the CB-03-01/26 study, 1 (0.3%) patient in the vehicle group had an SAE of hematoma. There were no SAEs among patients who received clascoterone.

Withdrawal Due to Adverse Events

In the CB-03-01/25 study, there were 9 patients who experienced 9 TEAEs that led to study discontinuation: 3 (0.8%) patients in the clascoterone group and 6 (1.7%) patients in the vehicle group. In the CB-03-01/26 study, 10 (1.4%) patients discontinued due to AEs, including 2 (0.5%) patients treated with clascoterone and 8 (2.2%) patients treated with vehicle cream.

Mortality

No deaths were reported in either trial.

Notable Harms

In the CB-03-01/25 and CB-03-01/26 studies, the incidence of LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling or dryness, stinging or burning, and pruritus) was similar across treatment groups. In the CB-03-01/25 trial, 40.4% of patients in the clascoterone group and 49.4% of patients in the vehicle group experienced LSRs. In the CB-03-01/26 trial, 45.2% of patients in the clascoterone group and 42.0% of patients in the vehicle group experienced LSRs. The most common treatment-emergent LSRs were erythema in both pivotal trials (in 19 [5.4%] patients versus 30 [8.5%] patients for the CB-03-01/25 trial and in 27 [7.3%] patients versus 18 [5.0%] patients for the CB-03-01/26 trial).

Table 15: Summary of Harms Results — Safety Set

AE = adverse event; LSR = local skin reaction; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Note: AEs were classified as TEAEs (defined as all AEs occurring or worsening after the first dose of the drug). Nasopharyngitis is the only TEAE that was reported in more than 1% of patients and more than 5 patients.

^aAt least 1% of patients in any treatment group.

^bThe number (proportion) of patients in the assessment category of “not done” is not reported in this report.

Sources: Clinical Study Report for the CB-03-01/25 trial,¹⁸ Clinical Study Report for the CB-03-01/26 trial,¹⁹ and the sponsor’s summary of clinical evidence.²³

Critical Appraisal

Internal Validity

The CB-03-01/25 and CB-03-01/26 trials were multicentre, randomized, double-blind, vehicle-controlled studies. Randomization was blocked by study site and an interactive response technology for concealment of the randomization assignment was used, which was considered appropriate. Based on input from the clinical expert consulted by CDA-AMC for the purpose of the review, the following were identified as important treatment effect modifiers: age, sex, and ethnicity. In addition, sex was considered an important prognostic factor. Although randomization was not stratified by these variables, any potential impact on the efficacy results was not expected because the proportion of patients with the relevant demographic characteristics at baseline (prognostic factors and effect modifiers) were generally well balanced between the clascoterone and vehicle groups of both trials. There was no notable difference between treatment groups or baseline characteristics in either pivotal trial. Statistical analyses were, in general, appropriate for the outcomes evaluated. The study sample size, however, did not reach the threshold at which it could be adequately powered to detect the treatment difference in the primary end points between treatment groups. The sponsor noted that the study was also powered for the secondary end points and a hierarchical testing procedure was appropriately used to account for multiplicity in the primary end points.

Discontinuation was largely driven by loss to follow-up and patient withdrawal. Missing data in the primary end points were imputed by MI analysis under the MAR assumption. The sensitivity analysis of LOCF, BOCF, and PP was generally consistent with the primary analysis. However, the imputation based on worst-value and worst-case analyses was not consistent with the primary analysis for absolute change in ILC and NILC. The amount of missing data was considered relatively high in both the clascoterone and vehicle group in both trials (approximately 18%) at week 12. The MI approach used for missing data in the primary analysis relied on a MAR assumption that assumed that missing values for a given end point could be explained by observed values of that end point. It was noted that a majority of patients dropped out at the beginning of the study period (e.g., before visit 2) across both trials; this suggests that the imputation for missing values of end points at visit 4 were primarily informed by patients who completed the study. Given that a likely explanation for patient dropout was due to lack of response to treatment, patients who completed the study were not likely to be representative of patients who dropped out early. Therefore, the approach to account for missing data in the primary analysis may not have been adequate for addressing potential bias due to missing data, and sensitivity analyses suggest that the primary analysis may have overestimated the benefit of clascoterone for improving ILC and NILC at week 12.

The statistical testing strategy was implemented in both trials to control for type I error at the level of the individual study and at the level of the pool dataset of both studies. Pooled analyses were not preplanned. Secondary end points were adjusted for multiple comparisons when the null hypothesis of the primary efficacy outcome was rejected. Important subgroups of interest identified by the clinical expert consulted on this review were sex, age, and ethnicity. However, prespecified subgroup analyses were not conducted, except for by the investigational site.

Treatment response was based on lesion counts assessed by the investigator or designee. A central adjudication was not performed and hence there could potentially be interobserver variation in lesion counts if the same investigator was not available for each site visit. However, considering the double-blind design, the concern for potential subjectivity in lesion count impacting the efficacy results is low. In addition, the clinical expert was not concerned about the variation in counting lesions.

Major protocol deviations were uncommon across both trials. The most common protocol deviation was the use of prohibited concomitant medications. This occurred in less than 3% of patients in the CB-03-01/25 study and in less than 5% of patients in the CB-03-01/26 study; hence, the potential for bias was low.

External Validity

The population of interest, as per the reimbursement indication, is patients aged 12 years and older who have moderate to severe acne vulgaris. A notable group of patients with severe acne vulgaris (i.e., nodulocystic acne) were excluded from both trials. Hence, the sample population in the trials may not fully represent the general population of patients with severe acne vulgaris as noted in clinical practice in Canada.

Within the trials, approximately 16 patients in the CB-03-01/25 trial (N = 11 in the clascoterone group and N = 5 in the vehicle group) and 3 patients in the CB-03-01/26 trial (N = 2 in the clascoterone group and N = 1 in the vehicle group) were aged younger than 12 years. When comparing the datasets for patients 12 years or older versus 9 years or older (from the product monograph¹⁶ and the Clinical Study Reports^18,19), there were no changes to statistical significance that would meaningfully change conclusions on efficacy or harms. Given that the number of patients outside the reimbursement indication population was small, and that the clinical expert felt the results would not differ by age, the impact on the results of including these patients outside the reimbursement indication population is negligible. Although no Canadian sites were included in either trial, the clinical expert felt that the intervention and concomitant medications used in the trial and the schedule of assessment were considered generalizable to clinical practice in Canada.

The clinical expert felt that 12 weeks of follow-up was a reasonable and standard time point across acne trials and would be considered the earliest time point at which a change in lesion numbers would be noted with a therapy. However, the clinical expert noted that the optimal time point for follow-up for NILC would be 6 months. In addition, the clinical expert noted that change in absolute lesion counts is not relevant to clinical practice as it is not feasible for clinicians to be counting lesions and there is also a level of subjectivity to counting lesions. Instead, the clinical expert felt that the patient’s impression of change and the percentage change in lesion count were considered more clinically relevant.

Throughout the study period, approximately 18% or more of patients in each group of each study discontinued, mostly due to being lost to follow-up and patient withdrawal, while study discontinuation due to AEs or lack of efficacy was relatively low (less than 3%). The clinical expert indicated that patients with acne vulgaris are often not adherent to treatment, although more than 80% of patients adhered to the treatment regimen in both treatment groups of the CB-03-01/25 study and more than 95% of patients in both treatments groups of the CB-03-01/26 study. The clinical expert suggested some possible reasons for discontinuation, including a lack of response to treatment and inconvenience in travel to clinical trial visits. The clinical expert considered a study discontinuation rate of 18% to be relatively high.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform deliberations of the CDA-AMC expert committee, and a final certainty rating was determined as outlined by the GRADE Working Group.^20,21

• “High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate — The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word ‘likely’ for evidence of moderate certainty (e.g., ‘X intervention likely results in Y outcome’).

• Low certainty: Our confidence in the effect estimate is limited — The true effect may be substantially different from the estimate of the effect. We use the word ‘may’ for evidence of low certainty (e.g., ‘X intervention may result in Y outcome’).

