Reimbursement Review

Ruxolitinib (Opzelura)

Sponsor: Incyte Biosciences Canada Corporation

Therapeutic area: Nonsegmental vitiligo

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 of Application Submitted for Review

NOC = Notice of Compliance.

Introduction

Vitiligo is a chronic autoimmune disorder that causes progressive depigmentation of the skin due to the loss of melanocytes,^1-4 affecting up to 2% of the global population,^4,5 with an estimated prevalence in Canada of between 0.5% and 1%.⁶ It is categorized into nonsegmental vitiligo (presenting as symmetric patches), segmental vitiligo (affecting 1 side of the body), and mixed forms (displaying characteristics of both forms),⁴ with nonsegmental vitiligo being the most common form, accounting for approximately 80% of vitiligo cases.⁵ It can also have an unpredictable progression, often starting before age 12 and peaking around age 30.⁴ The pathogenesis of vitiligo involves autoimmune mechanisms targeting melanocytes, driven by increased oxidative stress and inflammatory pathways, leading to immune-mediated destruction.^1,7

Lesions often appear on the face, hands, and genital areas,⁸ and are often triggered by stress. Flares are also common, especially in individuals with more extensive skin involvement or darker skin tones.^7,9,10 Additionally, about 25% of patients have autoimmune comorbidities,¹¹ with thyroid disease being the most frequent.¹² The psychosocial impact of vitiligo is profound, often leading to depression, anxiety, and social stigma,^13-15 particularly when lesions are visible.^16,17 Children^13,18 and those with darker skin tones^9,14 or from cultures with stronger stigma about skin tone are particularly vulnerable.¹⁹ Vitiligo also carries both direct and indirect economic costs, including treatment expenses and lost productivity.^20,21

Diagnosis is based on physical exams, clinical history, and laboratory tests, with biopsies used in rare cases.^4,12,22-24 Because of the association with autoimmune conditions, thyroid function and the potential for other autoimmune disorders is often assessed.²³

Ruxolitinib in the form of a 1.5% cream was approved by Health Canada for the topical treatment of nonsegmental vitiligo in adult and pediatric patients aged 12 years and older (Notice of Compliance received on October 11, 2024). The sponsor’s reimbursement request aligns with this indication. This is the first review of ruxolitinib for this indication.

The recommended dosage is a thin layer of 1.5% ruxolitinib cream applied twice daily to affected skin areas, covering up to a maximum of 10% of the patient’s body surface area (BSA) per application.²⁵ Satisfactory repigmentation may require more than 24 weeks of treatment. If meaningful repigmentation is not observed by 24 weeks, re-evaluation by a health care provider is recommended.²⁵

Perspectives of Patient, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical experts consulted by Canada’s Drug Agency (CDA-AMC) for this review.

Patient Input

Input was submitted by the Canadian Skin Patient Alliance in collaboration with Vitiligo Voices Canada regarding the current review of ruxolitinib for nonsegmental vitiligo, based on a survey conducted in Canada between September 26 and October 15, 2024, with 19 respondents.

Participants were primarily from Ontario and Alberta, with others from Newfoundland, Nova Scotia, New Brunswick, Quebec, British Columbia, and Yukon. Survey respondents were predominantly white, and about one-half were aged 55 years or older.

According to the input, vitiligo’s impact extends beyond physical symptoms, affecting identity, emotional well-being, sense of belonging, and social interactions. Young individuals face bullying and social stigma, while many reported struggles with anxiety due to the condition’s unpredictable nature. Severe mental health consequences, such as depression and suicidal thoughts, were also reported, with challenges exacerbated for individuals with darker skin tones, some of whom faced heightened judgment due to cultural beauty standards.

Current treatment options were seen as inadequate. Patients who responded to the survey reported frustration with inconsistent results, side effects, high costs, and access barriers, particularly for patients living in rural areas, due to the need for frequent clinic visits. The patients who provided input through the patient groups noted that topical corticosteroids, the first-line therapy, were largely ineffective, as were other treatments, such as vitamin D derivatives and immunomodulators. Some patients reported limited effectiveness with depigmentation therapy (monobenzone) and narrowband UV-B phototherapy, although responses varied, and these treatments posed challenges due to the need for frequent clinic appointments and additional costs. None of those who responded had experience with ruxolitinib.

Those who responded to the survey emphasized the need for a treatment that is effective, easy to use, and capable of delivering reliable repigmentation with lasting results. They also prioritized fewer side effects, increased affordability, and greater accessibility, ideally through at-home or simpler solutions.

Clinician Input

Input From Clinical Experts Consulted for This Review

Vitiligo can range from being barely perceptible to cosmetically distressing, with patients having different perceptions of their condition. The disease site and degree of repigmentation matter, as areas of the skin affected by vitiligo in visible sites will be more difficult to hide and therefore have a greater effect on the patient. Partial repigmentation is not necessarily associated with improvement in health-related quality of life (HRQoL), as the visibility of vitiligo can still negatively affect patients’ HRQoL.

The clinical experts consulted for this review emphasized that the choice of treatment will be based on the impact that the disease has on a patient’s life. Options include conservative camouflage, which is usually not readily accepted by patients and does not modify disease mechanisms or provide any degree of disease improvement. The mainstays of treatment are topical corticosteroids and calcineurin inhibitors, which address the underlying inflammatory attack on the melanocytes. Other alternative treatments include phototherapy, which may be combined with topical treatments. However, according to the clinical experts, approximately one-half of the patients routinely seen in clinical practice become refractory due to disease resistance, while some other patients discontinue treatments due to unacceptable toxicity.

As none of the other currently available therapies are approved by Health Canada for the treatment of nonsegmental vitiligo, the clinical experts indicated that topical ruxolitinib has the potential to be a first-line therapy for nonsegmental vitiligo, or it could be reserved as a second-line option for patients refractory or intolerant to current mainstay treatments. They noted that the absence of comparative evidence against the drugs currently used in clinical practice was considered a substantial limitation. The experts also emphasized that the place in therapy for ruxolitinib would depend on whether it can provide clinically meaningful improvements for patients who have the highest unmet need. These patients were identified as those with darker skin tones; those likely to experience a greater decline in HRQoL due to the increased visibility of the condition; and those with affected lip-tip, periocular, and/or perioral regions, which are highly visible and often resistant to repigmentation.

The clinical experts expected treatment with ruxolitinib to be discontinued if there was a lack of efficacy or disease progression after 24 weeks or once the skin was fully repigmented. The clinical experts noted that referring patients to a specialist, such as a dermatologist, was preferable. They also indicated that it would be appropriate to restrict the amount of medication used by patients, limiting administration to 10% of the BSA.

Clinician Group Input

Two clinician groups, comprising 12 clinicians, provided input for this review: the Canadian Dermatology Association in collaboration with the Dermatologist Association of Ontario and Dermatology Association of Saskatchewan (with 8 clinicians contributing to the input), and the Southwestern Ontario Dermatologists Group (with 4 clinicians contributing).

Both groups agreed that, aside from ruxolitinib, no effective treatments for vitiligo are available in Canada. Current options include off-label use of corticosteroids, calcineurin inhibitors, and narrowband UV-B phototherapy, with systemic drugs and surgical grafting considered for more severe cases. Despite these treatments, vitiligo remains difficult to manage, with no cure available and a high recurrence rate. The core treatment goals, as outlined by both groups, are to achieve visible repigmentation and halt disease progression, although attaining high levels of repigmentation remains challenging. The Canadian Dermatology Association emphasized the need for maintenance therapy to prevent relapse, while the Southwestern Ontario group focused on reducing stress on melanocytes to improve outcomes.

Both groups described 1.5% ruxolitinib cream as a transformative first-line therapy for vitiligo in patients aged 12 years and older. It targets the underlying disease mechanisms and has a favourable safety profile, allowing for prolonged maintenance use.

Treatment response for vitiligo is typically assessed based on repigmentation and disease progression. The primary outcome measures include the Vitiligo Area Scoring Index (VASI), Investigator’s Global Assessment, Vitiligo Noticeability Scale (VNS), and global impression scales.

Regarding treatment discontinuation, input from the Canadian Dermatology Association suggested stopping treatment after 6 months without repigmentation, while others recommended extending it to 18 months. The Southwestern Ontario group stressed that, after 1 year, an inadequate response based on patient-reported outcomes, physician assessments, disease progression, and adverse events (AEs) should lead to discontinuation. Both groups agreed that vitiligo can be diagnosed by any physician, but dermatologists are ideally suited for diagnosis, treatment selection, and monitoring to ensure the best long-term outcomes.

Drug Program Input

Drug programs provide input on each drug being reviewed through the CDA-AMC reimbursement review process by identifying issues that may affect their ability to implement a recommendation. For this review, the drug plans provided questions pertaining primarily to initiation and prescribing of therapy. These questions were addressed by the clinical experts consulted for this review. The clinical experts’ responses are included in the Drug Program Input section (Table 4).

Clinical Evidence

Systematic Review

Description of Studies

Two studies were reviewed: TRuE-V1 (n = 330) and TRuE-V2 (n = 344) were phase III, multicentre, double-blind, vehicle-controlled randomized controlled trials (RCTs) identically designed to evaluate the efficacy and safety of 1.5% ruxolitinib topical cream, applied twice daily to depigmented areas, for the treatment of nonsegmental vitiligo in adult and pediatric patients aged 12 years and older.

The primary outcome was the proportion of patients achieving an improvement in the Facial Vitiligo Area Scoring Index (F-VASI) score of at least 75% from baseline at week 24. Additional levels of VASI thresholds were assessed as secondary end points in the trials. The VASI score evaluates the objective response to treatment, capturing the overall surface area of vitiligo involvement and the degree of repigmentation. However, while the VASI score is a validated instrument, it is not routinely used in clinical practice. Evidence in the literature suggests that a 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index (F-VASI75), and 50% or more improvement from baseline on the Total Vitiligo Area Scoring Index (T-VASI50), would likely result in a clinically meaningful change in repigmentation for patients with nonsegmental vitiligo.²⁶ Patient-reported noticeability was assessed as a key secondary outcome using the VNS, a validated instrument for which scores of 4 (a lot less noticeable) or 5 (no longer noticeable) have been used as the minimal clinically important difference (MCID).

HRQoL was an exploratory outcome in both studies and was assessed using the Dermatology Life Quality Index (DLQI) and the Children’s Dermatology Life Quality Index (CDLQI), as well as the Vitiligo-Specific Quality of Life Instrument (VitiQoL). The DLQI is a 10-item questionnaire designed to assess the impact of skin conditions on an adult’s life, while the CDLQI is a similar questionnaire for children. The instrument covers domains such as symptoms, daily activities, relationships, work or school, and emotional well-being. The maximum total score on either index is 30, with higher scores denoting a greater negative impact on quality of life. The VitiQoL is a specialized, patient-reported HRQoL assessment tool designed to measure the impact of vitiligo on patients’ lives. The total score can range from 0 to 90, with higher scores denoting a greater reduction in quality of life.

Efficacy Results

Vitiligo Area Scoring Index

For the primary outcome, which was the proportion of patients achieving an F-VASI75, treatment with ruxolitinib was associated with between-group differences in the response rate of 22.3% (95% confidence interval [CI], 14.2 to 30.5; P < 0.0001) in the TRuE-V1 trial and 19.5% (95% CI, 10.5 to 28.4; P = 0.0004) in the TRuE-V2 trial over 24 weeks versus vehicle treatment. In absolute effects in the TRuE-V1 trial, 60 patients (30.8%) who applied ruxolitinib achieved the outcome compared to 7 patients (7.8%) who applied the vehicle treatment. In the TRuE-V2 trial, 62 patients (31.2%) who applied ruxolitinib achieved the outcome compared to 11 patients (11.2%) who applied the vehicle cream.

An F-VASI75 has been reported in the literature as a threshold for treatment success based on perceptions of patients with vitiligo and dermatologists; however, no MCID for between-group differences were reported. The presence of an important effect was determined by the clinical experts consulted for this review. The difference between treatments in terms of repigmentation was considered clinically meaningful, but the clinical experts noted that the overall impact was difficult to assess. In clinical practice, partial repigmentation as measured by the F-VASI may not necessarily be associated with a meaningful change for patients, as long as the disease remains visible. The minimal clinically important objective response can be highly variable across patients depending on how the disease affects their daily lives. Evidence of moderate certainty suggests that treatment with ruxolitinib likely results in a clinically important increase in the proportions of patients achieving an F-VASI75 compared to vehicle treatment.

Treatment with ruxolitinib was also likely associated with a clinically important increase in the proportions of patients achieving other VASI thresholds, such as a 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index (F-VASI90), over 24 weeks compared to vehicle treatment. A total of 31 patients (15.9%) who applied ruxolitinib in the TRuE-V1 trial achieved an F-VASI90 compared with 2 patients (2.2%) who applied the vehicle cream; in the TRuE-V2 trial, 33 patients (16.6%) who applied ruxolitinib achieved the outcome compared with 1 patient (1.0%) who applied the vehicle cream. The between-group differences in the response rate were 13.2% (95% CI, 7.5% to 18.8%; P = 0.0038) in the TRuE-V1 trial and 15.0% (95% CI, 9.3% to 20.7%; P = 0.0065) in the TRuE-V2 trial. Results for T-VASI50 responses were consistent with those for F-VASI90 responses. However, results for the more conservative threshold of a 75% or more improvement from baseline on the Total Vitiligo Area Scoring Index (T-VASI75) were deemed by the clinical experts to be unlikely to constitute a meaningful change for the patients.

Vitiligo Noticeability Scale

Patient-reported noticeability, assessed using the VNS, suggests that treatment with ruxolitinib likely results in a clinically important increase in the proportions of patients achieving a VNS of 4 (a lot less noticeable) or 5 (no longer noticeable) over 24 weeks compared to vehicle treatment. Among patients who applied ruxolitinib, the proportions of patients who responded to treatment were 25% in the TRuE-V1 trial and 21% in the TRuE-V2 trial, resulting in between-group differences in the response rate versus vehicle treatment of 21.2% (95% CI, 14.3% to 28.1%; P = 0.0002) in the TRuE-V1 trial and 15.5% (95% CI, 8.5% to 22.6%; P = 0.0013) in the TRuE-V2 trial. Uncertainty was introduced by the absence of a reported MCID for differences between treatments, and by the fact that, as was the case for the VASI, a less noticeable condition may not necessarily be associated with a meaningful change for patients, as long as the disease remains visible.

Health-Related Quality of Life

The clinical experts consulted for this review indicated that treatment of vitiligo is targeted at improving current and future HRQoL rather than focusing on surface area of involvement and degree of repigmentation. This was also consistent with patient and clinician input, which emphasized the importance of improving the psychosocial impact of the disease on quality of life. In the trials, HRQoL was assessed as an exploratory outcome. Statistical testing was not adjusted for multiplicity, and the results should be considered supportive evidence.

Results suggest that treatment with ruxolitinib may not result in a clinically important improvement in HRQoL, as measured with the VitiQoL over 24 weeks compared to vehicle treatment. The mean between-group differences in change from baseline through 24 weeks in VitiQoL were −0.28 (95% CI, −4.51 to 3.95; P = 0.8976) in the TRuE-V1 trial and −3.52 (95% CI, −7.60 to 0.57; P = 0.0915) in the TRuE-V2 trial. Results for HRQoL assessed using the DLQI and CDLQI were deemed not clinically meaningful. There is currently no MCID established for these instruments in patients with vitiligo, and the absence of an important effect was determined by the clinical experts consulted for this review. This indicates that, despite observing an objective response to ruxolitinib in terms of overall surface area of involvement and degree of repigmentation, which can make the condition less noticeable in some patients, ruxolitinib did not improve the impact of the disease on HRQoL in the overall study population. Findings from post hoc analyses that compared the change in VitiQoL and DLQI from baseline to week 24 among patients who received ruxolitinib and achieved various levels of F-VASI responses and those who did not achieve such responses suggest that patients may observe improvement in their HRQoL with at least an F-VASI75; however, whether the improvement in HRQoL is clinical meaningful is uncertain. In addition, interpretation of these findings is limited by the post hoc nature of the analyses.

Harms Results

A relatively large proportion of patients receiving ruxolitinib in the TRuE-V1 trial (46%) and the TRuE-V2 trial (50%) experienced at least 1 AE. The most common treatment-emergent adverse events (TEAEs) were related to application site reactions (acne, pruritus, rash, and exfoliation) and infections. Serious adverse events (SAEs) were uncommon. Treatment with ruxolitinib appeared to be well tolerated, as few discontinuations were due to AEs. No deaths were reported throughout the trials’ duration. Findings for the treatment extensions in the TRuE-V1 and TRuE-V2 trials, as well as from the TRuE-V long-term extension (LTE) study, were consistent with those from the pivotal trials. Overall, the clinical experts indicated that the harms profile of ruxolitinib did not raise any new safety signals or any particular safety concerns. However, as with most clinical trials, the studies were not powered to detect infrequent AEs, or those with a lag time.

Critical Appraisal

Interpretation of the findings is limited by the fact that the key efficacy evidence for ruxolitinib is focused on objective response to treatment. Because vitiligo can range from being barely perceptible to cosmetically distressing, and because different individuals are likely to have different priorities and objectives when assessing the magnitude of response to treatment, the clinical meaningfulness of an objective response is uncertain. As the TRuE-V1 and TRuE-V2 trials included a vehicle control group, there is no direct evidence comparing ruxolitinib to other therapies currently used for vitiligo. The comparative effectiveness and safety of ruxolitinib relative to other available treatment options, which were considered well accepted overall and routinely prescribed according to the clinical experts, are therefore unknown.

The TRuE-V1 and TRuE-V2 trials may be generalizable to a selected sample of individuals living in Canada with vitiligo. The majority of patients included in the studies were white and had a lighter skin colour. However, vitiligo is particularly visible in patients with darker skin tones and, as such, is likely to present with an increased impact on quality of life in these patients. Because few patients with darker skin tones were included in the studies, the effect of ruxolitinib in these patients is uncertain. In addition, there is a possibility that the trial population was not representative of patients whose condition interferes substantially with their daily life, considering the lower than expected use of prior therapies despite a long-lasting disease duration, as well as the relatively low level of HRQoL impairment at baseline. Few adolescents were enrolled in the trials, and there are limited data to interpret in this younger age group. The follow-up duration of 24 weeks was considered relatively short, as the disease generally improves over a longer period of time. Although the clinical experts considered the follow-up period sufficient to capture improvements in objective response, treatment with ruxolitinib is likely to continue over the long term, and evidence beyond the studies’ follow-up duration is limited.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and 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 expert committee deliberations, and a final certainty rating was determined by a process outlined by the GRADE Working Group.^27,28

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, 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.

For the GRADE assessments, findings from the TRuE-V1 and TRuE-V2 trials were considered together and summarized narratively per outcome because the populations, interventions, designs, and outcome measures of these studies were similar.

The selection of outcomes for the GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, 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:

• improvements in F-VASI

• patient-reported decrease in noticeability (VNS)

• HRQoL (VitiQoL)

• harms.

Table 2 presents the GRADE summary of findings for ruxolitinib versus vehicle cream.

Table 2: Summary of Findings for Ruxolitinib Versus Vehicle Cream for Patients With Vitiligo

CI = confidence interval; F-VASI = Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; HRQoL = health-related quality of life; LSM = least squares means; MCID = minimal clinically important difference; NA = not applicable; NR = not reported; OR = odds ratio; RCT = randomized controlled trial; SAEs = serious adverse event; SE = standard error; VASI = Vitiligo Area Severity Index; VitiQoL = Vitiligo-Specific Quality of Life; VNS = Vitiligo Noticeability Scale.

Notes: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, 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.

^aVASI: Rated down 1 level for imprecision, due to uncertainty surrounding the outcome measure and MCID. The F-VASI score is not used in clinical practice; the instrument was developed specifically for clinical trial assessment. Validation studies were identified from the literature. While a 75% improvement in F-VASI has been suggested as a threshold for treatment success based on perceptions of patients with vitiligo and dermatologists, no MCID for between-group differences were reported. The presence of an important effect was informed by the clinical experts consulted for this review, but was deemed difficult to assess, as partial repigmentation as measured by the F-VASI score may not necessarily be associated with a meaningful change for patients as long as the disease remains visible.

^bVNS: Rated down 1 level for imprecision, due to uncertainty surrounding the outcome measure and MCID. While the VNS is a validated instrument, for which scores of 4 (a lot less noticeable) or 5 (no longer noticeable) have been used as the MCID, no MCID for between-group differences has been reported. The presence of an important effect was determined by the clinical experts consulted for this review, but was deemed difficult to assess, as a less noticeable condition may not necessarily be associated with a meaningful change for patients as long as the disease remains visible.

^cHRQoL: Rated down 2 levels for imprecision. The VitiQoL was assessed as an exploratory outcome. Statistical testing for the VitiQoL was not adjusted for multiplicity in the trial and should be considered as supportive evidence. In addition, there is currently no MCID established for this instrument in the literature; the absence of an important effect was informed by the clinical experts consulted for this review. The uncertainty surrounding the MCID precluded a definitive judgment on whether the bounds of the CI suggest a meaningful effect on either side of the null.

^dHarms: Rated down 1 level for imprecision, because of the low number of events in the study.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

LTE Studies

TRuE-V1 and TRuE-V2 Trials Open-Label Treatment Extension

Description of Studies

In the pivotal RCTs (TRuE-V1 and TRuE-V2), the double-blind controlled period was followed by a 28-week open-label treatment extension. Patients initially randomized to vehicle cream crossed over to ruxolitinib, while patients initially randomized to ruxolitinib received an additional 28 weeks of treatment with the active drug, as long as they completed the week 24 assessments with no safety concerns. During the treatment-extension period, patients continued to treat depigmented areas identified for treatment at baseline even if the area achieved full repigmentation.

Efficacy Results

The proportions of patients who achieved all the predefined thresholds in the VASI score (i.e., a 25% or more improvement from baseline on the Facial Vitiligo Area Scoring Index [F-VASI25], 50% or more improvement from baseline on the Facial Vitiligo Area Scoring Index [F-VASI50], F-VASI75, F-VASI90, and T-VASI75) were numerically higher in all treatment arms when compared to the corresponding proportions from the double-blind period. However, in the treatment-extension period, no statistical analysis was reported to assess whether the change from week 24 to week 52 was statistically significant, or to assess the magnitude of the between-group difference. Similar results were obtained in the proportions of patients who achieved a VNS of 4 (a lot less noticeable) or 5 (no longer noticeable). According to the clinical experts, results for HRQoL, assessed by the DLQI or CDLQI and the VitiQoL, suggest that observed within-group changes from baseline to week 52 were small and not clinically meaningful.

Harms Results

The proportions of patients who experienced at least 1 AE during the treatment extension ranged from 33.7% to 41.2% across treatment arms in the 2 trials. Few patients experienced SAEs. One patient discontinued due to application site eczema. No deaths were reported during the treatment extension.

Critical Appraisal

Conclusions regarding the efficacy and safety of ruxolitinib in the longer term are noncomparative due to the single-arm nature of the TRuE-V1 and TRuE-V2 trial open-label treatment extensions. The same limitations pertaining to the uncertain clinical impact of the F-VASI score and selected patient population, which were highlighted for the double-blind controlled period of the studies, also apply to the extension period.

TRuE-V LTE Study

Description of Studies

The TRuE-V LTE³¹ is a phase III, double-blind, vehicle-controlled, randomized withdrawal trial designed to assess the long-term efficacy and safety of ruxolitinib cream in patients with vitiligo. It follows the TRuE-V1 and TRuE-V2 studies and includes 2 cohorts: cohort A, which evaluates the duration of response after withdrawing ruxolitinib cream, and cohort B, which assesses the maintenance of response with continued treatment. The LTE study had a duration of 52 weeks, followed by a 30-day safety follow-up.

Cohort A involved a randomized withdrawal design, providing data on the duration of response after discontinuation and the maintenance of response with continued treatment. Participants who achieved complete or near-complete facial repigmentation (greater than or equal to an F-VASI90) at week 52 in either the TRuE-V1 or TRuE-V2 trial were assigned to this cohort. They were randomized in a 1:1 ratio to either continue 1.5% ruxolitinib cream or switch to vehicle cream during the LTE. Participants in cohort A who experienced a disease relapse (defined as less than an F-VASI75) received open-label ruxolitinib cream as rescue treatment until week 104 or the end of the trial. Cohort B included participants who did not achieve a response greater than or equal to an F-VASI90 at week 52 in the parent studies. These participants continued treatment with 1.5% ruxolitinib cream for the entire LTE period. Both clinician groups remained blinded in cohort A until after the primary analysis (week 104), while the treatment in cohort B was open-label.³¹

The primary outcome of the TRuE-V LTE study was the time to relapse in cohort A, defined as a loss of an F-VASI75 response. The key secondary outcome was the time to maintain an F-VASI90. Additional secondary outcomes included the proportion of patients achieving an F-VASI50, F-VASI75, F-VASI90, a VNS score of 4 (a lot less noticeable) or 5 (no longer noticeable), or a T-VASI75, and the time to regain F-VASI90 and F-VASI75 in patients who experienced disease relapse. Exploratory outcomes included changes in DLQI, CDLQI, and VitiQoL from week 52, and time to regain an F-VASI75 and F-VASI90 following a relapse. Safety outcomes were consistent with the TRuE-V1 and TRuE-V2 parent studies.

Statistical analyses were exploratory with no alpha control, and 95% CIs were used. Data from participants with noncompliance or incorrect randomization were excluded. Primary and secondary analyses used the intention to treat (ITT) extension population, and time to event data were analyzed using Kaplan-Meier and Cox models. Relapse incidence, subgroup analyses, and safety outcomes were summarized descriptively.³¹

Efficacy Results

Primary end point: Time to relapse (less than an F-VASI75) — In cohort A, a smaller proportion of patients on ruxolitinib experienced a disease relapse (14.5%) compared to the vehicle cream group (28.6%). The risk of relapse was lower in the ruxolitinib cream group (hazard ratio [HR] = 0.422; 95% CI, 0.180 to 0.990; P = 0.0414).³¹

Key secondary end point: Time to maintain an F-VASI90 — The majority of patients who achieved complete or near-complete repigmentation of the face in cohort A in the parent studies maintained this level of repigmentation with continued application of ruxolitinib cream beyond week 52. Of the cohort of patients who received vehicle cream, 55.4% lost their F-VASI90 response. The median time to loss of an F-VASI90 in the group of patients who received vehicle cream was 195.0 days (95% CI, 113.0 days to 372.0 days). Of the cohort of patients who applied ruxolitinib cream in the double-blind period then continued treatment with ruxolitinib and achieved an F-VASI90 response, 23.6% lost their F-VASI90 response. The median time to loss of an F-VASI90 response in this cohort was not evaluable. The risk of losing an F-VASI90 response was lower for patients who continued to use ruxolitinib cream compared with patients who applied vehicle cream (HR = 0.316; 95% CI, 0.165 to 0.606; P = 0.0003).

Additional secondary and exploratory end points — In cohort B, 86.4%, 66.1%, and 33.9% achieved an F-VASI50, F-VASI75, and F-VASI90, respectively, with ruxolitinib cream at week 104, compared to 69.9%, 47.3%, and 28.0% of those who switched to ruxolitinib, respectively.

In cohort A, the proportions of participants continuing on 1.5% ruxolitinib cream who achieved a T-VASI75 were 42.1% at week 52 and 55.3% at week 104. Among participants using vehicle cream, 38.6% achieved a T-VASI75 at week 52 and 39.1% achieved it at week 104.

In cohort B, for those who continued using 1.5% ruxolitinib cream, at week 52, 12.2% achieved a T-VASI75 and by week 104, 30.5% achieved this threshold. Among participants initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during the TRuE-V LTE study, 3.4% achieved a T-VASI75 at week 52 and 18.3% reached the threshold at week 104.

In cohort A, the proportions of participants receiving blinded treatment who reported a VNS score of 4 (a lot less noticeable) or 5 (no longer noticeable) had their response remain generally stable compared to that of week 52. Among participants receiving 1.5% ruxolitinib cream, 50.0% reported a score of 4 or 5 at week 104, compared to 42.1% at week 52. Among participants receiving vehicle cream, 56.5% reported a score of 4 or 5 at week 104, compared to 49.1% at week 52.

In cohort B, the proportions of participants achieving a VNS score of 4 or 5 for those who continued using 1.5% ruxolitinib cream had their response remain generally stable (43.3% at week 104 versus 35.3% at week 52). The VNS score of 4 or 5 increased from week 52 to week 104 for those initially randomized to the vehicle cream who switched to 1.5% ruxolitinib cream during the TRuE-V LTE study (30.1% at week 104 versus 11.9% at week 52).

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In exploratory end points, the median time to regain an F-VASI75 was 85.0 days for patients who experienced disease relapse and switched to open-label rescue treatment, whereas 62.5% of patients on ruxolitinib regained an F-VASI75 after a median of 205.0 days.³¹

Harms Results

The overall incidences of TEAEs and application site reactions for cohort A were higher among patients who applied ruxolitinib cream (55.2% and 6.9%, respectively) compared with the vehicle cream treatment group (36.2% and 3.4%, respectively). One participant treated with 1.5% ruxolitinib cream in cohort A (1.7%) had a serious TEAE, and no participant had a TEAE with a fatal outcome or a TEAE leading to study drug discontinuation.

The overall incidences of TEAEs and application site reactions in cohort B were 50.9% and 8.5%, respectively, among patients who continued receiving 1.5% ruxolitinib cream compared to 50.0% and 5.1% for participants initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during the LTE study. The incidences of serious TEAEs were 3.1% in patients treated with ruxolitinib cream and 3.4% in those initially treated with vehicle cream. The only TEAE leading to study drug discontinuation in cohort B was ████ ███████ accident (involving 1 participant) that the investigator assessed was unlikely to be related to the study drug.