• Very low certainty: We have very little confidence in the effect estimate — The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as ‘very uncertain.’”

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, the imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect; if this was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance was unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null.

The reference points for the certainty of evidence assessment for efficacy end points and notable harms (LSRs) were set according to the presence or absence of an important effect based on thresholds informed by the clinical expert.

For the GRADE assessments, findings from the CB-03-01/25 and CB-03-01/26 studies were considered together and summarized narratively per outcome because these studies were identical in population, interventions, design, and outcome measures.

Results of GRADE Assessments

Clascoterone Versus Placebo

Table 2 presents the GRADE summary of findings for clascoterone 1% cream versus vehicle cream.

LTE Studies

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CDA-AMC review team.

Description of Studies

One LTE study (the CB-03-01/27 trial) has been summarized to provide evidence regarding clascoterone. This was a multicentre, open-label, LTE study that combined patients from the CB-03-01/25 and CB-03-01/26 pivotal studies. The primary objective was to determine the long-term safety of clascoterone cream, applied twice daily (morning and evening) for an additional 9 months in patients with acne vulgaris who participated in the phase III pivotal studies for a total treatment duration of up to 12 months. For patients randomized to clascoterone in the pivotal studies, the total active treatment period was 12 months and for patients randomized to vehicle cream, the total active treatment period was 9 months. The end points for the primary objective were systemic and local TEAEs, including LSRs (telangiectasia, skin atrophy, striae rubrae, erythema, edema, scaling or dryness, stinging or burning, and pruritus). The number of patients with each IGA severity score was the efficacy end point. The study consisted of a baseline visit, LTF visits at LTF month 1, month 3, month 6, and month 9, and follow-up phone calls at LTF month 4.5 and month 7.5.

All patients applied clascoterone cream twice daily (morning and evening) to the face and, if designated by the investigator and desired by the patient, to the trunk for truncal acne for an additional 9 months of treatment. (Truncal acne had not been treated with clascoterone in the previous controlled studies.) Treatment on the face and/or trunk could be discontinued if or when acne cleared (having achieved an IGA score of 0 or 1) and restarted if or when acne worsened (an IGA score of 2 or greater), according to the assessment of the investigator for each treatment area (face and trunk).

Populations

Inclusion and exclusion criteria were the same as those in the pivotal trials described earlier in this report. Patients in the LTE study must have been enrolled in 1 of the phase III pivotal studies, must have completed the assigned treatment regimen without any material noncompliance with study requirements or treatment dosing (an adherence of 80% or greater), and must have completed the final study visit (visit 4 in the pivotal studies).

Baseline Characteristics

There were more female patients (62.6%) than male patients (37.4%) and the mean age of patients was 19.2 years (median = 17 years). The mean weight of patients at baseline was 66.76 kg (median = 63.10 kg) and the mean BMI of patients was 23.16 kg/m² (median = 21.80 kg/m²). Baseline characteristics are summarized in Table 16.

Table 16: Summary of Baseline Characteristics for CB-03-01/27 Study — ITT Population

BMI = body mass index; ITT = intention to treat; SD = standard deviation.

Note: Patients were summarized overall and according to the treatment (either clascoterone or vehicle cream) that they received in the phase III pivotal studies (the CB-03-01/25 and CB-03-01/26 trials).

Sources: Sponsor’s summary of clinical evidence²³ and Clinical Study Report for the CB-03-01/27 trial.⁵²

Interventions

All patients applied clascoterone twice daily (morning and evening) to the entire face and, if designated by the investigator and desired by the patient, to the trunk for acne for an additional 9 months of treatment.

Any medications that were used before the start of this study were recorded as part of the phase III pivotal study (the CB-03-01/25 or CB-03-01/26 trial).

Prohibited medications or therapies on the face or trunk during the study included the following:

• light treatments (including artificial tanning devices, blue light, and laser)

• systemic spironolactone

• systemic retinoid therapy

• all topical acne therapies other than the ones on the allowed medications list (e.g., retinoids, azelaic acid, dapsone).

The following supplemental products and/or procedures were allowed at the discretion of the investigator on the face or trunk if control of acne was insufficient during the study:

• hormonal contraceptives

• the occasional use of systemic antibiotics for acne (not to exceed 12 continuous weeks) or for other medical needs

• systemic corticosteroids (for other medical needs)

• the occasional use of intralesional corticosteroid injections for nodular or cystic acne lesions (low dose [e.g., approximately 2 mg triamcinolone per cubic cm]) or for other medical needs

• the occasional use of topical steroids or topical antibiotics for up to 10 continuous days (for other medical needs) within the treatment area (face and/or trunk)

• topical antiacne cleansers (not leave-on products) that have benzoyl peroxide (5% or less) or salicylic acid (2% or less) as their only active ingredient within the treatment area (face and/or trunk).

Outcomes

The main outcomes measured were safety outcomes:

• the incidence of any local and systemic TEAEs

• the number of patients with the presence of each individual LSR for each treatment area, as applicable, at each time point collected (baseline, LTF month 1, LTF month 3, LTF month 6, and LTF month 9, and any unscheduled visits).

A treatment-emergent LSR was defined as any LSR ongoing from the CB-03-01/25 or CB-03-01/26 trial if the patient originally received clascoterone or any new LSR after the baseline preapplication assessment. In addition, any LSR worsening after the baseline preapplication assessment was considered treatment-emergent from the time of worsening, regardless of the scores pattern after worsening.

The efficacy outcome measured was the number of patients with each IGA severity score for each treatment area, as applicable, at each time point collected (baseline, LTF month 1, LTF month 3, LTF month 6, and LTF month 9).

Statistical Analysis

Approximately 600 participants had to be enrolled to have 300 participants on-study at 6 months and 100 participants on-study at 12 months. These treatment durations included the 0 months or 3 months of active treatment in the phase III pivotal studies.

The ITT set included all enrolled individuals and was used for efficacy analyses. The safety set was used for safety analysis and included all participants who had received at least 1 application of the study drug.

Summary tables (descriptive statistics or frequency tables) are provided for baseline variables, efficacy variables, and safety variables. Continuous variables are described by descriptive statistics (number, mean, standard deviation [SD], adherence value percentage, minimum, median, and maximum). Frequency counts and the percentage of individuals within each category are provided for categorical data. No further statistical testing was performed. No statistical hierarchy was explored.

Adherence to the study drug was evaluated at each visit and overall, according to the following calculation: 100 multiplied by the number of applications divided by the number of scheduled applications. Nonadherence was defined as a value of less than 80%.

Descriptive statistics were used to summarize exposure to the study drug at each visit. The date and time of the first and last application, the total amount of the study drug used (calculated as the number of grams applied for each patient from the weights of the returned study drug), and the mean daily amount of the study drug applied (calculated as the total amount of the study drug used divided by the number of days of treatment) were listed.

All AEs were coded using Medical Dictionary for Regulatory Activities version 18.1. Individual TEAEs (i.e., all the AEs occurring or worsening after the first dose of the study drug) were listed with the number and percentage tabulated. Missing data were not replaced.

Results

Patient Disposition

Of the 609 screened and enrolled patients (with 317 patients randomized to the clascoterone group and 292 patients randomized to the vehicle group in the preceding pivotal studies), 2 patients were not treated with the study drug in the LTE and were excluded from the safety population. Of 607 patients who were treated with at least 1 dose of clascoterone during the LTE period (safety population), 57.2% completed the study. The most common reasons for discontinuation were withdrawal by patient (16.6%), being lost to follow-up (14.8%), and lack of efficacy (4.9%). The distribution of reasons for discontinuing the study was similar between groups, except for AEs (2.8% in the clascoterone group versus 0% in the vehicle group) and nonadherence (0.3% in the clascoterone group versus 1.4% in the vehicle group) (Table 17).