Critical Appraisal

Internal validity: Cohort A of the TRuE-V LTE trial employed appropriate random allocation using an interactive response technology system. Allocation concealment was ensured, and both patients and investigators remained blinded to treatment assignment until the study’s conclusion. Baseline characteristics between groups were well balanced, supporting the validity of comparisons. The single-arm design of cohort B introduced potential bias in assessing efficacy outcomes, as both participants and investigators were aware of the treatment being administered. This lack of blinding could lead to detection bias. Additionally, the single-arm nature of the study inherently carries a high risk of bias, which may influence the assessment of subjective treatment outcomes. No conclusions can be made on the comparative efficacy and safety.

Participants selected for the TRuE-V LTE trial represented a subsample of the parent trials, consisting of those who completed the parent trials without safety concerns following ruxolitinib use. This selection process may have introduced a risk of selection bias, as it could limit the representativeness of the wider patient population.

The TRuE-V LTE trial had a high dropout rate and, unlike the pivotal trials, imputation methods to address missing data were not employed, increasing the risk of attrition bias. The substantial number of missing participants may have skewed the results and affected interpretation of the findings.

External validity: The TRuE-V LTE trial consisted of patients who took part in the pivotal studies (TRuE-V1 and TRuE-V2), and it is reasonable to expect that the same strengths and limitations regarding generalizability apply to the extension studies. While the studies were conducted in centres in Europe and North America, the patient population of those studies may be reflective of the patient population in Canada and the clinical evidence is generalizable to Canada.

Indirect Comparisons

As the TRuE-V1 and TRuE-V2 trials included a vehicle control group, there is no direct evidence comparing ruxolitinib to the currently used off-label therapies for vitiligo to inform the reimbursement question. In addition, the sponsor submitted no indirect evidence. Although potential studies were identified to perform an indirect treatment comparison, the sponsor rated the feasibility of conducting robust evidence synthesis as low, limiting the feasibility of such a comparison. As a result, the comparative efficacy and safety of ruxolitinib compared with any off-label therapies for the treatment of vitiligo is unknown.

Studies Addressing Gaps in the Evidence From the Systematic Review

No studies addressing gaps were submitted by the sponsor.

Conclusions

In patients with nonsegmental vitiligo, findings of moderate certainty from the TRuE-V1 and TRuE-V2 trials suggest that treatment with ruxolitinib likely results in a clinically important improvement in the F-VASI score compared with vehicle treatment, based on thresholds identified in the literature for a clinically meaningful change in repigmentation. The clinical experts consulted for this review indicated that the VASI score can be relevant to inform on the objective response to treatment by capturing the overall surface area of vitiligo involvement and degree of repigmentation. However, given that vitiligo can range from being barely perceptible to cosmetically distressing, different individuals are likely to have different priorities and objectives when assessing the magnitude of response to treatment. The clinical impact of objective response on patients’ daily lives is therefore uncertain and, as noted by clinician and patient input, should be interpreted together with findings on HRQoL. Based on results from exploratory analyses, patients who applied ruxolitinib in the studies did not experience a clinically meaningful improvement in their HRQoL. This suggests that, despite making the condition less noticeable, treatment with ruxolitinib did not improve the negative impact of the disease on patients’ lives in the overall study population as measured by HRQoL metrics. In patients who received ruxolitinib, analyses of change in HRQoL among patients achieving an F-VASI threshold and those who did not suggest that patients may observe an improvement in their HRQoL with a response of at least an F-VASI75. However, whether the improvement in HRQoL is clinical meaningful is uncertain, and interpretation of these findings is limited by the post hoc nature of the analyses. A relatively large proportion of patients in the TRuE-V1 and TRuE-V2 trials experienced AEs, most notably involving application site reactions and infections, although ruxolitinib appeared to be well tolerated, with few reports of SAEs and withdrawals due to AEs. The overall harms profile did not raise any particular safety signal.

Special consideration should be given to the fact that vitiligo can have a profound effect on patients. Historically, this condition has been perceived negatively, carrying significant cultural implications, with patients and families facing stigma and social isolation. The condition is particularly visible in patients with darker skin tones, for whom it can be associated with a loss of identity and lowered self-esteem, resulting in a marked reduction in quality of life. The patient input noted dissatisfaction with current treatment options, creating a need for more effective, accessible, and tolerable therapies. However, external validity issues in the TRuE-V1 and TRuE-V2 trials preclude making definitive conclusions about the effect of ruxolitinib in individuals with the greatest unmet need. The majority of patients included in the studies were white and had a lighter skin colour, based on the Fitzpatrick Scale skin type classification. In addition, it is likely that the trials included patients whose condition did not interfere substantially with their daily life, given the lower than expected use of prior therapies despite long-lasting disease and relatively low level of HRQoL impairment at baseline.

Evidence is limited beyond the studies’ follow-up duration, even though treatment with ruxolitinib is likely to continue over the long term. However, results from extension studies suggest that the findings are consistent with those from the pivotal evidence over the 2-year follow-up. Because the TRuE-V1 and TRuE-V2 trials included a vehicle control group, there is no direct evidence comparing ruxolitinib to other currently used therapies for vitiligo to inform the reimbursement question. The comparative effectiveness and safety of ruxolitinib relative to other treatment options are therefore unknown.

Introduction

This report reviews and critically appraises the evidence submitted by the sponsor on the beneficial and harmful effects of 1.5% ruxolitinib topical cream for the treatment of nonsegmental vitiligo in adult and pediatric patients aged 12 years and older.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

Vitiligo is a chronic autoimmune disorder characterized by the progressive loss of the pigment-producing cells in the skin known as melanocytes, leading to depigmented patches on various parts of the body.^1-4 These lesions are typically white and nonscaly.⁴ The global prevalence of vitiligo is estimated to range from 0.5% to 2%,^4,5 with the prevalence in Canada estimated at between 0.5% and 1%.⁶

Vitiligo is classified into 3 primary types: nonsegmental vitiligo, which is the most common form, presenting as symmetric patches; segmental vitiligo, which affects 1 side of the body and usually develops earlier; and mixed vitiligo, which displays characteristics of both forms.⁴ Nonsegmental vitiligo can be further categorized into subtypes, including generalized (symmetric patches), acrofacial (affecting the face, hands, and feet), mucosal (affecting the genital and oral mucosa), focal (isolated lesions), and universal (affecting 80% to 90% of the BSA).^4,32 Nonsegmental vitiligo accounts for approximately 80% of vitiligo cases⁵ and can have an unpredictable progression, often beginning before the age of 12 years and peaking around age 30.⁴

The pathogenesis of nonsegmental vitiligo is driven by autoimmune mechanisms that target melanocytes. These cells experience stress due to protein misfolding and increased production of reactive oxygen species,¹ which triggers inflammatory pathways, particularly the Janus kinase (JAK) pathway activated by interferon (IFN)-gamma.⁷ This leads to the release of chemokines CXCL9 and CXCL10, which recruit autoreactive CD8+ T cells to melanocytes, initiating immune-mediated destruction. The accumulation of these T cells correlate with disease severity and is central to vitiligo’s pathogenesis.⁷

Vitiligo lesions, which may progress to complete depigmentation, can have smooth or irregular borders, and may appear red, inflamed, or brown due to hyperpigmentation. Itching is common in some cases.^33,34 Flares are often triggered by stress, with two-thirds of patients reporting flare-ups during such periods, particularly those with more extensive skin involvement, darker skin tones, or facial lesions.^7,9,10 Common lesion sites include the face, hands, and genital areas,⁸ with facial vitiligo significantly affecting patient self-esteem.³⁵ In nonsegmental vitiligo, children often develop facial lesions, while adults tend to have lesions on the arms. Early-onset vitiligo (before the age of 12 years) typically affects the eyelids and lower extremities, while later-onset vitiligo (after the age of 12 years) is more common on the upper extremities.³⁶

Approximately 25% of patients with vitiligo have at least 1 autoimmune comorbidity,¹¹ with thyroid disease being the most common.¹² Other associated autoimmune conditions include atopic dermatitis, psoriasis, alopecia areata,^37,38 and, less frequently, rheumatoid arthritis, inflammatory bowel disease, and lymphoma.³⁹

The psychosocial impact of vitiligo is profound, often leading to depression, anxiety, and social stigma,^13-15 particularly when depigmentation occurs in visible areas.^16,17 Some studies found that individuals with vitiligo experience higher rates of suicidal ideation and attempts compared with the general population.^40-42 Children are particularly vulnerable to bullying and stigmatization,^13,18 while those with darker skin tones^9,14 or from cultures in which stronger stigma are more common face heightened challenges.¹⁹ These issues can lead to social isolation, low self-esteem, and discrimination, particularly in public-facing jobs.^13,18,43

Economically, vitiligo incurs direct costs for treatments such as phototherapy, medication, and psychological support, as well as for over-the-counter medications, clothing, and camouflage.^20,21 Indirect costs, such as absenteeism and decreased productivity, further exacerbate the financial burden on both patients and society.²¹

The diagnosis of vitiligo relies on physical examination, clinical history, laboratory tests, and, in rare cases, biopsies.^4,12,22-24 A Wood’s lamp may be used to detect depigmented areas, and biopsies are performed in atypical cases to rule out other conditions.⁴ Laboratory tests primarily assess thyroid function and test for autoimmune disorders, given the high prevalence of such conditions in patients with vitiligo.²³

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following have been summarized and validated by the review team.

The clinical experts consulted for this review indicated that the choice of treatment for vitiligo is based on the impact that the disease has on a patients’ life. There are no Canadian guidelines for the treatment of vitiligo, and no approved therapeutics in Canada indicated for repigmentation in patients with vitiligo. The current treatment modalities are therefore used off-label.

Nonpharmacological options include conservative camouflage products, including cover-up makeup, skin tanners, and clothing, but the experts consulted for this review noted that these are usually not well accepted by patients. Camouflage only reduces the visibility of the vitiligo and, while targeting the social and quality of life aspects, does not modify disease mechanisms or provide disease improvement.

The mainstays of treatment are topical corticosteroids and calcineurin inhibitors. These address the underlying inflammatory attack on the melanocytes. However, the use of topical corticosteroids may be limited by skin atrophy, especially with chronic use. Other alternative treatments include phototherapy, which may be also combined with topical treatments. Oral therapies, such as corticosteroids, may be used in rare, acute circumstances.

According to the clinical experts, although the off-label treatments currently used are typically well accepted, some patients experience a lack of efficacy, which can include incomplete and/or uneven repigmentation. In addition, approximately one-half of the patients routinely seen in clinical practice become refractory due to disease resistance, while some other patients discontinue treatments due to unacceptable toxicity. The patient input emphasized the lack of satisfaction with current treatment options and the need for more effective, accessible, and tolerable therapies for vitiligo.

Drug Under Review

Key characteristics of 1.5% ruxolitinib cream are summarized in Table 3, along with other treatments available for nonsegmental vitiligo.

Ruxolitinib in the form of 1.5% cream was approved by Health Canada for the topical treatment of nonsegmental vitiligo in adult and pediatric patients aged 12 years and older (Notice of Compliance received on October 11, 2024). The sponsor’s reimbursement request aligns with this indication. This is the first review of ruxolitinib for this indication.

Table 3: Key Characteristics of Ruxolitinib

BSA = body surface area; JAK = Janus kinase.

^aHealth Canada–approved indication.

Source: Ruxolitinib (Opzelura) product monograph.²⁵

The recommended dosage is a thin layer of 1.5% ruxolitinib cream applied twice daily to affected skin areas, covering up to a maximum of 10% of the BSA per application.²⁵ Ten percent of the BSA is roughly 10 times the size of the patient’s hand, including the palm and fingers.^44,45 Satisfactory repigmentation may require more than 24 weeks of treatment. If meaningful repigmentation is not observed by 24 weeks, re-evaluation by a health care provider is recommended.²⁵

Ruxolitinib is a JAK inhibitor that selectively targets the JAK1 and JAK2 isoforms. By inhibiting JAK signalling, it modulates gene expression through the recruitment of signal transducers and activators of transcription to cytokine receptors. In vitiligo, autoimmune cytotoxic T lymphocytes that produce IFN-gamma are thought to destroy melanocytes.⁴⁶ These lymphocytes are recruited to lesional skin via IFN-gamma–dependent chemokines such as CXCL10. Ruxolitinib reduces CXCL10 levels by inhibiting JAK1-dependent and JAK2-dependent signalling.⁴⁶

Although topical corticosteroids and 0.1% tacrolimus are prescribed in Canada for the treatment of vitiligo, these therapies are prescribed off-label, as there are no approved therapeutics in Canada indicated for repigmentation in patients with vitiligo.

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on input provided by patient groups.

Input was submitted by the Canadian Skin Patient Alliance in collaboration with Vitiligo Voices Canada regarding the current review of ruxolitinib for nonsegmental vitiligo. This submission was based on data collected from a patient and caregiver survey conducted between September 26 and October 15, 2024.

The survey received responses from 19 participants across Canada, with the majority from Ontario (36.84%), followed by Alberta (21.05%) and smaller groups from Newfoundland and Labrador and British Columbia (10.53% each), and from Nova Scotia, New Brunswick, Quebec, and Yukon (5.26% each). No survey respondents were from Prince Edward Island, Manitoba, Saskatchewan, Northwest Territories, or Nunavut.

Among the survey respondents who provided demographic details (n = 13), 53% were aged 55 years and older, 23% were aged 25 to 34 years, 15% were aged 35 to 44 years, and 8% were aged 45 to 54 years. In terms of ethnicity, 61.5% identified as white, 15.4% as South Asian, and 1 respondent identified as Southern European, Southeast Asian, and West Asian or Middle Eastern. The group included 10 females and 3 males, with 2 survey respondents serving as caregivers. Among those who reported the duration of their vitiligo (n = 12), 33% had the condition for less than 5 years, 25% for 5 to 10 years, and another 25% for more than 20 years. Disease severity was most commonly rated as moderate (33%) or severe (33%). Common comorbidities included autoimmune diseases (50%) and mental health conditions such as depression or anxiety (30%).

According to the input, vitiligo has significant impacts on individuals and their families. Seventy-five percent of survey respondents reported that it affected their sense of identity, while 42% noted its impact on daily activities and social life. Additionally, 25% experienced a diminished sense of belonging, 33% faced challenges in intimate relationships, and 25% reported issues in family relationships. Young individuals in particular reportedly struggled with bullying and social stigma. The input stated that the unpredictable progression of vitiligo heightens anxiety and helplessness and, in severe cases, suicidal ideation and attempts can occur. Sociocultural beauty standards intensify the emotional strain of the disease, particularly for those with darker skin tones, leading to feelings of alienation and judgment.