Exposure to Study Treatments

In the ITT population (N = 609), 88.5%, 68.5%, 49.9%, and 20.2% of patients remained in the study at 3 months, 6 months, 9 months, and 12 months of follow-up, respectively. In the safety population (N = 607), 88.6%, 68.5%, 49.9% and 20.3% of patients remained in the study at 3 months, 6 months, 9 months, and 12 months of follow-up, respectively (Table 18). Between the 2 nominal comparison groups, no significant differences in attrition were found during the LTE period (Table 18).

Table 17: Patient Disposition in CB-03-01/27 Study^a

ITT = intention to treat.

^aPatients are summarized overall and according to the original treatment (either study drug or vehicle) that they received in the phase III pivotal studies (the CB-03-01/25 and CB-03-01/26 trials).

^bPatients whose lesions cleared and opted out from the study.

^cPatient did not complete the treatment period because of a lack of study drug or vehicle; due to repeated temperature excursions, all of the study drug or vehicle was put in quarantine.

^dOther reasons for discontinuation were due to a patient moving 2 hours away for school or due to it being inconvenient to continue in the study, due to a patient not wanting to continue treatment application, due to a patient leaving the country for study abroad, and due to a patient who went abroad.

Sources: Sponsor’s summary of clinical evidence²³ and Clinical Study Report for the CB-03-01/27 trial.⁵²

The maximum duration of exposure, with the inclusion of the pivotal studies, was 12 months for treatment of the face and 9 months for treatment of the trunk. The mean daily amount of study drug used in the safety and ITT sets was 2.3 g of clascoterone (range, 0.2 g to 13.0 g, including treatment of both the face and trunk, where applicable). In the 2 nominal comparison groups (in both the ITT and safety set), the mean daily amount of study drug used was 2.3 g, with a range 0.22 g to 7.82 g in the clascoterone group and a range of 0.30 g to 13.0 g in the vehicle group.

In the ITT set, 85.4% of patients treated on the face and 76.9% of patients treated on the trunk showed an overall adherence rate greater than 80% (Table 19). Adherence data in the safety set were not provided by the sponsor.

Table 18: Duration of Exposure to Clascoterone Across Controlled and Follow-Up Periods in CB-03-01/27 Study

ITT = intention to treat.

Source: Clinical Study Report for the CB-03-01/27 trial.⁵²

Table 19: Summary of Treatment Adherence — ITT Set

ITT = intention to treat.

Source: Clinical Study Report for the CB-03-01/27 trial.⁵²

Efficacy

The majority (83.1%) of patients showed facial IGA scores that were mild or moderate in severity at baseline, with the overall proportion of patients whose skin was clear or almost clear increasing over time being greatest (ITT population = 181 of 609 [29.7%] patients) at the end of the study (day 274). The proportion of patients whose skin was clear or almost clear increased over the time period of treatment with clascoterone from 9.9% at baseline to 29.7% at day 274. There was a similar proportion of patients whose skin was clear or almost clear on the face at the end of the study between patients originally assigned to treatment with the vehicle cream (ITT population = 30.2% of patients) and clascoterone (ITT population = 29.3% of patients) in the phase III pivotal studies at day 274. A similar trend was observed in patients whose trunk had been treated with clascoterone during the LTE period. The proportion of patients with clear or almost clear skin on the trunk increased from 4.8% at baseline to 31.5% at day 274, with a similar distribution of patients between the 2 nominal comparison groups assigned in the phase III pivotal trials (Table 20).

Table 20: Summary of IGA Results — ITT Population

IGA = Investigator’s Global Assessment; ITT = intention to treat.

Sources: Sponsor’s summary of clinical evidence²³ and Clinical Study Report for the CB-03-01/27 trial.⁵²

Harms

Refer to Table 21 for a summary of harms.

Of 607 patients in the safety set, 110 (18.1%) patients experienced at least 1 TEAE. The only TEAEs reported for at least 1.0% of patients were nasopharyngitis (2.6%) and upper respiratory tract infection (1.3%).

Six patients experienced serious TEAEs, including coronary artery dissection, dizziness, depression and suicide attempt, eosinophilic gastroenteritis, fatigue, and induced abortion.

Ten (1.7%) patients discontinued the study drug due to TEAEs and 9 of these patients discontinued the study due to the TEAEs.

Overall, the most frequently reported LSRs were erythema (6.9% on the face and 1.2% on the trunk), scaling or dryness (4.0% on the face and 0.7% on the trunk), and pruritus (1.6% on the face and 0% on the trunk). In general, a higher proportion of patients who originally received clascoterone had treatment-emergent LSRs compared to patients who originally received vehicle cream. For example, 9.8% of patients who had received clascoterone in the parent trials compared to 3.8% of patients who had been assigned to the vehicle group in the parent trials experienced treatment-emergent erythema on the face.

Table 21: Summary of Harms Results From the Long-Term Extension Study — Safety Set

LSR = local skin reaction; NR = not reported; SAE = serious adverse event.

^aFrequency greater than 1% in any group.

^bSkin reactions included application site swelling, application site dryness, cystic acne, application site acne, conglobate acne, and acne.

^cOther reasons included depression, eosinophilic gastroenteritis, polycystic ovaries, dizziness, suicide attempt, hair colour changes, induced abortion, coronary artery dissection, and fatigue.

^dTreatment-emergent LSRs on the face and trunk at day 274.

Sources: Clinical evidence summary²³ and Clinical Study Report for the CB-03-01/27 trial.⁵²

Critical Appraisal

Internal Validity

Based on the LTE results and discussion with the clinical expert, clascoterone 1% cream appears to be safe when used for up to 1 year of treatment. According to the clinical expert, among AEs that occurred more frequently in the clascoterone cohort compared to the vehicle cohort, skin atrophy is the most noteworthy event (5% in the clascoterone group versus 1% in the vehicle group). The LTE study suggested that patients who use clascoterone for up to 1 year of treatment may continuously improve or maintain improved skin affected by acne vulgaris. However, the study was not randomized and no formal statistical testing for efficacy outcomes (which were not primary objectives) was conducted. Furthermore, there was no true comparator tested during the LTE period. Therefore, definitive conclusions about the comparative effectiveness of clascoterone cannot be reached. Also, there may be a selection bias as those who benefited from clascoterone treatment during the pivotal trials were most likely to continue and a high adherence rate was an inclusion criterion for the LTE study. Another issue was the high attrition rate where at 9 months, only about 20% of patients remained in the LTE study; patients discontinued the study due to patient withdrawal (16.6%), being lost to follow-up (14.8%), and a lack of efficacy (4.9%) in the safety population. This attrition rate for the LTE study may lead to an underestimation of potential safety risks and an overestimation of the effectiveness of clascoterone treatment as patients with AEs and a lack of response are more likely to drop out from the study. Lastly, patient group input mentioned that HRQoL, such as mental health, anxiety, depression, and self-esteem, were important to patients. However, this aspect of treatment effect was not assessed.

External Validity

Because the patients were rolled over from the pivotal trials, generalizability concerns and issues similar to those in the main trials apply to the LTE study.

Indirect Evidence

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CDA-AMC review team.

Objectives for the Summary of Indirect Evidence

In the absence of head-to-head evidence comparing clascoterone 1% cream against other relevant therapies used in the management of acne vulgaris, the sponsor submitted 1 indirect treatment comparison in the form of an NMA indirectly comparing the treatment effect of clascoterone to other treatments in patients with mild to moderate acne vulgaris.

Description of Indirect Comparisons

Objectives

The sponsor submitted an NMA that aimed to evaluate the relative efficacy and safety of the treatment of clascoterone 1% cream applied twice daily compared to other topical or hormonal therapies in patients aged 9 years and older with mild to moderate acne vulgaris.

The reference or base case of the sponsor-submitted NMA was to compare clascoterone with benzoyl peroxide and other topical retinoids (i.e., adapalene, tretinoin, and trifarotene). The sponsor detailed that this approach was chosen based on the assumption that newly diagnosed patients with moderate papulopustular acne (i.e., the majority of patients across trials and the patients most represented in trials of clascoterone) would first be prescribed a topical monotherapy as per current clinical practice guidelines.