Moreover, the input indicated that patients with vitiligo and their caregivers face significant challenges with current treatment options. Emotional exhaustion stemming from inconsistent treatment results was reported by 40% of respondents, adversely affecting family dynamics and heightening the psychological burden on caregivers, often leaving them feeling helpless. While 3 patients who responded had never used any treatment and none had experience with the drug under review, 9 participants reported trying various options, including topical corticosteroids (commonly considered the first-line therapy), vitamin D derivatives, oral steroids, topical immunomodulators, and calcineurin inhibitors. None of these 9 participants found topical corticosteroids effective, with 44.4% stating they “did not work at all” and 22.2% indicating they “did not work very well.” Vitamin D derivatives, oral steroids, immunomodulators, calcineurin inhibitors, tattooing, and various transplant surgeries were similarly deemed ineffective by those who responded. Although some patients reported limited effectiveness from narrowband UV-B phototherapy and depigmentation therapy with monobenzone, responses varied significantly.

Patients also reported various treatment-related side effects, such as skin thinning (n = 1), irritation (n = 2), and burning (n = 1), leading some to discontinue treatment due to adverse reactions, inconvenience, high costs, or access challenges — particularly for rural patients requiring frequent clinic visits. Treatments such as phototherapy posed specific barriers due to the necessity for regular clinic appointments and additional costs, which were particularly burdensome for those in remote areas. This cycle of ineffective treatments has left many patients feeling exhausted and disillusioned; 10 out of 12 patients expressed interest in new treatments, while only 1 out of 11 patients reported satisfaction with current options, underscoring the need for more effective, accessible, and tolerable therapies.

Survey respondents articulated distinct goals for the new treatments. The majority (83%) prioritized efficacy, seeking reliable repigmentation that reduces patchiness and delivers lasting, comprehensive results. They also hoped for treatments with fewer side effects (75%), increased affordability (67%), and greater accessibility, ideally through at-home or simpler solutions. Preferences included ease of use (50%), flexibility for daily life (33%), and consistent results across diverse skin tones to minimize psychological burdens.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise in 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 development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of vitiligo.

Unmet Needs

Vitiligo can range from being barely perceptible to cosmetically distressing. Experience from clinical practice suggests that patients will have different perceptions of their condition. The clinical management of vitiligo is therefore based on assessing its impact on the daily life of each individual patient.

There are currently no Health Canada–approved therapies for nonsegmental vitiligo. According to the clinical experts consulted for this review, although the off-label treatments currently used are typically well accepted, approximately one-half of the patients routinely seen in clinical practice become refractory due to disease resistance while some other patients discontinue treatments due to unacceptable toxicity. In addition, response varies by anatomic site. For example, while the cheeks and neck are typically more responsive to therapies, lip-tip, periocular, and perioral regions tend to be resistant, making repigmentation more difficult to achieve when these areas are affected. The disease site and degree of repigmentation matter, as areas affected by vitiligo in visible sites will be more difficult to hide and therefore have a greater impact on the patient. Partial repigmentation is not necessarily associated with improvement in HRQoL, which can be affected as long as the disease is visible.

The clinical experts emphasized that there is a need for effective and well-tolerated therapies for the treatment of vitiligo.

Place in Therapy

The choice of treatment for vitiligo is based on the impact of the disease on a patient’s life. Conservative camouflage options, including cover-up makeup, skin tanners, and clothing, can be a first step, but the clinical experts noted that such measures are usually not well accepted by patients. Camouflage only reduces the visibility of the vitiligo and, while targeting the social and quality of life aspects, does not modify disease mechanisms or provide any sort of disease improvement.

The mainstays of treatment are topical corticosteroids and calcineurin inhibitors, which address the underlying inflammatory attack on melanocytes. However, the use of topical corticosteroids may be limited by skin atrophy, particularly with chronic use. Other alternative treatments include phototherapy, which may be also combined with topical treatments. The use of oral therapies such as corticosteroids is considered rare. Assessing the presence or absence of other concomitant autoimmune diseases, and ensuring knowledge of sun protection, are also important parts of the clinical evaluation.

Topical ruxolitinib would constitute a new class of medication for the treatment of nonsegmental vitiligo. Its overarching anti-inflammatory mechanism of action would be similar to that of topical corticosteroids and calcineurin inhibitors; however, its individual immunosuppressant action through the JAK-inhibition pathway would be unique. As none of the other current therapies are approved by Health Canada, the clinical experts indicated that topical ruxolitinib may be a first-line therapy for nonsegmental vitiligo or reserved as a second-line option for patients refractory or intolerant to current mainstay treatments. The experts did not expect that ruxolitinib would cause a shift in the current treatment paradigm. They noted that the absence of comparative evidence against the drugs currently used in clinical practice was considered a substantial limitation. The experts also highlighted that the place in therapy for ruxolitinib would depend on its potential to provide clinically meaningful improvements for patients, as certain highly visible disease sites pose greater treatment challenges, to the point that HRQoL may not be deemed superior if repigmentation is only partial. Finally, it is unknown whether ruxolitinib can be safely combined with phototherapy without increasing the risk of skin cancer.

Patient Population

Patients whose characteristics are similar to those of patients included in the pivotal clinical studies would be best suited for treatment with ruxolitinib.

Although the impacts of the disease vary from patient to patient, the clinical experts indicated that those with darker skin tones are likely to experience a greater impact on quality of life because of the increased visibility of vitiligo. However, such patients constituted only a small proportion of the studies’ populations.

Assessing the Response Treatment

Treatment of vitiligo is targeted at improving the current and future impact on quality of life, as the effect of visible dermatoses can be profound. The goals of therapy include repigmentation and stopping disease progression to ultimately reduce the psychosocial impacts on quality of life.

The key outcomes in the clinical trials assessed repigmentation and disease progression; however, HRQoL was assessed both as a secondary and as an exploratory outcome. The instruments used were scores developed specifically for clinical trials of vitiligo treatments, and according to the clinical experts, are not used in clinical practice. In their experience, the most important parameter to assess efficacy would be HRQoL, as partial repigmentation may not be meaningful for all patients and the disease has a greater impact in certain sites, which is not captured by the VASI score.

The experts indicated that response to treatment should be assessed after 24 weeks, although some level of improvement may continue to be observed over time. An F-VASI75 was identified as a reasonable threshold for objective response to treatment, although the F-VASI does not inform on the level of improvement in HRQoL.

Discontinuing Treatment

In the absence of unacceptable toxicity, the clinical experts expected that patients and providers would discontinue ruxolitinib if there were a lack of efficacy or disease progression, which would be assessed after a minimum of 24 weeks, or once the skin is fully repigmented. However, the experts noted that the clinical trials showed some evidence of improvement in repigmentation up to 52 weeks. They advised that ruxolitinib should continue to be reimbursed if disease recurs after treatment is discontinued because of full skin repigmentation.

Prescribing Considerations

The clinical experts noted that referring patients to a specialist, such as a dermatologist, would be preferable. Although the diagnosis is generally straightforward, experience in managing vitiligo is considered important. The experts noted that patients referred to them sometimes have other hypopigmented conditions, such as postinflammatory hypopigmentation, pityriasis alba, pityriasis versicolour, nevoid hypopigmented or depigmented conditions, idiopathic hypomelanosis, or trauma-induced depigmentation. The experts indicated that it would be appropriate to consider restrictions on the amount of medication used by patients so that the treatment area does not exceed 10% of the BSA.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Two clinician groups, comprising 12 clinicians, provided input for this review: the Canadian Dermatology Association in collaboration with the Dermatologist Association of Ontario and Dermatology Association of Saskatchewan (with 8 clinicians contributing to the input), and the Southwestern Ontario Dermatologists Group (with 4 contributing clinicians). Input from the Canadian Dermatology Association drew on clinical experience, research expertise, medical literature, and insights from national and international meetings. In contrast, input from the Southwestern Ontario Dermatologists Group was based on a review of articles focused on vitiligo and its treatments.

The clinician groups stated that, aside from the recently approved ruxolitinib, no effective treatments for vitiligo are available in Canada. The dermatologists from Southwestern Ontario reported that most current treatment modalities are used off-label. These include topical corticosteroids, calcineurin inhibitors, and prostaglandin analogues that modulate immunity and promote melanocyte proliferation, while narrowband UV-B phototherapy is the primary option for extensive cases. Laser treatments are effective but limited in accessibility. Systemic drugs such as corticosteroids and immunosuppressants are used to stabilize progression when topical treatments fail, and surgical grafting is reserved for those whose condition remains stable.

While the Canadian Dermatology Association noted the absence of formal guidelines for vitiligo, both clinician groups agreed that core treatment goals include visible repigmentation and halting disease progression, although achieving high levels of repigmentation can be challenging. The Canadian Dermatology Association focused on the need for maintenance therapy to prevent recurrence after successful treatment, while the dermatologists from Southwestern Ontario emphasized the importance of reducing intrinsic stress on melanocytes.

Both clinician groups acknowledged that vitiligo is among the most challenging conditions to treat, with off-label therapies showing limited effectiveness and tolerability. Current options, such as topical corticosteroids, cannot be used over the long term due to side effects, and some treatments are not covered by public health plans, reducing both adherence and outcomes. The Canadian Dermatology Association also noted that no existing treatments reverse the disease, with around 40% of patients experiencing recurrence. One Southern Ontario dermatologist added that patients with vitiligo often face delayed diagnoses and misdiagnoses and tend to believe that health care providers underestimate the severity of their condition, leading to frustration and low compliance. Both groups emphasized the urgent need for new, safe, accessible, and effective long-term therapies to address these unmet needs.

Both clinician groups described 1.5% ruxolitinib cream, which is a targeted monotherapy option for patients aged 12 years and older, as a transformative first-line therapy for vitiligo. It directly addresses the disease’s underlying mechanisms by inhibiting CD8+ T-cell activity and the IFN-gamma pathway, while also improving repigmentation by inhibiting the JAK-STAT protein pathway. With a favourable safety profile, it allows for prolonged maintenance use. The Canadian Dermatology Association noted the potential of ruxolitinib to be combined with narrowband UV-B phototherapy or antioxidants for enhanced effects against IFN-gamma and reactive oxygen species. The Southwestern Ontario Dermatologists Group stated that ruxolitinib cream is best suited for patients with mild to moderate vitiligo, particularly those with visible lesions on areas that significantly affect daily life, such as the face, hands, and genitals. However, patients with rapidly spreading vitiligo affecting more than 50% of their BSA may initially require systemic immunosuppressants and are not ideal candidates for this treatment.

Both clinician groups agreed that treatment response for vitiligo is assessed based on how well it results in repigmentation and halts disease progression. The Southwestern Ontario Dermatologists Group noted that the VASI is a suitable end point in clinical trials, with a clinically meaningful response defined as a 50% improvement in both F-VASI and T-VASI scores after 1 year. The Canadian Dermatology Association panel, while agreeing that a F-VASI75 at 24 weeks is an appropriate end point for a clinical trial, emphasized that it should not be used as a strict cut-off in practice, as it may overlook meaningful improvements, particularly for patients with visible lesions. They suggested reassessing treatment response at 52 weeks or longer. Additionally, the Southwestern Ontario Dermatologists Group considered the Investigator’s Global Assessment and patient-reported outcomes, such as the VNS and global impression scales, to be the most effective measures of treatment outcomes for vitiligo.

Regarding treatment discontinuation, input from the Canadian Dermatology Association indicated that some experts suggest discontinuing treatment after 6 months with no repigmentation, while others recommend extending this period to 18 months. The Southwestern Ontario Dermatologists Group stressed that, after 1 year, an inadequate response based on patient-reported outcomes and physician assessments, along with factors such as disease progression and AEs should be considered for discontinuation. Both clinician groups agreed that, while vitiligo can be diagnosed by any physician and treated in various settings, dermatologists are ideally suited for diagnosis, treatment selection, and monitoring to ensure optimal long-term outcomes.

Drug Program Input

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

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

BSA = body surface area; F-VASI = Facial Vitiligo Area Scoring Index; MACE = major adverse cardiovascular event; T-VASI = Total Vitiligo Area Scoring Index.

Clinical Evidence

The objective of this Clinical Review report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of 1.5% ruxolitinib topical cream for the treatment of nonsegmental vitiligo in adult and pediatric patients aged 12 years and older. The focus will be placed on comparing ruxolitinib to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of ruxolitinib is presented in 2 sections, with CDA-AMC’s 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. Our 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. No indirect evidence or additional studies addressing important gaps in the systematic review evidence were submitted.

Included Studies

Clinical evidence from the following are included in the review and appraised in this document:

• 2 pivotal RCTs identified in the systematic review

• 1 open label treatment-extension period from the 2 pivotal RCTs

• 1 long-term extension study.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

Description of Studies

Two studies were identified and included in the systematic review. The TRuE-V1 study (n = 330) and the TRuE-V2 study (n = 344) were phase III, multicentre, double-blind, vehicle-controlled RCTs designed to evaluate the efficacy and safety of 1.5% ruxolitinib topical cream, applied twice daily to depigmented areas to treat nonsegmental vitiligo in adult and pediatric patients aged 12 years and older. The 2 studies had identical designs. The primary outcome was the proportion of patients achieving an F-VASI75 at week 24.

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

AE = adverse event; DB = double-blind; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; F-PaGIC-V = Facial-Patient’s Global Impression of Change-Vitiligo; F-PhGVA = Facial-Physician Global Vitiligo Assessment; F-VASI = Facial Vitiligo Area Scoring Index; F-VASI25 = 25% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI50 = 50% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; HADS = Hospital Anxiety and Depression Scale; RCT = randomized controlled trial; TE = treatment-extension; T-PaGIC-V = Total-Patient’s Global Impression of Change-Vitiligo; T-PhGVA = Total-Physician Global Vitiligo Assessment; TSQM = Treatment Satisfaction Questionnaire for Medication; T-VASI = Total Vitiligo Area Scoring Index; T-VASI25 = 25% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI50 = 50% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI75 = 75% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI90 = 90% or more improvement from baseline on the Total Vitiligo Area Scoring Index; VitiQoL = Vitiligo-Specific Quality of Life Instrument; VNS = Vitiligo Noticeability Scale; WHO-5 = World Health Organization–Five Well-Being Index.

Source: Incyte Corporation (2021),^29,30 ClinicalTrials.gov (2022).^50,51 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

The study design for the TRuE-V1 and TRuE-V2 trials is illustrated in Figure 1. Eligible patients were randomized in a 2:1 ratio to receive either ruxolitinib or a vehicle cream over the 24-week controlled treatment period. Randomization was performed using interactive response technology and stratified by baseline skin type (Fitzpatrick Scale skin type I and type II versus type III to type VI) and by region (North America or Europe). The double-blind controlled period was followed by a 28-week open-label treatment extension, in which patients who had been randomized to the vehicle cream crossed over to ruxolitinib. Results from the treatment-extension period (i.e., at 52 weeks) are presented in the LTE Studies section of this report.

Figure 1: TRuE-V1 and TRuE-V2 Study Design

BID = twice a day; BSA = body surface area; EOT1 = first end of treatment; EOT2 = second end of treatment; EOS = end of safety; F-VASI = Facial Vitiligo Area Scoring Index; Rux = ruxolitinib; T-VASI = Total Vitiligo Area Scoring Index.

Source: TRuE-V1 and TRuE-V2 Clinical Study ReportsCSRs.^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Populations

Inclusion and Exclusion Criteria

Patients aged 12 years and older were eligible for the trial if they had nonsegmental vitiligo with depigmented areas covering at least 0.5% of the BSA on the face (F-VASI score of ≥ 0.5) and at least 3% of the BSA on nonfacial areas (T-VASI score of ≥ 3). The maximum total body vitiligo area allowed was 10% of the BSA, including both facial and nonfacial areas.

Patients were excluded from the trial if they had segmental vitiligo, complete leukotrichia within any lesions on the face, or a dermatologic disease confounding vitiligo assessment. Other key exclusion criteria included previous use of JAK inhibitors, as well as recent use of any biological or experimental therapy, phototherapy, immunomodulating treatments, or topical treatments.

Interventions

Patients received either 1.5% ruxolitinib topical cream or a matching administration-vehicle cream that did not contain the active drug. Both were applied as a thin film twice daily to the depigmented vitiligo areas identified for treatment at baseline and were continued even if the areas began to improve. Further vitiligo areas could be treated if they were created through an expansion of existing areas and as long as the total BSA affected did not exceed 10%.

No rescue therapy was allowed. Patients needed to discontinue all drugs used for the treatment of vitiligo from screening through the final safety follow-up visit. Over-the-counter preparations deemed acceptable by the investigator, as well as camouflage makeups, were permitted.

Outcomes

A list of efficacy end points assessed in this Clinical Review 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 by the clinical experts consulted for this review and input from patient and clinician groups and public drug plans. Using the same considerations, end points were selected that were considered to be most relevant to inform expert committee deliberations and end points were finalized 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 expert committee deliberations were also assessed using GRADE.

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

AE = adverse event; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; DLQI = Dermatology Life Quality Index; F-VASI25 = 25% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI50 = 50% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; SAE = serious adverse event; TSQM = Treatment Satisfaction Questionnaire for Medication; T-VASI50 = 50% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI75 = 75% or more improvement from baseline on the Total Vitiligo Area Scoring Index; VitiQoL = Vitiligo-Specific Quality of Life; VNS = Vitiligo Noticeability Scale.

^aOutcomes included in the Grading of Recommendations Assessment, Development and Evaluation assessment.

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

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Vitiligo Area Scoring Index

A VASI score may be determined for facial vitiligo (F-VASI) or total body vitiligo (T-VASI).

Facial Vitiligo Area Scoring

The primary outcome in the TRuE-V1 and TRuE-V2 studies was the proportion of patients achieving an F-VASI75 at week 24. The F-VASI is measured by the percentage of vitiligo involvement on the face, as a proportion of the BSA, and the degree of depigmentation.

The percentage of the BSA involved is assessed using the palmar method, in which the hand unit is based on the patient’s hand size. As such, a handprint represents 1% of BSA, while a thumbprint corresponds to 0.1% of BSA. For each site on the face with vitiligo involvement, the degree of depigmentation is then estimated; complete depigmentation results in a score of 100%, while the absence of any depigmentation yields a score of 0%. The percentage of BSA is multiplied by the degree of depigmentation and the products are summed together for each affected site on the face to produce a score from 0 to 3, with higher scores indicating higher involvement.

Total Vitiligo Area Scoring Index

The T-VASI includes contributions from all body regions, divided into 6 separate sites: head and neck, hands, upper extremities, trunk, lower extremities, and feet. For each body region, the percentage of BSA affected is determined and multiplied by the degree of depigmentation in the same way that was outlined for the F-VASI. The scores obtained for each of the 6 body regions are summed to produce a score between 0 and 100, with higher scores indicating higher involvement.

The VASI score was developed for clinical trial assessments. The clinical experts indicated that the VASI score is not used in clinical practice. The sponsor reported that the VASI score is a validated, sensitive, and quantitative approach for assessing the extent of depigmentation. Part of the validation analyses were performed using studies from the ruxolitinib drug development program, and additional validation studies were identified from the literature. A 75% improvement in F-VASI has been suggested as a threshold for treatment success based on perceptions of patients with vitiligo and dermatologists.⁵² In addition, evidence in the literature from a mixed-method study suggests that an F-VASI75 and T-VASI50 would likely result in a clinically meaningful change in repigmentation for patients with nonsegmental vitiligo.²⁶ However, there are no known MCID values for between-group differences.

Vitiligo Noticeability Scale

The VNS, which measures patient-rated vitiligo noticeability on a 5-point scale, is a validated outcome designed to assess changes in the visibility of vitiligo lesions over time from a patient’s perspective.⁵³ Patients compare their current skin appearance to its state before treatment and rate it on a scale where 1 indicates “more noticeable,” 2 “as noticeable,” 3 “slightly less noticeable,” 4 “a lot less noticeable,” and 5 “no longer noticeable.” A successful treatment outcome is typically reflected by a score of 4 or 5, signalling significant improvement in noticeability.⁵³

Dermatology Life Quality Index and Children’s Dermatology Life Quality Index

The DLQI is a nonspecific, 10-item questionnaire that measures how much the skin condition has affected the patient over the previous 7 days. The instrument covers domains such as symptoms, daily activities, relationships, work or school, and emotional well-being. Each item is scored on a 4-point Likert scale (0 = not at all, 1 = a lot, 2 = a little, 3 = very much). The maximum total DLQI score is 30. Higher scores denote a greater negative impact on quality of life.

The DLQI has evidence to support its validity and reliability, but not responsiveness, in patients with vitiligo. Based on a review of the literature, no MCID has been established for this instrument in patients with vitiligo. However, in patients with various inflammatory skin conditions, the use of an anchor-based approach suggests that a within-group change of at least 4 points from baseline in the DLQI may be consistent with clinically meaningful improvements for patients.⁵⁴

The CDLQI is similar to the DLQI but designed for children. It was used in the TRuE-V1 and TRuE-V2 trials to assess HRQoL in patients aged at least 12 years but younger than 16 years.

Vitiligo-Specific Quality of Life

The VitiQoL is a 15-item, specialized, patient-reported HRQoL assessment tool requiring patients to rate various aspects of their condition using a 7-point scale, ranging from 0 (“Not at all”) to 6 (“All of the time”). Questions relate to participation limitation, stigma, and behaviour. The total score can range from 0 to 90, with higher scores indicative of a greater negative impact on quality of life.⁵⁵ The VitiQoL has evidence to support the validity and reliability, but not responsiveness, in patients with vitiligo. According to the literature, no MCID has been established for this instrument in patients with vitiligo.

Harms

The safety analysis included AEs, SAEs, and AEs leading to study discontinuation.

Table 7: Summary of Outcome Measures and Their Measurement Properties

BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DLQI = Dermatology Life Quality Index; F-VASI = Facial Vitiligo Area Scoring Index; HRQoL = health-related quality of life; ICC = intraclass correlation coefficient; MCID = minimal clinically important difference; NSV = nonsegmental vitiligo; PaGIC-V = Patient’s Global Impression of Change-Vitiligo; PhGVA = Physician Global Vitiligo Assessment; T-VASI = Total Vitiligo Area Scoring Index; VASI = Vitiligo Area Scoring Index; VitiQoL = Vitiligo-Specific Quality of Life; VNS = Vitiligo Noticeability Scale; vs. = versus.

Statistical Analysis

A summary of the statistical analyses is presented in Table 8.

End Point Analyses in the Studies and Handling of Missing Data

The primary analysis was based on the ITT population. Exact logistic regression was used to test the primary hypothesis for superiority of ruxolitinib compared with vehicle treatment on the percentage of patients achieving an F-VASI75 at 24 weeks. This model included the treatment group and stratification factors (geographic region and skin type). The unadjusted P value between ruxolitinib versus vehicle cream was compared at a 2-sided alpha of 0.05. The odds ratio and 95% CI in response rates (ruxolitinib versus vehicle cream) at week 24 were also computed. Rescue therapy was not allowed in the studies; as such, patients who received rescue therapy were considered to have a protocol violation and were imputed as a patient who did not respond to treatment. All patients who were missing the F-VASI assessment at a given visit in the double-blind period were handled using multiple imputation under a missing at random assumption. Missing scores were imputed by fully conditional specification. The multiple imputation method used treatment and observed stratification factors as predicators.

For the primary end point, 3 sensitivity and supportive analyses were laid out in the statistical analysis plan: the nonresponder imputation, which was used as an alternative method to handle missing data; the last observation carried forward, which was used for patients who were missing postbaseline values and where the last observed nonmissing postbaseline value was used to fill in missing values at week 24; and a tipping point analysis, which was conducted to examine the potential effects of missing data. In the latter analysis, the missing F-VASI75 response at week 24 in each treatment group was replaced by a range of values from the most conservative to the most aggressive case. The most conservative case was that all missing patients who applied ruxolitinib were patients who did not respond to treatment and all missing patients who applied the vehicle cream were patients who did respond to treatment, while the opposite was true for the most aggressive case. For each scenario, between-treatment comparisons were performed using a Fisher exact test.

Key secondary efficacy end points (e.g., F-VASI50, F-VASI90, and VNS response) were analyzed using methods similar to those outlined for primary efficacy end points. For other secondary efficacy analyses, summary statistics were presented. Continuous outcomes were planned to be analyzed using a mixed-effect model with repeated measurements, if applicable. Categorical outcomes were planned to be analyzed using exact logistic regression models similar to those specified in the primary and key secondary analyses, if applicable.^29,30

Sample Size and Power Calculation

For the TRuE-V1 and TRuE-V2 trials, a sample size of approximately 300 patients randomized in a 2:1 ratio to ruxolitinib or vehicle cream and stratified by baseline skin type and region was determined to provide sufficient statistical power (> 85%) to detect a difference between ruxolitinib and vehicle cream in primary and key secondary end points. A Fisher exact test with a 2-sided alpha of 0.05 was used to provide a conservative evaluation of statistical power and was accurate when the expected number of patients who did respond to treatment in the vehicle group was small.

Statistical Testing and Multiplicity

Data from the 2 treatment groups were compared using exact logistic regression for binary end points, presented with relative risk, and were compared with the use of an analysis of covariance model for facial BSA affected by vitiligo.

A gatekeeping testing strategy for the primary and key secondary analyses was implemented to control the overall type I error rate. These end points were tested in a fixed sequence at a 2-sided alpha of 0.05 in the following order:

1. Proportion of patients achieving F-VASI75 at week 24.

2. Proportion of patients achieving F-VASI50 at week 24.

3. Proportion of patients achieving F-VASI90 at week 24.

4. Proportion of patients achieving T-VASI50 at week 24.

5. VNS response at week 24.

6. Percent change from baseline in facial BSA at week 24.

Each end point was tested only if the null hypothesis for the primary end point and the secondary end points in previous steps was rejected. All additional secondary and exploratory end points were reported as observed without adjustments for multiplicity and analyses were summarized with the use of descriptive statistics.

Subgroup Analyses

Subgroup analyses were performed for the primary end point based on the following patient characteristics and baseline variables:

• skin type (Fitzpatrick Scale skin types I and II versus types III, IV, V, and VI)

• age category I (12 to 17 years, ≥ 18 to 64 years, and ≥ 65 years)

• age category II (≤ 40 years and > 40 years)

• region (North America and Europe)

• sex

• race (Asian, Black or African American, white, not reported, and other)

• facial BSA (< 1.5% and ≥ 1.5%).

Subgroup efficacy analyses were prespecified; however, the statistical tests that were performed to evaluate differences in effects between subgroups were not reported. Whether the comparability of the treatment arms was checked, and whether multiplicity was taken into account, was not reported for either trial.

Changes in Statistical Methods and Planned Analyses After Unblinding or Database Lock

The data from patients at TRuE-V2 study site 710 (N = 13) were removed from all efficacy analyses performed on the ITT population because of noncompliance with the study protocol resulting in serious concerns with the data quality. However, data from these patients were included in all safety analyses because all patients applied the study drug at least once.

Table 8: Statistical Analysis of Efficacy End Points in the TRuE-V1 and TRuE-V2 Trials

ANCOVA = analysis of covariance; BSA = body surface area; CI = confidence interval; CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DLQI = Dermatology Life Quality Index; F-VASI = Facial Vitiligo Area Scoring Index; F-VASI25 = 25% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI50 = 50% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; NA = not applicable; NR = not reported; TEAE = treatment-emergent adverse event; T-VASI = Total Body Vitiligo Area Scoring Index; T-VASI25 = 25% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI50 = 50% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI90 = 90% or more improvement from baseline on the Total Vitiligo Area Scoring Index; VitiQoL = Vitiligo-Specific Quality of Life; VNS = Vitiligo Noticeability Scale.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Analysis Populations

Table 9: Analysis Populations of the TRuE-V1 and TRuE-V2 Trials

^aThe primary analysis population for demographics, baseline characteristics, and efficacy analyses was changed from the full analysis set to the intention-to-treat population after unblinding and the database lock based on feedback from the FDA.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Results

Patient Disposition

Of the 452 patients screened for the TRuE-V1 trial, 122 (27.0%) did not meet the eligibility criteria while 330 (73.0%) were randomized in the study. In the TRuE-V2 trial, 138 (28.6%) of the 482 patients screened did not meet the eligibility criteria and 344 (71.4%) were initially randomized. However, 13 patients from 1 study site, including 7 patients (3.2%) who applied ruxolitinib and 6 patients (5.5%) who applied vehicle cream, were excluded from the efficacy analyses due to serious protocol violations. No further details were reported. As a result, the randomized efficacy population consisted of 331 patients.

Numerically more patients who did not receive active treatment discontinued the TRuE-V1 study (12.7% with ruxolitinib and 17.4% with vehicle cream), and these proportions were similar in the TRuE-V2 trial (13.1% with ruxolitinib and 13.8% with vehicle cream). The most frequent reasons for discontinuation were withdrawal by patient, which was numerically higher in patients who applied vehicle cream in both studies, as well as those lost to follow-up. Details are supplied in Table 10.

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

Source: Incyte Corporation (2021).^29,30

Baseline Characteristics

The baseline characteristics that are most relevant to this review or that may affect the interpretation of the study results are outlined in Table 11.

The mean age of patients was 40.2 years (standard deviation [SD] = 15.85 years) in the TRuE-V1 trial and 38.7 years (SD = 14.46 years) in the TRuE-V2 trial, with patients ranging in age from 12 to 79 years. A total of 36 patients were aged younger than 18 years in the TRuE-V1 trial (25 patients who applied ruxolitinib and 11 patients who applied vehicle cream) as well as in the TRuE-V2 trial (30 patients who applied ruxolitinib and 6 patients who applied vehicle cream). The majority of patients included in the studies were white, had a Fitzpatrick Scale skin type of II, III, or IV, and had a facial BSA involvement of less than 1.5%. The median times since diagnosis were 11.1 years in the TRuE-V1 trial and 13.0 years in the TRuE-V2 trial, with 58% of patients in the TRuE-V1 trial and 65% of patients in the TRuE-V2 trial having received prior therapy for vitiligo.