Study Selection Methods

The comparator studies eligible for inclusion in the submitted NMA were selected according to a systematic review. The systematic review for the NMA was defined by the relevant population, intervention, comparator, outcome, and study design described in Table 22.

Table 22: PICOS for the Systematic Review Informing the Sponsor-Submitted NMA

CDA-AMC = Canada’s Drug Agency; ILC = inflammatory lesion count; NILC = noninflammatory lesion count; NMA = network meta-analysis; PICOS = population, intervention, comparator, outcomes, and study design; RCT = randomized controlled trial.

^aIncluded in reference-case analysis.

Source: Network meta-analysis technical document.⁵³

Clinical evidence for the systematic review informing the NMA was identified using multiple electronic databases (Table 23). The systematic literature review was based on an updated search focused on studies published after June 2020. Citation titles and abstracts were independently screened by 2 reviewers to identify relevant publications according to predefined criteria described in Table 23. Citations judged to be potentially relevant during the initial screening of titles and abstracts were independently assessed by 2 reviewers through full-text screening, with any selection disagreements adjudicated by a third reviewer. Data extraction of included studies was performed by a single reviewer and verified by a second reviewer. The risk of bias of the studies included in the systematic review informing the NMA was assessed using the Cochrane Risk of Bias 2 tool; risk of bias assessment was carried out by 2 independent reviewers, with a third reviewer to arbitrate discrepancies. Risk of bias assessments were conducted overall at the study level, without a focus on specific outcomes.

Of note, while the reimbursement indication is for patients with moderate and severe acne vulgaris, the study population in the majority of studies included in the NMA were patients with mild and moderate acne vulgaris. The sponsor posited that because the majority of the patient populations in the pivotal clascoterone trials was considered to have moderate acne vulgaris, the NMA reflects the treatment options and outcomes of the relevant patient population.

Table 23: Study Selection and Methods for Sponsor-Submitted NMA

NMA = network meta-analysis; RoB = Risk of Bias.

Sources: Network meta-analysis technical document⁵³ and the sponsor’s summary of clinical evidence.²³

NMA Analysis Methods

Indirect comparisons of clascoterone 1% cream to benzoyl peroxide (2.5% cream or 3.1% gel or 5% cream; applied once daily), tretinoin (0.025% cream or 0.04% gel or 0.05% cream; applied once daily), tazarotene (0.045% gel or 0.1% cream; applied once daily), adapalene (0.1% cream or 0.15% gel or 0.3% cream; applied once daily), and trifarotene (0.005% cream; applied once daily) were based on a generalized linear model framework under a Bayesian approach.

Changes in inflammatory and noninflammatory lesions at 12 weeks were analyzed as continuous outcomes and modelled with a normal likelihood and identity link function. Summary effect measures for these outcomes were expressed as mean differences with 95% CrIs. It was unclear if all outcome data were available per study group, whether a mixture of study group data and contrast level data were synthesized, or whether data cleaning or conversions were performed to achieve a common format. The mean change from baseline to week 12 was imputed using 1 of 3 methods depending on data availability:

• subtracting baseline counts from mean lesion counts at 12 weeks

• multiplying the percentage reduction in mean counts by baseline counts

• imputing from median and interquartile range estimates from 1 trial of 609 patients (4.8% of patients in network).

The SD of change scores was imputed using a tiered approach as follows:

• if available, the SD was calculated from the available standard error, P value, z statistic, or t statistic using standard formulas

• if available, the SD was estimated from the interquartile range and sample size using methods described by Wan et al.⁵⁴

• if no indirect measure of variation was available, the arithmetic mean of SDs reported from all other studies was used.

Study discontinuation for any reason at 12 weeks was analyzed as a dichotomous outcome and was modelled with a binomial likelihood and logit link function. Summary effect estimates for this outcome were expressed as RR with 95% CrI. Whether any special considerations were considered to handle 0 cells within the analyses of discontinuations for any reason was not detailed.

Methods of analysis are summarized in Table 24. An RE model was used for each network. A distribution of priors based on empirical data for RE models for the coefficient parameter (Normal[0,1x104]) and a uniform prior for the between-study variance were used (distribution details were not formally specified). It was unclear whether a common variance was used for all treatment comparisons. No sensitivity analyses involving the use of different prior distributions were performed.

Treatment nodes for evidence networks were constructed according to individual ingredients and their underlying strengths. Different preparations (e.g., gel, cream) with slightly different strengths but equivalent pharmacodynamic properties were grouped together. This included grouping tretinoin 0.04% (microsphere) gel (from 2 trials) and tretinoin 0.05% cream, adapalene 0.15% gel (from 1 trial) and 0.1% cream, clindamycin phosphate 1.2% gel (from 5 trials) and clindamycin 1% cream, tazarotene 0.045% polymeric lotion (from 3 trials) and tazarotene 0.1% cream, and benzoyl peroxide 3.1% gel (from 1 trial) and benzoyl peroxide 2.5%. Placebo treatments of different types (e.g., oral placebo, topical vehicles) were considered equivalent and presented as a single node within NMAs. No comparison of placebo response was presented to justify this approach.

Model fit was assessed by comparing the total residual deviance with the number of unconstrained data points, deviance information criterion (DIC), and between-study variance (I²). Model convergence was assessed by visually inspecting trace and density plots of posterior effect size estimates and checking that the potential scale reduction factor produced by the Gelman-Rubin-Brooks plots fell below 1.05. The risk of publication bias was not explored (e.g., funnel plots, comparison-adjusted funnel plots), nor were assessments of the certainty of the evidence evaluated using the GRADE framework presented. The assessment of consistency was conducted by comparing the posterior mean deviance of the individual data points from an unrelated means model against their posterior mean deviance in the corresponding consistency model. Additionally, results from the NMA and sensitivity analyses were compared to those from frequentist pairwise meta-analyses. Of note, different approaches for the assessment of consistency were used, including forest plots comparing findings from direct evidence, indirect evidence, and NMAs within closed loops. Moreover, no comparisons with results from pairwise meta-analyses were presented in the NMA report.⁵³

Sensitivity analyses included network metaregression analyses, adjusting for differences in baseline lesion counts, the proportion of female participants, mean age, and the use of in-study blinding, as well as additional unadjusted NMAs omitting outlier studies. Sensitivity analyses were also performed using different approaches to the handling of missing data (e.g., the use of the arithmetic mean of SDs to replace missing SD values versus the use of the largest SD). Of note, the method of how potential effect modifiers were identified (e.g., via systematic review and/or consultation with clinical experts) was not provided.

Table 24: Analysis Methods for Sponsor-Submitted NMA

CrI = credible interval; DSU = decision support unit; ILC = inflammatory lesion count; NA = not applicable; NICE = National Institute for Health and Care Excellence; NILC = noninflammatory lesion count; RR = risk ratio; TSD = technical support document.

Sources: Network meta-analysis technical document.⁵³ and the sponsor’s summary of clinical evidence.²³

Results of NMAs

Summary of Included Studies

Overall, 62 reports of 68 studies were included in the systematic review. Publications containing multiple trials were not included. Trials that could not be connected to the evidence network were excluded from the reference-case analysis. The reference- or base-case analysis included a total of 29 studies: 19 studies informing the evidence for both lesion outcomes and all 29 studies informing the evidence for discontinuations.

Studies included in the reference- or base-case NMA are presented in Figure 2. Differences in control treatments across the studies included were not described. Outcomes assessed at 12 weeks were available across all included trials. Methods used for lesion counting were not specified, nor was the extent of imputation of SDs using different approaches provided. All studies were RCTs with 28 (72%) studies employing a single-blinded or double-blinded approach. As depicted in Figure 1 and Figure 4 of 60 evaluated trials were appraised as being at high risk of bias, while 39 of 60 trials and 17 of 60 trials were assessed overall as being at a low risk of bias or having some concerns, respectively.