Overall, baseline characteristics appeared to be balanced between treatment groups in the TRuE-V1 and TRuE-V2 trials. Although there was a slight numerical difference in the proportions of male and female patients in the TRuE-V1 trial, the clinical experts did not expect this to affect the course of the disease and/or response to treatment. However, according to experts, the impact of a visible skin condition such as vitiligo on quality of life may vary according to several different factors, including sex. The clinical experts indicated that patients included in the trials likely constituted a selected sample of the patient population seen in clinical practice, particularly as the proportions of patients with darker skin tones were small. Although vitiligo affects all races and types of skin tones, the experts noted that patients with darker skin tones are likely to present with an increased impact on quality of life, which can be attributed to the increased visibility of the condition.

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

BSA = body surface area; F-VASI = Facial Vitiligo Area Scoring Index; ITT = intention to treat; SD = standard deviation; T-VASI = Total Vitiligo Area Scoring Index.

^aFitzpatrick Scale: Type I: always burns, never tans (pale peach; blond or red hair; blue eyes; freckles); type II: usually burns, tans minimally (peach; fair; blond or red hair; blue, green, or hazel eyes); type III: sometimes mild burn, tans uniformly (light brown; fair with any hair or eye colour); type IV: burns minimally, always tans well (moderate brown); type V: very rarely burns, tans very easily (dark brown); type VI: never burns, always tans (deeply pigmented dark brown to darkest brown).

^bCategories are as reported in study.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Exposure to Study Treatments

Exposure to study treatment is outlined in Table 12. The median exposure duration during the double-blind treatment period was 168 days in both studies, which was consistent with the planned duration of 24 weeks (168 days). Patient exposure suggests notable variation among patients in the amount of the study drug applied, which appeared to be inconsistent with the usage of topical treatments in clinical practice according to the clinical experts. The experts consulted for this review indicated that it is uncertain if drug usage observed in the trials would be mirrored in real-world practice, but that it is likely that drug usage will be higher in the real-world setting. No additional detail was provided by the sponsor to explain the high level of variability observed.

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

██ █ █████████████ ███ █ ████████ ███ █ ████████ ██ █ ████████ ███████████

ITT = intention to treat.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Prior Medications

The most frequently used prior medications for vitiligo in the TRuE-V1 trial were tacrolimus (█████), pimecrolimus (████), triamcinolone (████), clobetasol (████), hydrocortisone (████), and mometasone furoate (████). Similarly, in the TRuE-V2 trial, these were tacrolimus (█████), pimecrolimus (████), hydrocortisone (████), and clobetasol (████). In both trials, the most common reason for discontinuing prior vitiligo treatment was lack of efficacy (█████ ███ █████, respectively).

Concomitant Medications

Most patients received concomitant medications in the studies; the most commonly used are presented in Table 13. Slight numerical differences were evident between treatment arms. However, overall the clinical experts did not expect these differences to have a clinically meaningful impact on the disease course or the treatment response.

Table 13: Summary of Most Commonly Used Concomitant Medications From Studies Included in the Systematic Review (ITT Population) [Redacted]

███ █ ██████████████████████████████ ██ █ ██████ ██████ ███████ ████████████████████████ ███

ITT = intention to treat.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Efficacy

Detailed efficacy results for the double-blind treatment period, at 24 weeks, are presented in Table 14. Results for the open-label treatment-extension period, at 52 weeks, are presented in the LTE Studies section of this report.

Vitiligo Area Scoring Index

Proportions of Patients Achieving F-VASI75

Throughout the TRuE-V1 24-week double-blind treatment period, 60 patients (30.8%) who applied ruxolitinib achieved an F-VASI75, compared with 7 patients (7.8%) who applied vehicle cream. The TRuE-V2 trial yielded consistent results, with 62 patients (31.2%) who applied ruxolitinib achieving an F-VASI75, compared with 11 patients (11.2%) who applied vehicle cream. The between-group differences in the response rate were 22.3% (standard error [SE] = 4.15; 95% CI, 14.2 to 30.5; P < 0.0001) in the TRuE-V1 trial and 19.5% (SE = 4.56; 95% CI, 10.5 to 28.4; P = 0.0004) in the TRuE-V2 trial. The use of an F-VASI75, which was identified in the literature as the threshold for clinically meaningful change in repigmentation,²⁶ was considered relevant by the clinical experts to assess the objective response to treatment.

Sensitivity Analyses

The various sensitivity analyses aligned with the main analysis. In the TRuE-V1 trial, the between-group differences in response rate were 20.7% (SE = 3.80%) for the nonresponder imputation analysis and 21.5% (SE = 4.00%) for the last observation carried forward analysis. In the TRuE-V2 trial, the between-group differences in the response rate were 17.8% (SE = 4.17%) for the nonresponder imputation analysis and 18.0% (SE = 4.41%) for the last observation carried forward analysis.

The tipping point at which significance would have been lost required extreme assumptions in both studies. In the TRuE-V1 trial, 63.2% of patients (12 of 19) with missing data in the vehicle group would need to be patients who did respond to treatment, while the corresponding proportion would need to be no more than 3.8% of patients (1 of 26) in the ruxolitinib group. In the TRuE-V2 trial, 81.8% of patients (9 of 11) with missing data in the vehicle group would need to be patients who did respond to treatment, while the corresponding proportion would need to be no more than 4.3% (1 of 23) in the ruxolitinib group.

Subgroup Analyses

Subgroup analyses identified by the clinical experts relevant in the context of vitiligo included race (Asian; Black or African American) and skin type (Fitzpatrick Scale skin type III, IV, V, and VI). In the TRuE-V1 trial, 5 of 11 patients (45.5%) of Black or African American ethnicity who applied ruxolitinib achieved an F-VASI75, compared with none of the 3 patients (0.0%) who applied the vehicle cream (response rate difference of 45.5%; SE = 15.01%). In patients of Asian ethnicity, 2 of 4 patients (50.0%) who applied ruxolitinib and none of the 2 patients (0.0%) who applied the vehicle cream achieved the outcome (response rate difference of 50.0%; SE = 25.00%). Finally, in patients with Fitzpatrick Scale skin type III, IV, V, and VI skin, the corresponding proportions were 41 of 120 patients (34.2%) who applied ruxolitinib, compared with 3 of 55 patients (5.5%) who applied the vehicle cream (response rate difference of 28.7%; SE = 5.30%).

In the TRuE-V2 trial, 4 of 10 patients (40.0%) of Black or African American ethnicity who applied ruxolitinib achieved an F-VASI75, compared with 1 of 3 patients (33.3%) who applied the vehicle cream (response rate difference of 6.7%; SE = 31.32%). In patients of Asian ethnicity, 3 of 11 patients (27.3%) who applied ruxolitinib and none of the 5 patients (0.0%) who applied the vehicle cream achieved the outcome (response rate difference of 27.3%; SE = 13.43%). Finally, in patients with Fitzpatrick Scale skin type III, IV, V, and VI skin, the corresponding proportion was 45 of 147 patients (30.6%) who applied ruxolitinib, compared with 10 of 70 patients (14.3%) who applied the vehicle cream (response rate difference of 16.3%; SE = 5.65%).

Proportions of Patients Achieving F-VASI90

In the TRuE-V1 trial, 31 patients (15.9%) who applied ruxolitinib achieved an F-VASI90, compared with 2 patients (2.2%) who applied the vehicle cream. The TRuE-V2 trial produced consistent results with 33 patients (16.6%) who applied ruxolitinib achieving an F-VASI90, compared with 1 patient (1.0%) who applied the vehicle cream. The between-group differences in the response rate were 13.2% (SE = 2.89; 95% CI, 7.5 to 18.8; P = 0.0038) in the TRuE-V1 trial and 15.0% (SE = 2.92; 95% CI, 9.3 to 20.7; P = 0.0065) in the TRuE-V2 trial.

Proportions of Patients Achieving F-VASI50

In the TRuE-V1 trial, 102 patients (52.3%) who applied ruxolitinib achieved an F-VASI50, compared with 15 patients (16.7%) who applied the vehicle cream. Results in the TRuE-V2 trial were consistent, with 102 patients (51.3%) who applied ruxolitinib achieving an F-VASI50, compared with 20 patients (20.4%) who applied the vehicle cream. The between-group differences in the response rate were 34.2% (SE = 5.18; 95% CI, 24.1 to 44.4; P < 0.0001) in the TRuE-V1 trial and 30.6% (SE = 5.36; 95% CI, 20.0 to 41.1; P < 0.0001) in the TRuE-V2 trial.

Proportions of Patients Achieving F-VASI25

In the TRuE-V1 trial, 138 patients (70.8%) who applied ruxolitinib achieved an F-VASI25, compared with 25 (27.8%) who applied the vehicle cream. In the TRuE-V2 trial, 125 patients (62.8%) who applied ruxolitinib achieved an F-VASI25, compared with 31 (31.6%) who applied the vehicle cream. The between-group differences in the response rate were 39.8% (SE = 5.74; 95% CI, 28.6 to 51.1; P < 0.0001) in the TRuE-V1 trial and 31.9% (SE = 5.74; 95% CI, 20.7 to 43.2; P < 0.0001) in the TRuE-V2 trial.

Proportions of Patients Achieving T-VASI75

In the TRuE-V1 trial, 9 patients (4.6%) who applied ruxolitinib achieved a T-VASI75, compared with 2 patients (2.2%) who applied the vehicle cream. In the TRuE-V2 trial, 17 patients (8.5%) who applied ruxolitinib achieved a T-VASI75, compared with 2 patients (2.0%) who applied the vehicle cream. The between-group differences in response rate were 2.3% (SE = 1.86; 95% CI, −1.4 to 5.9; P = 0.2921) in the TRuE-V1 trial and 6.1% (SE = 2.25; 95% CI, 1.7 to 10.5; P = 0.0436) in the TRuE-V2 trial.

Proportions of Patients Achieving T-VASI50

In the TRuE-V1 trial, 43 patients (22.1%) who applied ruxolitinib achieved a T-VASI50, compared with 4 patients (4.4%) who applied the vehicle cream. In the TRuE-V2 trial, 49 patients (24.6%) who applied ruxolitinib achieved a T-VASI50, compared with 7 patients (7.1%) who applied the vehicle cream. The between-group differences in the response rate were 15.5% (SE = 3.63; 95% CI, 8.3 to 22.6; P = 0.0020) in the TRuE-V1 trial and 17.1% (SE = 3.87; 95% CI, 9.5 to 24.7; P = 0.0006) in the TRuE-V2 trial.

Facial Body Surface Area

Percent Change From Baseline in Facial BSA

The least squares mean percent changes from baseline through 24 weeks in facial BSA were −28.9% (SE = 2.22%) in patients who applied ruxolitinib and −9.5% (SE = 3.25%) in patients who applied the vehicle cream in the TRuE-V1 trial, for a between-group difference of −19.3% (95% CI, −27.05% to −11.64%; P < 0.0001). Similarly, in the TRuE-V2 trial, the corresponding changes from baseline were −26.4% (SE = 2.57%) in patients who applied ruxolitinib and −7.0% (SE = 3.82%) in patients who applied the vehicle cream, for a between-group difference of −19.5% (95% CI, −28.46% to −10.45%; P < 0.0001).

Vitiligo Noticeability Scale

Proportions of Patients Achieving a VNS of “A Lot Less Noticeable” or “No Longer Noticeable”

In the TRuE-V1 trial, 49 patients (25.1%) who applied ruxolitinib achieved a VNS of 4 (a lot less noticeable) or 5 (no longer noticeable) compared with 3 patients (3.3%) who applied the vehicle cream. The TRuE-V2 trial yielded consistent results, with 41 patients (20.6%) who applied ruxolitinib achieving the outcome, compared with 5 patients (5.1%) who applied the vehicle cream. The between-group differences in response rate were 21.2% (SE = 3.54; 95% CI, 14.3 to 28.1; P = 0.0002) in the TRuE-V1 trial and 15.5% (SE = 3.58; 95% CI, 8.5 to 22.6; P = 0.0013) in the TRuE-V2 trial.

Treatment Satisfaction Questionnaire for Medication

Treatment Satisfaction Questionnaire for Medication Score at Week 24

The least squares mean Treatment Satisfaction Questionnaire for Medication (TSQM) scores at week 24 were 65.68 (SE = 1.62) in patients who applied ruxolitinib and 51.47 (SE = 2.37) in patients who applied the vehicle cream in the TRuE-V1 trial, for a between-group difference of 14.21 (95% CI, 8.6 to 19.9; P < 0.0001). However, in the TRuE-V2 trial, the corresponding TSQM scores were 61.09 (SE = 1.66) in patients who applied ruxolitinib and 48.51 (SE = 2.36) in patients who applied the vehicle cream, for a between-group difference of 12.59 (95% CI, 6.9 to 18.3; P < 0.0001).

Dermatology Life Quality Index and Children’s Dermatology Life Quality Index

Change From Baseline in DLQI (Aged 16 Years)

The mean changes from baseline through 24 weeks in DLQI were −1.15 (SD = 3.796) in patients who applied ruxolitinib and −0.79 (SD = 3.355) in patients who applied the vehicle cream in the TRuE-V1 trial, for a between-group difference of −0.32 (95% CI, −1.26 to 0.62; P = 0.4970). Similarly, in the TRuE-V2 trial, the corresponding changes from baseline were −1.19 (SD = 4.075) in patients who applied ruxolitinib and −0.71 (SD = 3.988) in patients who applied the vehicle cream, for a between-group difference of −0.60 (95% CI, −1.60 to 0.39; P = 0.2350). The maximum total DLQI score was 30, with higher scores denoting a greater negative impact on quality of life. The clinical experts consulted for this review did not consider the magnitude of the between-group difference to be clinically meaningful.

Change From Baseline in CDLQI (Aged Younger Than 16 Years)

The mean changes from baseline through 24 weeks in CDLQI were −0.25 (SD = 2.113) in the 16 patients aged younger than 16 years who applied ruxolitinib and 0.00 (0.00) in the 3 patients in this age group who applied the vehicle cream in the TRuE-V1 trial. In the TRuE-V2 trial, the corresponding changes from baseline were 0.00 (SD = 1.837) in the 17 patients who applied ruxolitinib and −2.33 (SD = 8.505) in the 3 patients who applied the vehicle cream. No between-group difference was reported for this outcome in either study.

Vitiligo-Specific Quality of Life

Change From Baseline in VitiQoL

The mean changes from baseline through 24 weeks in VitiQoL were −6.34 (SD = 17.433) in patients who applied ruxolitinib and −6.37 (SD = 15.988) in patients who applied the vehicle cream in the TRuE-V1 trial, for a between-group difference of −0.28 (95% CI, −4.51 to 3.95; P = 0.8976). In the TRuE-V2 trial, the corresponding changes from baseline were −6.07 (SD = 18.148) in patients who applied ruxolitinib and −2.64 (SD = 14.462) in patients who applied the vehicle cream, for a between-group difference of −3.52 (95% CI, −7.60 to 0.57; P = 0.0915). VitiQoL scores range from 0 to a maximum of score of 90, where higher scores denote a greater negative impact on quality of life. The clinical experts consulted for this review did not consider the magnitude of the between-group difference to be clinically meaningful.

Post Hoc HRQoL Analyses

Findings from post hoc analyses in patients who received ruxolitinib compared the change in VitiQoL and DLQI from baseline to week 24 between patients who achieved various levels of F-VASI and those who did not. Results suggest that patients who achieved at least an F-VASI75 may observe an improvement in their HRQoL; however, whether this improvement is clinically meaningful is uncertain. In addition, interpretation of these findings is limited by the post hoc nature of the analyses. Detailed results are presented in Appendix 1.

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

ANCOVA = analysis of covariance; BSA = body surface area; CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DLQI = Dermatology Life Quality Index; F-VASI = Facial Vitiligo Area Scoring Index; F-VASI25 = 25% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI50 = 50% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; ITT = intention to treat; LSM = least squares mean; NR = not reported; SD = standard deviation; SE = standard error; T-VASI50 = 50% or more improvement from baseline on the Total Vitiligo Area Scoring Index; T-VASI75 = 75% or more improvement from baseline on the Total Vitiligo Area Scoring Index; VASI = Vitiligo Area Scoring Index; VitiQoL = Vitiligo-Specific Quality of Life; VNS = Vitiligo Noticeability Scale.

^aMultiple imputation: missing F-VASI score was imputed by fully conditional specification. Multiple imputation method used treatment and observed stratification factors as predicators.

^bAn exact logistic regression statistical model was used to estimate the difference between groups for all VASI and VNS outcomes reported in the table.

^cStatistical testing at week 24 for these end points was adjusted for multiple comparisons (e.g., hierarchal testing).

^dAn ANCOVA statistical model was used to estimate the difference between groups in change from baseline in facial BSA.

^eStatistical testing for these end points was not controlled for multiple comparisons.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Harms

Data for harms outcomes included in the review are presented in Table 15.

Adverse Events

In the TRuE-V1 trial, 45.7% of patients who applied ruxolitinib and 38.5% of patients who applied vehicle cream experienced at least 1 AE; in the TRuE-V2 trial, the corresponding proportions were 50.0% with ruxolitinib and 33.9% with vehicle cream, respectively. The most common TEAEs across the 2 studies included application site acne and pruritus, headache, and AEs related to infections.

Serious Adverse Events

In the TRuE-V1 trial, 6 patients (2.7%) who applied ruxolitinib and 1 patient (0.9%) who applied vehicle cream experienced SAEs. Serious TEAEs reported with active treatment were anal fistula, appendicitis, concussion, hepatic infectious mononucleosis, kidney contusion, and myocarditis.

In the TRuE-V2 trial, 2 patients (0.9%) who applied ruxolitinib experienced SAEs, that included coronary artery stenosis and ureterolithiasis. No patient who applied vehicle cream experienced an SAE.

Withdrawals Due to AEs

In the TRuE-V1 trial, 1 patient (0.5%) who applied ruxolitinib and 1 patient (0.9%) who applied vehicle cream discontinued due to AEs; the reasons for withdrawal were fatigue, nausea, and headache. In the TRuE-V2 trial, 1 patient (0.4%) who applied ruxolitinib discontinued due to an AE of application site rash. No patient who applied vehicle cream discontinued treatment.

Mortality

No deaths were reported in the studies.

Notable Harms

The sponsor identified application site reactions as a harm of special interest.

In the TRuE-V1 trial, 38 patients (17.2%) who applied ruxolitinib and 7 patients (6.4%) who applied vehicle cream reported an application site reaction. The most frequently reported were acne (5.9% and 0%, respectively), pruritus (5.0% and 3.7%), and rash (2.3% and 0.9%).

In the TRuE-V2 trial, 30 patients (13.2%) who applied ruxolitinib and 7 patients (6.1%) who applied vehicle cream reported an application site reaction. The most frequently reported were acne (5.7% and 2.6%, respectively) and pruritus (5.3% and 1.7%).

Table 15: Summary of Harms Results From Studies Included in the Systematic Review (Safety Population)

AE = adverse event; NR = not reported; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Internal Validity

Study Design

The TRuE-V1 and TRuE-V2 RCTs were designed to evaluate the efficacy and safety of ruxolitinib compared to a vehicle cream over a 24-week controlled treatment period. Patients were allocated to treatment groups using an appropriate methodology (interactive response technology), with randomization stratified by relevant and clinically important potential prognostic factors, particularly baseline skin type. The double-blind controlled period was followed by a 28-week open-label treatment extension, in which all patients received ruxolitinib. This provided uncontrolled and complementary findings regarding the long-term efficacy and safety of the drug.

Patient Population

Most baseline characteristics appeared to be balanced between treatment groups in both studies, except in the proportions of male and female patients in the TRuE-V1 trial, in which some imbalance between treatment groups was observed. The clinical experts consulted for this review indicated that sex is not expected to affect the course of the disease and/or response to treatment. Although the impact of a visible skin condition such as vitiligo on quality of life may vary according to different factors, including sex, the experts agreed that this baseline difference was unlikely to be clinically important enough to bias the results.

There were numerically more discontinuations in patients who applied the vehicle cream in the TRuE-V1 trial, which could introduce bias against ruxolitinib if patients did not respond to treatment; however, most of the discontinuations were due to withdrawal by patient or loss to follow-up. This concern was also mitigated by the use of multiple imputations to account for missing data. Patient disposition was balanced between treatment groups in the TRuE-V2 trial. In this latter study, patients from 1 study site were excluded from the efficacy analyses due to a serious protocol violation, representing 3.2% of patients who applied ruxolitinib and 5.5% of patients who applied the vehicle cream. No further details were reported. Nevertheless, as the discontinuation rate was low and the difference between treatment arms was small, it is not expected that this would affect the findings.

Interventions

As both the TRuE-V1 and TRuE-V2 trials included a vehicle control group, there is no direct evidence comparing ruxolitinib to other currently used therapies for vitiligo. This absence restricts the trials’ ability to assess comparative effectiveness and safety relative to other available treatment options.

No rescue therapy was allowed and patients needed to discontinue all drugs used for the treatment of vitiligo, minimizing the impact of this potential confounding factor. Both ruxolitinib and vehicle cream were to be continued, even if the affected area improved. The clinical experts consulted for this review did not expect the use of the reported concomitant medications to have a clinically meaningful impact on the disease course or on the treatment response.

Outcome Measures

The primary outcome in the TRuE-V1 and TRuE-V2 trials was an F-VASI75. Additional levels of F-VASI and T-VASI thresholds were assessed as secondary end points in the trials. The clinical experts indicated that, while the VASI score was not used in clinical practice, the instrument has been developed specifically for clinical trial assessment. The sponsor reported that the VASI score was validated. Part of the validation analyses was performed using studies from the ruxolitinib drug development program, and validation studies were identified from the literature. As for the MCID, a 75% improvement in the F-VASI has been suggested as a threshold for treatment success based on a mixed-method study and on perceptions of patients with vitiligo and dermatologists; however, no MCID for between-group differences was reported. Patient-reported noticeability was also assessed as a key secondary outcome using the VNS, a validated instrument for which scores of 4 (a lot less noticeable) or 5 (no longer noticeable) have been used as the MCID.

The use of the VASI score was considered relevant by the clinical experts to assess the objective response to treatment, as the VASI score captures the overall surface area of vitiligo involvement and the degree of repigmentation. However, a substantial limitation to the interpretation of the findings is that this instrument does not inform on the level of improvement in HRQoL, which was identified by the clinical experts as the main treatment goal of vitiligo. Experience from clinical practice suggests that partial repigmentation may not necessarily be associated with a meaningful change for patients, and HRQoL may be affected for as long as the disease is visible. For example, the clinical experts noted that improvements seen in responsive areas, such as the cheeks and neck, may be of little importance if other known resistant sites, such as the periocular and perioral areas, cannot be repigmented. Areas affected by vitiligo in these highly visible sites will be more difficult to hide and therefore be more consequential for the patient, particularly when compared to other areas on the body.

However, the studies were not designed to test primarily for differences in HRQoL. This outcome was measured using the DLQI and CDLQI as well as the VitiQoL and was assessed as an exploratory outcome. Evidence is available supporting the validity and reliability but not the responsiveness, of the DLQI and CDLQI as well as the VitiQoL in patients with vitiligo. As the DLQI and CDLQI are not disease-specific instruments, not all of their items are relevant to the clinical assessment of vitiligo, and they may not be sufficiently sensitive to capture nuanced details of how vitiligo patients handle their disease burden, a shortcoming that was confirmed by the clinical experts. Based on the literature, there is currently no MCID established for these instruments in patients with vitiligo. However, the use of an anchor-based approach for patients with various inflammatory skin conditions suggests that a within-group change from baseline of at least 4 points in the DLQI or CDLQI may be consistent with clinically meaningful improvements for patients.

Statistical Analysis

All patients with missing F-VASI assessments were handled using multiple imputations under a missing at random assumption. The key assumptions regarding missing data were tested in prespecified sensitivity analyses (i.e., nonresponder imputation, last observation carried forward, and tipping point analysis) and results of these sensitivity analyses demonstrated the robustness of the findings from the primary analysis to violations in the assumed missing data mechanism.

The TRuE-V1 and TRuE-V2 studies used a gatekeeping testing strategy for the primary and key secondary analyses to control the overall type I error rate. Other outcomes of interest to this review (e.g., proportions of patients achieving an F-VASI25 and T-VASI 75, as well as HRQoL as measured by the DLQI, CDLQI, and VitiQoL) were not controlled for multiplicity of testing.

Prespecified subgroup analyses included those for skin type and race, which were considered by the clinical experts to be particularly relevant to the treatment of vitiligo. However, because so few patients with darker skin tones were included, these subgroups were underpowered. The statistical tests that were performed to evaluate the differences in effects between subgroups, as well as whether the comparability of the treatment arms was checked and whether multiplicity was taken into account, were not reported for either trial. As such, the findings should be viewed as supplementary.

As with most clinical trials, the studies were not powered to detect infrequent AEs or those with a lag time.

External Validity

Population

Because patients with leukotrichia and segmental vitiligo were excluded from the trial, its findings are not generalizable to these patients.

The majority of patients included in both studies were white and had a Fitzpatrick Scale skin type of II, III, or IV (i.e., ranging from fair peach to moderate brown). Although vitiligo affects all races and types of skin colour, the clinical experts indicated that patients with darker skin tones are likely to present with an increased impact on quality of life, which can be attributed to the increased visibility of the condition. Of the 661 patients in the TRuE-V1 and TRuE-V2 trials combined, 31 patients (4.7%) were Black or African American, 26 (3.9%) were Asian, and 2 (0.3%) were Native Hawaiian or Pacific Islander. As for skin colour according to the Fitzpatrick Scale skin type, 43 patients (6.5%) had skin type V (i.e., dark brown) and 13 patients (2.0%) had skin type VI (i.e., deeply pigmented dark brown to darkest brown). The fact that the patients with potentially the greatest unmet need for an effective treatment were not adequately represented in the studies is a significant concern for external validity of the findings.

Given the natural trajectory of the disease, the clinical experts indicated that a longer disease duration is likely to be associated with a more severe, refractory condition. In both the TRuE-V1 and TRuE-V2 trials, the median time since diagnosis exceeded 10 years. However, despite a long-lasting disease, an important proportion of patients in both trials never received treatment aiming to improve their condition. Overall, 62% of patients had received prior therapy, a proportion that the clinical experts described as low. The experts expected that, in clinical practice, virtually all patients who sustain a negative impact from vitiligo would seek and receive treatment, particularly when the long-lasting diagnosis of patients in the studies is considered. According to the experts, this suggests that the trial population may not be representative of patients whose condition interferes substantially with their daily life. This is consistent with the relatively low level of HRQoL impairment observed at baseline, as measured by the DLQI, CDLQI, and VitiQoL. Of the patients who received treatment in the trials, 40% reported discontinuing therapy due to lack of efficacy.

Overall, only 11% of patients enrolled in the TRuE-V1 and TRuE-V2 trials combined were adolescents; there are therefore limited data to interpret in this younger age group.

Intervention and Comparator

Patient exposure to ruxolitinib and vehicle cream in the trials indicates notable variation among patients in the amount of the study drug applied, which appeared to be inconsistent with the usage patterns of topical treatments in clinical practice, according to the clinical experts. No additional details were provided by the sponsor to explain the high level of variability observed. The clinical experts consulted for this review indicated that it is uncertain if the amounts of the drug used in the trials would be mirrored in real-world practice, but they noted that it is likely that drug usage rates will be higher in the real-world setting.

Overall, the treatment options currently available in clinical practice for vitiligo are well accepted and routinely prescribed, even if they are being used off-label, according to the clinical experts, who noted that patients who first seek treatment will typically be offered a few options. Over time, approximately one-half of patients may become refractory due to disease resistance, and others will discontinue treatments due to unacceptable toxicity. The absence of comparative evidence between ruxolitinib and these drugs was therefore considered a substantial limitation.

Outcomes

The clinical experts noted that the primary clinical assessment of vitiligo in the trials using the VASI score was not representative of routine clinical practice in Canada, where treatment is targeted at improving current and future quality of life rather than only focusing on reducing the surface area of involvement and degree of repigmentation. This was also consistent with patient and clinician input, all of which emphasized the importance of improving the psychosocial impact of the disease on quality of life. The experts pointed out that several additional key issues of vitiligo have an important impact on HRQoL, including the disease site and associated visibility, the level of heterogeneity in repigmentation, and differences between the colour of the affected, repigmented area and background skin tone, as well as family and cultural influences.

Because the treatment of vitiligo in clinical practice is highly individualized, the clinical experts indicated that the clinical meaningfulness of the difference between the 2 treatments, when expressed solely in terms of VASI score improvements, can be highly variable among patients, depending on how the disease affects their daily lives. As such, the overall impact of achieving the VASI score MCID on daily life was difficult to assess according to the clinical experts, as different individuals are likely to have different priorities and objectives when assessing the response to treatment, and as the instrument is not used in clinical practice.

Follow-up

The follow-up duration of 24 weeks was considered relatively short, as the disease generally improves over a longer period of time. However, it was considered sufficient to assess changes in the VASI outcomes and capture improvements in objective response to treatment. Nevertheless, treatment is likely to continue over the long-term and evidence from beyond the studies follow-up duration is limited.

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 expert committee deliberations, and a final certainty rating was determined as outlined by the GRADE Working Group:^27,28

• 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, 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.

For the GRADE assessments, findings from the TRuE-V1 and TRuE-V2 trials were considered together and summarized narratively per outcome because populations, interventions, designs, and outcome measures of the 2 studies were similar.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for ruxolitinib versus vehicle cream.

LTE Studies

Contents within this section have been informed by materials submitted by the sponsor. The following have been summarized and validated by the review team.