A table of baseline study characteristics presented in the sponsor NMA is provided in Appendix 1 (Table 30). The trial population varied with respect to baseline ILCs and NILCs (they ranged from approximately 7 lesions to 45 lesions and approximately 10 lesions to 80 lesions, respectively), the proportion of patients who were female (this ranged from 30% to 100%), and the average age (this ranged from 17.1 years to 30.2 years). Between-study heterogeneity on some covariates of interest (i.e., the duration of acne, acne severity, and prior therapies) could not be assessed by the sponsor due to limited reporting of these covariates in the primary studies. Likewise, comparability of the included studies based on key inclusion and exclusion criteria across trials could not be assessed. Potential sources of heterogeneity across the included studies identified by the CDA-AMC review team are summarized in Table 25.

The report does not clearly state how candidate sources of heterogeneity were established. Methodologic factors for consideration were informed by risk-of-bias assessments, and statistical factors related to model type (RE versus fixed-effects) and the approach to imputation of missing data. The review presents information regarding a set of selected study-level factors (the number of study centres, blinding, the average patient age, the proportion of female patients, the duration of acne, acne severity, baseline counts of ILCs and NILCs, and previous therapies), highlighting that the number of centres, study blinding, baseline lesion counts, average age at enrolment, and the proportion of female patients were reported across most studies.⁵³ Sensitivity analyses related to these factors were performed where sufficient data were available. Evidence tables were also provided; these provide numeric details regarding study-level demographics (refer to Appendix 1). The provided information shows that upon inspection, trials of clascoterone were associated with higher mean baseline lesion counts than most trials.

Figure 1: Risk of Bias Summary From Sponsor SR and NMA Report

D1 = domain 1; D2 = domain 2; D3 = domain 3; D4 = domain 4; D5 = domain 5; NMA = network meta-analysis; RCT = randomized controlled trial; SR = systematic review.

Source: Network meta-analysis technical document.⁵³

Table 25: Assessment of Clinical and Methodological Homogeneity for NMAs

ILC = inflammatory lesion count; NILC = noninflammatory lesion count; NMA = network meta-analysis; NR = not reported; SR = systematic review.

Sources: Network meta-analysis technical document.⁵³ Details included in the table are from the sponsor’s summary of clinical evidence.²³

Evidence Network

The evidence networks for the underlying reference-case analyses for change in both ILCs and NILCs at 12 weeks and for study discontinuations for any reason at 12 weeks is depicted in Figure 2. The NMA evidence for change in ILCs and NILCs was based on 19 studies (12,216 patients) and 8 nodes, while the NMA evidence for study discontinuation for any reason at 12 weeks was based on 29 studies (20,226 patients) and 10 nodes. For both evidence networks, almost all comparisons were against placebo. The most frequently studied intervention in both networks was tazarotene 1%; clascoterone was studied in a total of 3 studies versus placebo. In both networks, most other treatments were studied in only 1 to 2 trials.

A descriptive summary of the NMA model fit suggested that there were no concerns with the adequacy of the model fit based on an approximately equal number of constrained data points and corresponding posterior total deviance for each analysis. There was no evidence of violations of the consistency assumption based on the plots of direct, indirect, and NMA-derived estimates of treatment effect for each closed loop within the evidence network for each outcome and the P values from the results of inconsistency tests. However, unrelated means models and corresponding DIC values and deviance residuals were not reported. Pairwise comparisons were not reported.

Main NMA Results

The reference-case NMA results of all outcomes are summarized in Table 26. Only comparisons between clascoterone and other treatments are presented.

Table 26: Summary of Clascoterone Comparisons From RE NMA, Reference-Case Analyses

CrI = credible interval; MD = mean difference; NA = not applicable; NMA = network meta-analysis; RE = random effects; RR = risk ratio; SR = systematic review; vs. = versus.

Note: Data were drawn from league tables provided in Appendix 4 of the sponsor SR and NMA report. Statistically significant results are shown in bold font.

Sources: Network meta-analysis technical document.⁵³ Details included in the table are from the sponsor’s summary of clinical evidence.²³

Figure 2: Evidence Networks Informing Reference-Case NMAs

NMA = network meta-analysis.

Source: Network meta-analysis technical document.⁵³

Mean Change in Inflammatory Lesions at 12 Weeks

Measures of model fit for the primary analyses showed no concerns when the number of study arms was compared to the total posterior residual deviance (38 data points versus residual deviance of 29.7).

Based upon the NMA of the 19 included studies (12,226 patients), pairwise comparisons versus placebo showed beneficial effects (i.e., a reduction in lesions) for all relevant interventions. Pairwise comparisons from the NMA of clascoterone with each of the active therapies are shown in Table 26; clascoterone was favoured in comparisons versus placebo based upon estimated treatment effects and their corresponding 95% CrI, while the possibility of no difference (as reflected by a 95% CrI that included the null value of 0) could not be ruled out when clascoterone was compared with other active treatments.

Secondary network metaregression analyses for the mean change in inflammatory lesions at 12 weeks included univariable adjustments for the mean number of baseline lesions, the mean patient age, the proportion of female patients, and the presence of blinding in the study design. In general, the DIC values were comparable to those of the primary unadjusted model, and treatment effects for clascoterone were generally stable. Slight reductions in the magnitude of treatment effects of clascoterone versus placebo from –5.2 (95% CrI, –7.2 to –3.2) to –2.9 (95% CrI, –5.6 to –0.21) were noted in metaregression analyses that adjusted for baseline lesion counts. Other secondary analyses based on a fixed-effects NMA model and exploring different approaches to the imputation of missing SDs resulted in comparable estimates of treatment effect for clascoterone.

Mean Change in Noninflammatory Lesions at 12 Weeks

Measures of model fit for the primary analyses showed no concerns when the number of study arms was compared to the total posterior residual deviance (38 data points versus residual deviance of 32.6).

Based upon the NMA of the included 19 studies (12,226 patients), pairwise comparisons versus placebo showed beneficial effects for each of the different treatments that were included. Comparisons of clascoterone with each of the active therapies are shown in Table 26; clascoterone was favoured in comparisons versus placebo based upon estimated treatment effects, while the possibility of no difference could not be ruled out in comparisons with active treatments.

Secondary network metaregression analyses for the mean change in noninflammatory lesions at 12 weeks included univariable adjustments for the mean number of baseline lesions, the mean patient age, the proportion of female patients, and the presence of blinding in the study design. In general, the DIC values were comparable to those of the primary unadjusted model, and treatment effects for clascoterone were generally stable. Slight reductions in the magnitude of treatment effect of clascoterone versus placebo from –8.0 (95% CrI, –12.0 to –4.3) to –7.3 (95% CrI, –12.0 to –3.0) were noted in metaregression analyses that adjusted for baseline lesion counts. Other secondary analyses based on a fixed-effects NMA model and exploring different approaches to the imputation of missing SDs resulted in comparable estimates of treatment effect for clascoterone.

Study Discontinuations for Any Reason at 12 Weeks

Measures of model fit for the primary analyses showed no concerns when the number of study arms was compared to the total posterior residual deviance (63 data points versus residual deviance of 40.9).

Based upon the NMA of the included 29 studies (20,219 patients), pairwise comparisons versus placebo showed beneficial effects (based upon the direction of point estimates) for each of the different treatments with the exception of tazarotene 1% (RR = 1.30; 95% CrI, 1.10 to 1.50). Comparisons of clascoterone with each of the active therapies are shown in Table 26; clascoterone was found to be associated with a similar risk of discontinuation (i.e., 95% CrIs included the null value of 1) when compared to placebo and other active treatments with the exception of tazarotene 1%, which demonstrated an increased risk of discontinuation (RR = 0.71; 95% CrI, 0.53 to 0.94); thus, the result favoured clascoterone.

From the secondary analysis (reference-case analysis) of discontinuation for any reason at 12 weeks, metaregression analyses based on the use of blinding within studies increased the estimated treatment effect of clascoterone versus placebo, though model DIC was comparable to the unadjusted model (101.17 versus 98.98, respectively). The DIC from a fixed-effects NMA of the same data was also similar to that of the RE NMA (101.17 versus 99.60, respectively). The systematic review and NMA did not quantitatively or visually explore variability in the rate of discontinuations for any reason across the placebo groups of included trials and thus, it is unclear whether a control group metaregression analysis may have been of value in terms of addressing any bias in findings from NMA for this outcome. No corresponding metaregression analysis was performed for the covariates of age, baseline lesion count, and proportion of female participants.

Scenario NMA Analyses Results

Unadjusted NMAs were performed for 3 different scenario analyses against additional sets of comparator treatments.

Scenario 1: Hormonal Therapies

The evidence network for scenario 1 included placebo, clascoterone, spironolactone, and oral contraceptives as comparators and consisted of 10 RCTs (N = 3,851) for change in inflammatory lesions, and 8 RCTs (N = 2,496) for NMAs of noninflammatory lesions and discontinuations for any reason. The evidence network for scenario 1 is illustrated in Figure 3 and the results are summarized in Figure 6 in Appendix 1. Briefly, clascoterone was associated with the largest treatment effect versus placebo for both lesion outcomes and was more efficacious than placebo; however, the possibility of a null difference against spironolactone and oral contraceptives could not be ruled out based on comparative treatment effects and 95% CrIs. For discontinuations, no differences between any of the treatments and placebo were noted.

Scenario 2: First-Line Monotherapies

The evidence network for scenario 2 included placebo and 11 treatments, including clascoterone, benzoyl peroxide 5%, benzoyl peroxide 2.5%, adapalene 3%, adapalene 0.1%, oral contraceptive, oral or topical spironolactone, tazarotene 1%, tretinoin 0.05%, tretinoin 0.025%, and trifarotene 0.005%. The networks consisted of between 10 nodes and 12 nodes from 24 RCTs to 34 RCTs (N range, 13,137 participants to 22,234 participants) dependent on outcome, and with certain comparators only having data for inclusion in the NMA of study discontinuations for any reason at 12 weeks. The evidence network for scenario 2 is illustrated in Figure 4 and the results are summarized in Figure 7 in Appendix 1. Briefly, all treatments were found to be better than placebo for both inflammatory and noninflammatory lesions while a null difference could not be ruled out when all treatments were compared to each other in pairwise comparisons. For discontinuations for any reason at 12 weeks, all treatments except tazarotene 1% were associated with 95% CrIs that included the null value of 1 when compared to placebo; clascoterone was associated with an estimated RR of 0.90 (95% CrI, 0.72 to 1.20) compared to placebo.

Figure 3: Comparison With Hormonal Therapies (Scenario 1)

Source: Network meta-analysis technical document.⁵³

Scenario 3: Topical and Hormonal Therapies

The evidence network for scenario 3 included placebo and 25 treatments, including clascoterone, benzoyl peroxide 5%, benzoyl peroxide 2.5%, adapalene 3%, adapalene 0.1%, oral contraceptive, oral or topical spironolactone, tazarotene 1%, tretinoin 0.05%, tretinoin 0.025%, trifarotene 0.005%, erythromycin 1.5%, clindamycin 1.2% and benzoyl peroxide 3.1% and adapalene 0.15%, clindamycin 1% and adapalene 0.15%, clindamycin 1% and benzoyl peroxide 5%, clindamycin 1% or 1.2% and benzoyl peroxide 2.5% to 3.1%, clindamycin 1% or 1.5%, adapalene 0.1% or 0.15% and benzoyl peroxide 2.5% or 3.1%, adapalene 0.3% and benzoyl peroxide 2.5%, spironolactone and benzoyl peroxide 5%, and spironolactone and benzoyl peroxide 2.5%. The networks consisted of between 42 RCTs and 54 RCTs (N range, 21,255 participants to 32,843 participants) dependent on outcome, and with certain comparators only having data for inclusion in the NMA of study discontinuations for any reason at 12 weeks. The evidence network for scenario 3 is illustrated in Figure 5 and results are summarized in Figure 8 in Appendix 1. Briefly, some but not all treatments were found to be better than placebo for inflammatory and noninflammatory lesions. Clascoterone was clinically better than placebo for both outcomes, but a null difference could not be ruled out in comparisons with all other active treatments. For discontinuations for any reason, all treatments except tazarotene 1% were associated with 95% CrIs that included 1 when compared to placebo; clascoterone was associated with an estimated RR of 0.90 (95% CrI, 0.68 to 1.20) compared to placebo, and no evidence of a difference was found when compared to other active therapies.

Critical Appraisal of Sponsor-Submitted NMA

Considerations for the critical appraisal of the NMAs presented in the sponsor’s systematic review and NMA report are provided as follows and address considerations of validity, transparency, scope, appropriateness, the handling of between-study heterogeneity, the potential for publication bias, and other factors.

• Internal and external validity: Certain elements of the systematic review and NMAs presented in the sponsor NMA report are unclear. Thus, while the report describes the use of well-established NMA models from National Institute for Health and Care Excellence technical support documents and includes a variety of important elements for systematic reviews and NMAs (such as the engagement of an information specialist for searching, the involvement of multiple reviewers for study selection and data extraction, an assessment of between-study heterogeneity, the inclusion of analyses of consistency, and the consideration of sensitivity analyses to establish robustness of findings), certain challenges exist to fully grasp the internal validity of the systematic review and NMA provided. This includes a lack of clarity about the initial systematic reviews that informed the updates, uncertainty about the contribution of included trials to different networks, and the inclusion of study populations that appear to represent a broad spectrum of severity of acne vulgaris ranging from mild to severe that may introduce complexities when estimating treatment effects. Regarding external validity, the included study populations consisted of a range of male and female participants aged between 9 years and 30 years, with a range of baseline lesion counts. No clear violations of the transitivity assumption were noted, though judgments were partly limited by the unavailability of enrolment criteria across studies. Study populations were considered to be reasonably reflective of the real-world population of interest for acne vulgaris. However, it was noted that for the specific interests in moderate to severe disease, study populations in some of the included RCTs were broader and included mild disease as well.

• Prespecification of methods: The sponsor’s NMA report indicated that no protocol for the review was prepared. Its authors indicated that this work was an update of a prior review; however, details with regard to a protocol or prior registration for the original review were not provided. Thus, the ability to assess review performance was limited. Raw data informing the NMAs and model code were not readily available to verify analyses (though the preparation of datasets may be feasible from outcome data included as 1 element in a larger table of the NMA report). Supplemental information from the sponsor clarifies that the population of interest was “adults and children aged 12 years or older with acne vulgaris characterized by comedones, inflammatory papules or pustules, with or without an occasional nodule,” and the sponsor sought to include studies that ranged from mild to severe acne vulgaris to facilitate comparisons with other treatments. A 2022 NMA published in the British Journal of Dermatology⁵⁵ included several considerations to address variability in the availability of information from study to study regarding the severity of acne vulgaris (e.g., the consideration of nodule counts, the number of inflammatory lesions when the severity of acne was not clearly described); similar information may have been helpful in the context of the current systematic review and NMA with regard to managing clinical heterogeneity.

  Figure 4: Comparison With All First-Line Monotherapy Options (Scenario 2)

  

  Source: Network meta-analysis technical document.⁵³

  Figure 5: Comparison With All Topical and Hormonal Treatment Options (Scenario 3)

  

  Source: Network meta-analysis technical document.⁵³

• Consideration of relevant comparators: NMAs in the sponsor’s report considered a reference-case analysis that included clascoterone (applied twice daily) with benzoyl peroxide and other topical retinoids (i.e., adapalene, tretinoin, and trifarotene), while scenario analyses broadened the treatments compared to include oral contraceptives, spironolactone, and several combination therapies. Input from the clinical expert consulted by CDA-AMC suggested that combination therapies are commonly used to manage moderate to severe acne vulgaris; this may suggest that the scenario 3 analyses may be of greater interest for consideration. Clinical expert input also suggested that oral isotretinoin, oral antibiotics, and topical dapsone could have been considered, though the clinical expert acknowledged certain limitations to doing so (e.g., guidelines recommend antibiotic use for a maximum of 3 months to 6 months, some patients will not agree to treatment with isotretinoin, topical dapsone is not covered by public plans). The submission request seeks status as a first-line therapy for moderate to severe acne, which may explain the choice of treatments in reference-case analyses.

• Follow-up duration and outcomes: All analyses are based upon 12-week outcomes that were commonly available across the included trials. Long-term effectiveness and safety are not clear based upon these data. It is unclear whether reasons for discontinuation may vary between treatments. Additionally, the clinical expert consulted by CDA-AMC noted that there may be additional outcomes of relevance to patients, such as the clearance of acne (which also includes the achievement of “clear” or “almost clear” on the IGA scale), the prevention of acne sequelae (e.g., scarring, postinflammatory hyperpigmentation), and the use of the Dermatology Life Quality Index or Cardiff Acne Disability Index (to measure psychological impacts of acne such as anxiety, depression, and emotional distress).

• Between-study heterogeneity: There is some degree of heterogeneity between studies in terms of baseline lesion counts, the proportion of female participants, and participant age. The sponsor NMA report included metaregression analyses to explore the effects of these variables on estimates of treatment effect, which appeared reasonably robust. Of note, the variability of these covariates by treatment comparison was unclear based on the information provided, and variability in enrolment criteria could not be assessed as this information was not available in the report; therefore, it is possible that minor differences between study populations exist after adjustment for mean baseline lesion counts. Trials of clascoterone were associated with populations that had higher baseline lesion counts than most other trials in reference-case NMAs and thus, treatment effects measuring changes from baseline in lesion counts relative to other treatments may be subject to some degree of bias. The clinical expert noted that ideally, subgroups by age, sex, and ethnicity would be available. Regarding analyses of the binary outcome of discontinuation for any reason, variability in the rate of withdrawal among the placebo groups was not inspected. Often with binary outcomes, it can be informative to look for important variability to consider whether there is a need for the performance of a control group network metaregression analysis to address any bias related to such differences. The report involved a feasibility assessment to explore the impact of variation in additional effect-modifying clinical variables, including the duration of acne, acne severity, and previous therapies received; however, these were often not reported in the included RCTs.

• Handling of data imputation: The systematic review and NMA involved the use of a tiered approach to handle the imputation of mean changes in lesion count from baseline, where necessary, and also to estimate corresponding SD values for changes in lesion count, where necessary. These approaches appear to align with commonly used approaches for meta-analysis.

• Risk of bias of included trials: Risk-of-bias assessments identified 50% of the included trials to be at a low risk of bias while most of the remaining studies were associated with some concerns. Assessments were performed only at the study level (i.e., they were not performed for specific outcomes).

• Appropriateness of syntheses, model fit, and consistency of evidence: The variability of certain traits between studies was noted, and the clinical relevance of combining studies wherein the severity of acne vulgaris appeared to range from mild to severe was considered unclear. From a quantitative perspective, model fit statistics identified no concerns in reference-case analyses when inspecting the numbers of included study arms and corresponding measures of total residual deviance. Checks of the consistency assumption also identified no concerns and thus, do not suggest that the combining of the evidence base was inappropriate.

• Subgroup and sensitivity analyses: While the review provides no details about a priori efforts to identify potential effect modifiers that involved clinical expert consultation or a review of the literature, the sponsor pursued sensitivity analyses based upon the availability of certain established characteristics (baseline lesion count, age, and the proportion of female patients) and certain statistical considerations (RE versus fixed-effects model, the approach to impute missing SD, and the use of blinding). Findings with regard to the treatment effects of clascoterone appeared to be generally consistent; regarding the effects of baseline lesion count, there was some reduction of treatment effects of clascoterone in network metaregression analyses. The impact of other effect modifiers was not explored (i.e., the duration of acne, acne severity, and previous therapies received) due to limited reporting in the included RCTs.

• Potential publication bias: The sponsor report did not include an assessment of publication bias and does not discuss the issue; in addition, no searching for grey literature was performed. For reference, the NMA by Mavranezouli et al.⁵⁵ noted some potential evidence for the risk of small study bias in their analyses related to mild to moderate acne focused on percentage change in baseline lesions.

Studies Addressing Gaps in the Systematic Review Evidence

No other relevant evidence in support of clascoterone 1% cream was provided by the sponsor.

Discussion

Summary of Available Evidence

The systematic review conducted by the sponsor included 2 identical phase III, randomized, double-blind, vehicle-controlled, parallel-group trials, the CB-03-01/25 study (N = 708) and the CB-03-01/26 study (N = 732). In both trials, patients were randomized 1:1 to either clascoterone 1% or vehicle cream for 12 weeks of treatment. In both trials, the primary objective was to determine the safety and efficacy of clascoterone 1% cream versus the vehicle cream applied twice daily for 12 weeks in patients with facial acne vulgaris. The outcomes measured in the trials and selected for GRADE assessment included global success (i.e., the proportion of patients aged 12 years and older achieving treatment success at week 12), lesion counts (i.e., the change from baseline to week 12 in NILC, ILC, and TLC), and notable harms (i.e., LSRs).

The CB-03-01/25 study was conducted primarily in the US and the CB-03-01/26 study was conducted primarily in Europe. Neither trial had any study sites in Canada. In the CB-03-01/25 study, the median age for both treatment groups was 18 years (range, 9 years to 58 years) and in the CB-03-01/26 study, the median age for both treatment groups was also 18 years (range, 10 years to 50 years). In the CB-03-01/25 trial, the majority of patients had an IGA score of 3 indicating moderate (83% and 82% of patients in the clascoterone and vehicle groups, respectively) at baseline. The mean baseline ILC was approximately 42 lesions, and the mean baseline TLC ranged between 60 lesions and 100 lesions in the CB-03-01/25 trial. Similarly in the CB-03-01/26 trial, the majority of patients had an IGA score of 3 indicating moderate (83% and 87% of patients in the clascoterone and vehicle groups, respectively) at baseline. The mean ILC and TLC at baseline was approximately 42 lesions and 63 lesions, respectively, in the CB-03-01/26 trial. Overall, baseline characteristics were generally similar between treatment groups across both pivotal trials. Patients were enrolled from January 21, 2016, to April 11, 2018, in the CB-03-01/25 study and from November 16, 2015, to February 21, 2018, in the CB-03-01/26 study.

The sponsor also submitted an open-label LTE study, the CB-03-01/27 trial (N = 609), in which patients who completed the pivotal studies were able to enrol for an additional 9 months of treatment with clascoterone. The primary objective was to determine the longer-term safety of the drug while IGA was measured to assess efficacy. Because this was a continuation of the parent studies, patient characteristics were generally similar. A greater number of patients who originally received clascoterone (N = 317) rather than vehicle cream (N = 292) rolled over into the LTE study.

In the absence of direct comparative evidence of clascoterone to other relevant comparators, the sponsor submitted a Bayesian NMA comparing the effects of clascoterone and different treatments on changes in the numbers of inflammatory lesions, noninflammatory lesions, and study discontinuations for any reason following 12 weeks of treatment. Reference-case analyses focused on comparisons of clascoterone with other monotherapies (benzoyl peroxide and other topical retinoids, such as adapalene, tretinoin, and trifarotene), while additional scenario analyses extended the comparators considered to include oral contraceptives, spironolactone, and combination therapies. Regarding the severity of acne vulgaris, studies enrolling populations that ranged from mild to severe (as indicated by a broad range of baseline numbers of inflammatory and noninflammatory lesions) were included. Unadjusted RE NMAs were conducted, as were secondary analyses to explore the potential effects of between-study variations in the mean numbers of baseline lesions, the mean participant age, the proportion of female participants, and the use of blinding in study design.

Interpretation of Results

Efficacy

Evidence from the CB-03-01/25 and CB-03-01/26 trials suggested that treatment with clascoterone was associated with greater treatment success based on the IGA scale compared to the vehicle (placebo) cream in patients aged 12 years and older with acne. Treatment success across the outcomes was achieved based on the trial definition (i.e., an IGA score of clear [0] or almost clear [1] and a 2-point or greater reduction on the IGA scale compared with baseline). According to the clinical expert, global response is a standard clinical outcome in the assessment of acne vulgaris and is considered an important clinical outcome. Although there is no gold standard for successful treatment of acne vulgaris, the clinical expert felt that a 10% difference in success was clinically meaningful for acne vulgaris and was supportive of the definition used in the trial as it aligned with Canadian clinical practice. Moreover, the definition of treatment success used for the IGA was consistent with FDA recommendations.^48,49 Similarly, treatment with clascoterone was associated with a greater reduction in absolute and percentage change in NILC, ILC, and TLC compared to vehicle cream, which the clinical expert noted is relevant to clinical practice in Canada. According to the clinical expert, percentage change from baseline was a more clinically relevant outcome than absolute lesion counts because it is not feasible for clinicians to be counting lesions at each visit. Moreover, the clinical expert felt that the threshold for success would be different for patients with primarily noninflammatory lesions versus those with primarily inflammatory lesions because noninflammatory acne lesions are slower to resolve and typically harder to treat.

These results, however, may be biased due to missing data, which may not have been fully accounted for by the MI approach used in the primary analysis. As noted in the critical appraisal, the imputations based on worst-value and worst-case analyses were not consistent with the primary analysis for absolute change in ILC and NILC. Input from the clinical expert suggested that only the results of the CB-03-01/26 study were clinically meaningful for the end points of global success and percentage change in NILC from baseline to week 12. The clinical expert noted that the main treatment goals of acne treatment are very minimal acne or the clearance of acne and the patient’s impression of change. In general, the clinical expert felt that 12 weeks was an appropriate and common time point at which to measure success in the context of a clinical trial; however, 6 months would be more relevant to measure treatment success according to the NILC in the clinical practice setting.

Patient groups and the clinical expert consulted by CDA-AMC identified mental health and HRQoL as important outcomes; however, these outcomes were not addressed in the evidence submitted by the sponsor. The clinical expert and clinician groups also emphasized the importance of patient satisfaction in assessing response to treatment because this varies greatly from patient to patient and impacts the treatment course.

Many treatment options (e.g., oral androgen inhibition) are contraindicated in male patients, thereby limiting available treatment options for them. Because female patients have more treatment options, there is a difference in unmet need between the sexes. Clascoterone is a first-in-class topical androgen receptor inhibitor therapy and could potentially fulfill an unmet need for males with acne vulgaris. However, subgroup analyses were not conducted by sex so no conclusions can be drawn about the prognostic effect of clascoterone in 1 group over the other or its ability to fulfill this unmet need.

Although the study population did not include patients with mild acne, the clinical expert felt that the results would still be generalizable to this population. Most patients with severe acne are more resistant to treatment; hence, the clinical expert did not feel that clascoterone would be the optimal first-line option for patients with severe acne. Overall, the clinical expert felt that a topical treatment such as clascoterone would be better suited for patients with mild or moderate acne. While the data presented in the report included a small number of patients aged 9 years to 11 years (who were permitted in the trials), the clinical expert noted that their inclusion would not have a major impact on the results, despite the indication being for patients aged 12 years or older.

The included pivotal studies were placebo-controlled and no direct comparative evidence between clascoterone and relevant active comparators was available. In an effort to address this evidence gap, the sponsor submitted 1 NMA indirectly comparing clascoterone to other topical and oral treatments for moderate to severe acne. Overall, the NMA evidence did not favour the treatment of either clascoterone or other active treatments. Sensitivity analyses were associated with relatively similar estimates of treatment effect. The additional 3 scenario NMAs indirectly comparing clascoterone to other sets of hormonal, monotherapy, and combination therapies found no important differences between treatments. Critical appraisal of the sponsor NMA report noted that in general, recommended methods for conduct and reporting were followed, though certain limitations were identified. Study populations of RCTs ranged from mild to severe based on mean baseline lesion counts, introducing challenges to the interpretation of findings and also concerns that the validity of treatment effects measuring changes in lesion count from baseline could be impacted. Trials of clascoterone were associated with populations that had higher baseline lesion counts than most other trials in reference-case NMAs and thus, treatment effects measuring changes from baseline in lesion counts relative to other treatments may be subject to bias. The variability of placebo or vehicle group responses across trials was not described in detail, and the appropriateness of combining these groups for the purposes of the NMA was unclear. Methods to identify effect modifiers of interest to judge the appropriateness of the transitivity assumption were unclear, and the effects of differences between study populations for specific effect modifiers (the duration of acne, acne severity, and previous treatments) could not be addressed due to limited reporting by the included trials. Input from the clinical expert suggested that certain additional treatments (oral antibiotics, isotretinoin, topical dapsone, and combination treatments) could have been included in reference-case analyses. Findings from NMAs should thus be interpreted with some degree of caution.

Harms

In both trials, patients with TEAEs, SAEs, withdrawals due to AEs, mortality, and notable harms were generally similar between groups and across the trials. At 12 weeks, the most common AEs reported in both trials was nasopharyngitis. Patients with SAEs and withdrawals due to AEs were relatively few in both groups and across the trials. No deaths were reported in either trial. The clinical expert did not express any concerns for the overall safety of clascoterone that would be expected to have an impact on clinical decision-making.

Similar to the pivotal trials, nasopharyngitis (2.6% in the overall population) was the most common TEAE in the LTE study. The clinical expert consulted by CDA-AMC stated that no long-term safety concern for clascoterone was detected during the extension period. However, the clinical expert felt that skin atrophy (5% in the clascoterone group versus 1% in the vehicle group) is a noteworthy AE.

Regarding indirect evidence, the sponsor’s NMA report presented findings from analyses of study discontinuations for any reason at 12 weeks. Overall, there was no strong evidence of any differences between clascoterone, and active treatments included in the evidence network with the exception of the comparison to tazarotene 1%, where clascoterone was associated with a reduced risk of discontinuation compared to tazarotene 1% (RR = 0.71; 95% CrI, 0.53 to 0.94) in the reference-case analysis. However, the uncertainty of these results must be considered due to limitations of the NMA that include the short duration of follow-up (12 weeks) and between-study heterogeneity.

Conclusion

The evidence in this review includes 2 sponsor-submitted, phase III, randomized, double-blind, vehicle-controlled trials, the CB-03-01/25 study (N = 708) and the CB-03-01/26 study (N = 732). The CB-03-01/25 and CB-03-01/26 studies assessed the safety and efficacy of treatment with clascoterone 1% cream compared to vehicle (placebo) cream in patients with moderate to severe acne vulgaris. The 2 trials demonstrated that 12 weeks of treatment with clascoterone 1% cream applied twice daily likely results in a clinically important improvement in achieving treatment success as defined by an IGA score of 0 or 1 and a 2-point or greater reduction from baseline when compared with vehicle cream. However, the evidence was uncertain with regard to the ability of clascoterone to reduce the number and percentage of lesions (NILC, ILC, and TLC) at week 12. There is no evidence for the effect of clascoterone on mental health and HRQoL, which was identified as a clinically important outcome by the clinical experts and patient groups. Most efficacy outcomes were affected by concerns for imprecision (i.e., CIs included the potential for little to no difference versus placebo). All outcomes were impacted by a risk of bias due to missing data and indirectness due to concerns with generalizability to patients with severe acne vulgaris in clinical practice in Canada.

Because there was no direct evidence comparing clascoterone to other treatments for acne vulgaris, the sponsor provided an NMA that assessed short-term efficacy versus multiple comparators. For comparisons between clascoterone and active treatments, the results of the NMA did not favour either treatment in terms of a reduction in inflammatory lesions. Higher baseline lesion counts in trials of clascoterone may also provide rationale to interpret treatment effects relative to other treatments in terms of changes from baseline with caution.

Regarding safety, clascoterone resulted in little to no clinically important difference in LSRs. Of note, few to no events were observed during follow-up for these notable harms. Based on the harms observed at week 12 and LTF at 12 months, the clinical expert suggested there were no concerns for the overall safety of clascoterone that would be expected to have an impact on clinical decision-making. In addition, the NMA found no important differences in safety outcomes between clascoterone, placebo, and active comparators.

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