TRuE-V1 and TRuE-V2 Trials Open-Label Treatment Extension

Description of TRuE-V1 and TRuE-V2 Trials Open-Label Treatment Extension

In the pivotal RCTs (TRuE-V1 and TRuE-V2), the double-blind controlled period was followed by a 28-week open-label treatment extension. The study design for TRuE-V1 and TRuE-V2 is presented in Figure 1. Patients initially randomized to the vehicle cream crossed over to ruxolitinib, while patients initially randomized to ruxolitinib received an additional 28 weeks of treatment with the active drug, as long as they completed the week 24 assessments with no safety concerns. During the treatment-extension period, patients continued to treat depigmented areas identified for treatment at baseline even if the area had fully repigmented. The evaluable population of the treatment extension consisted of all patients who applied ruxolitinib cream at least once in the treatment-extension period; this analysis set was used for all efficacy and safety assessments.

Results

Details of patient disposition are provided in Table 16. The proportions of patients who discontinued the study during the treatment extension ranged from 9.8% to 19.4% across treatment arms in the 2 trials.

Exposure to study treatment is outlined in Table 17. The median exposure duration during the treatment extension was ███ days in both studies, which was consistent with the planned duration of 28 weeks (196 days). Patient exposure suggests notable variation among patients in the amount of study drug applied, particularly in the TRuE-V2 trial.

The proportions of patients who received concomitant medications in the studies ranged from █████ ██ █████ across treatment arms in the 2 trials. The most commonly used medications are presented in Table 18.

Table 16: Summary of Patient Disposition (Treatment-Extension Period)

Source: Incyte Corporation (2021).^29,30

Table 17: Summary of Patient Exposure (Treatment-Extension Period) [Redacted]

Max = maximum; Min = minimum; SD = standard deviation.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Table 18: Summary of Most Commonly Used Concomitant Medications (Treatment-Extension Period) [Redacted]

ACE = angiotensin-converting-enzyme; DB = double-blind; HMG-CoA = 3-hydroxyl-3-methyl-glutaryl-coenzyme A.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Detailed efficacy results for the treatment-extension period, at 52 weeks, are presented in Table 19.

Throughout the TRuE-V1 and TRuE-V2 trials’ treatment extensions, which ranged from week 24 to week 52, the proportions of patients who achieved all predefined thresholds of reduction in the VASI score (i.e., F-VASI25, F-VASI50, F-VASI75, F-VASI90, and T-VASI75) were numerically higher in all treatment arms when compared to the corresponding proportions during the double-blind period (i.e., from start to week 24). Similar results were obtained in the proportions of patients who achieved a VNS score of 4 (a lot less noticeable) or 5 (no longer noticeable). However, in the treatment-extension period, no statistical analysis was reported to assess whether the change from week 24 to week 52 was significant, or to assess the magnitude of the between-group difference. Results for HRQoL, assessed using the DLQI, CDLQI, and VitiQoL, suggest that the observed within-group changes from baseline to week 52 were small and not clinically meaningful, according to the clinical experts. However, no between-group statistical analysis was reported.

Table 19: Summary of Key Efficacy Results (Treatment-Extension Period)

CDLQI = Children’s Dermatology Life Quality Index; CI = confidence interval; DLQI = Dermatology Life Quality Index; F-VASI25 = 25% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI50 = 50% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; SD = standard deviation; SE = standard error; T-VASI75 = 75% or more improvement from baseline on the Total Vitiligo Area Scoring Index; VitiQoL = Vitiligo-Specific Quality of Life; VNS = Vitiligo Noticeability Scale.

Source: Incyte Corporation (2021)^29,30 and the sponsor’s Summary of Clinical Evidence.

Harms data are presented in Table 20. The proportions of patients who experienced at least 1 AE during the treatment extension ranged from 33.7% to 41.2% across treatment arms in the 2 trials. Few patients experienced SAEs. One patient discontinued due to application site eczema. No deaths were reported during the treatment extension.

Table 20: Summary of Harms (Treatment-Extension Period)

AE = adverse event; NR = not reported; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

Source: Incyte Corporation (2021).^29,30 Details included in the table are from the sponsor’s Summary of Clinical Evidence.

Critical Appraisal

Due to the single-arm nature of the TRuE-V1 and TRuE-V2 trials open-label treatment extensions, the conclusions that can be drawn regarding the efficacy and safety of ruxolitinib in the longer term are noncomparative. The same limitations pertaining to the uncertain clinical impact of the F-VASI score that were highlighted for the double-blind controlled period of the studies also apply to the extension period. In addition, findings from both the TRuE-V1 and TRuE-V2 studies may be considered generalizable to a selected sample of the individuals in Canada with vitiligo. The majority of patients included in the studies were white and had lighter skin tones; however, vitiligo is particularly visible in patients with darker skin tones and is therefore likely to have a greater impact on the quality of life in these patients. Considering disease duration, prior therapies, and baseline HRQoL, the trial population may not be representative of patients whose condition interferes substantially with their daily life.

TRuE-V LTE Study

Description of TRuE-V LTE Study

The TRuE-V LTE³¹ is a phase III, double-blind, vehicle-controlled, randomized withdrawal LTE trial of the TRuE-V1 and TRuE-V2 studies, designed to assess the long-term efficacy and safety of ruxolitinib cream in patients with vitiligo. The study aimed to evaluate the duration of response following withdrawal of 1.5% ruxolitinib cream (cohort A) and the safety and maintenance of response with continued use of the cream (cohort B). The LTE study had a duration of 52 weeks, followed by a 30-day safety follow-up.

Eligible participants were assigned to either cohort A or cohort B based on their F-VASI responses at the time of enrolment in the LTE study (week 52).

Cohort A followed a randomized withdrawal design, providing data on the duration of response after discontinuation and the maintenance of response with continued treatment. Participants who achieved complete or near-complete facial repigmentation (greater than or equal to an F-VASI90) at week 52 in either the TRuE-V1 or TRuE-V2 trial were assigned to this cohort. They were randomized in a 1:1 ratio to either continue 1.5% ruxolitinib cream or switch to the vehicle cream during the LTE. Members of cohort A who experienced a disease relapse (defined as less than an F-VASI75) received open-label ruxolitinib cream as rescue treatment until week 104 or the end of the trial.³¹

Cohort B included participants who did not achieve a response of greater than or equal to an F-VASI90 at week 52 in the parent studies. These participants continued treatment with 1.5% ruxolitinib cream for the entire LTE period (Figure 2).

In cohort A, the participant, investigator, and sponsor remained blinded to treatment assignment until after database lock for the primary analysis (week 104); the treatment for cohort B was open-label.³¹

Figure 2: TRuE-V LTE Study Design

BID = twice a day; EOS = end of study; EOT = end of treatment; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; LTE = long-term extension; Rux = ruxolitinib.

¹All participants in cohort A used their randomly assigned treatment (either vehicle cream or 1.5% ruxolitinib cream) on both the face and total body.

²Rescue treatment: If, at any time, a participant in cohort A lost a clinically meaningful response on the face (< F-VASI75), the participant received open-label 1.5% ruxolitinib cream twice a day until week 104 or EOT.

Source: TRuE-V LTE Clinical Study Report.³¹

Outcomes

The primary outcome of the study was the time to relapse in cohort A. Relapse was defined as loss of an F-VASI75 response assessed as percentage improvement from baseline (day 1 of the parent study) to an F-VASI of less than 75%. The time to relapse was defined as the number of days from the week 52 randomization date to the first evaluation date at which the participant met the definition of relapse. The key secondary outcome was the time to maintain a response greater than or equal to an F-VASI90, defined as the number of days from week 52 randomization to the first evaluation date at which the participant achieved an F-VASI90.

Additional secondary outcomes that are included in this report:

• proportion of patients who achieve an F-VASI50, F-VASI75, or F-VASI90 during the LTE period

• proportion of patients achieving a VNS of 4 (a lot less noticeable) or 5 (no longer noticeable) during the LTE

• proportion of patients who achieve T-VASI75 during the LTE period

• time to regain at least an F-VASI90 and at least an F-VASI75 in patients whose disease relapsed after entering the LTE.

Exploratory outcomes included changes from week 52 in DLQI, CDLQI, and VitiQoL and time to regain a response greater than or equal to an F-VASI75 and greater than or equal to an F-VASI90 following disease relapse. Safety outcomes were consistent with those defined in the TRuE-V1 and TRuE-V2 parent studies.

Statistical Analysis

All statistical analyses were exploratory, with no alpha control implemented. Unless otherwise specified, all CIs were at the 95% level. The sample size was not determined by statistical power calculations. Three participants from cohort A were excluded from the ITT extension population due to incorrect randomization. Data from 2 participants at site 710 were excluded from both the ITT extension and cohort A efficacy analyses due to protocol noncompliance. Similarly, in cohort B, data from 2 participants at site 710 were excluded from efficacy analyses due to noncompliance.

The primary and key secondary analyses were conducted on the ITT extension population (participants achieving a response greater than or equal to an F-VASI90 at week 52). For participants who discontinued early, completed the study without meeting the event criteria, or received open-label rescue treatment without meeting event criteria, the time to event was censored at the last assessment date or the date of rescue treatment. Time to event data were analyzed using the Kaplan-Meier method, with treatment comparisons between 1.5% ruxolitinib cream twice a day and vehicle cream twice a day performed via the log-rank test. HRs and 95% CIs were estimated using a Cox proportional hazards model, accounting for treatment groups and stratification factors (skin type and region). Relapse incidence was summarized by treatment, and swimmer plots, including subgroup analyses by baseline characteristics, were provided. Secondary efficacy analyses for cohorts A and B used specific criteria for data inclusion. Safety outcomes, including TEAEs, lab values, and vital signs, were summarized descriptively.

Results

Baseline Characteristics

Baseline characteristics for cohort A and cohort B of the TRuE-V LTE study are summarized in Table 21. In cohort A, participants applying vehicle cream twice a day were primarily adults, with ████ aged 12 to younger than 18 years; their mean age was 39.3 years (SD = 12.49 years). Most were white (72.4%), had Fitzpatrick Scale skin type II or III (█████), and were female (53.4%). This group had a long history of vitiligo, with a mean time since diagnosis of █████ █████ ███ █ █████, and █████ had stable disease at baseline. Key disease metrics included F-VASI scores ranging from ████ ██ ████ ███████ █ █████, facial BSA involvement ranging from ████ ██ ████ ███████ █ ██████, T-VASI scores ranging from ████ ██ █████ ███████ █ █████, and total BSA involvement ranging from ████ ██ █████ ███████ █ ███████.³¹

Similarly, participants in the 1.5% ruxolitinib cream twice a day group were predominantly adults, with █████ aged 12 to younger than 18 years and a mean age of 42.9 years (SD = 15.95 years). The majority were white (82.8%), had Fitzpatrick Scale skin type II or III skin (█████), and were female (56.9%). They also had long-standing vitiligo, with a mean time since diagnosis of █████ █████ ███ █ ██████, and ███ had stable disease at baseline. Their baseline disease metrics were comparable: F-VASI scores ranged from ████ ██ ████ ███████ █ █████, facial BSA involvement ranged from ████ ██ ████ ███████ █ ██████, T-VASI scores ranged from ████ ██ █████ ███████ █ █████, and total BSA involvement ranged from ████ ██ █████ ███████ █ ██████.³¹

Members of cohort B (participants who did not achieve a response greater than or equal to an F-VASI90) were initially treated with the vehicle cream and then switched to ruxolitinib cream. It included █████ adults, with ████ aged 12 years to younger than 18 years; the mean age was 39.7 years (SD = 14.62 years). The majority were white (90.7%), had Fitzpatrick Scale skin type II or III skin ███████, and were female (51.7%). Most participants had long-standing vitiligo, with a mean time since diagnosis of █████ █████ ███ █ ██████, and █████ had stable disease at baseline. Disease metrics at baseline included F-VASI scores ranging from ████ ██ ████ ███████ █ █████, facial BSA involvement from ████ ██ ████ ███████ █ ██████, T-VASI scores from ████ ██ ████ ███████ █ █████, and total BSA involvement ████ ████ ██ █████ ███████ █ ██████.³¹

For participants in cohort B who continued with ruxolitinib cream, █████ were adults, and █████ were aged 12 to younger than 18 years; the mean age was 39.3 years (SD = 16.45 years). The majority were white (80.4%), had Fitzpatrick Scale type II or III skin ███████, and were female (57.6%). Like the previous group, this cohort comprised primarily individuals with long-standing vitiligo, with a mean time since diagnosis of █████ █████ ███ █ ██████, and █████ had stable disease at baseline. Baseline F-VASI scores ranged from ████ ██ ████ ███████ █ █████, facial BSA involvement ranged from ████ ██ ████ ███████ █ █████), T-VASI scores ranged from ████ ██ ████ ███████ █ █████, and total BSA involvement ranged from ████ ██ █████ ███████ █ ██████.³¹

Table 21: Summary of Baseline Demographic and Disease Characteristics of the TRuE-V LTE Study (FAS)

b.i.d. = twice a day; BSA = body surface area; FAS = full analysis set; F-VASI = Face Vitiligo Area Scoring Index; LTE = long-term extension; SD = standard deviation; T-VASI = Total Vitiligo Area Scoring Index

^aPatients randomized to vehicle cream in the double-blind period of the TRuE-V1 or TRuE-V2 trials who crossed over to receive 1.5% ruxolitinib cream after 24 weeks.

^bPatients who received 1.5% ruxolitinib cream since study start.

^cCategories are as reported in study.

Source: TRuE-V LTE Clinical Study Report.³¹

Patient Disposition

Patient disposition of the TRuE-V LTE study is summarized in Table 22. A total of 116 participants in cohort A and 342 in cohort B were enrolled across North America and Europe. In cohort A, 77.6% completed treatment, while 22.4% discontinued the study drug, primarily due to participant withdrawal or being lost to follow-up. Cohort B had a 78.9% treatment-completion rate, with 21.1% discontinuing the study drug, mostly for similar reasons, although 2 participants cited a lack of efficacy and 1 discontinued due to an AE.³¹

Table 22: Patient Disposition of the TRuE-V LTE Study

b.i.d. = twice daily; FAS = full analysis set; ITT = intention to treat; LTE = long-term extension; NA = not applicable.

^aPatients randomized to vehicle cream in the double-blind period of the TRuE-V1 or TRuE-V2 trials who crossed over to receive 1.5% ruxolitinib cream after 24 weeks.

^bPatients who received 1.5% ruxolitinib cream since the study start.

Source: TRuE-V LTE Clinical Study Report.³¹

Exposure to Study Treatments

Participants in cohort A (those who achieved a response of greater than or equal to an F-VASI90 at week 52) applied the study cream for durations that varied by their treatment group. Participants who were initially randomized to vehicle cream twice a day applied the study cream for a median of ██████ days. Those who experienced a disease relapse (less than an F-VASI75), applied 1.5% ruxolitinib cream twice daily for a median of ██████ days. Participants randomized to 1.5% ruxolitinib cream twice daily applied the study cream for a median of 364.00 days³¹ (Table 23).

The median daily amount of study drug applied was comparable across groups: ████ g for those randomized to 1.5% ruxolitinib cream twice daily, ████ g for those initially on vehicle cream twice a day who switched to ruxolitinib following relapse, and similar values for those who remained on vehicle cream twice a day. Study drug application compliance was high, with a median of ██████ ██████ █ █████ ██████ for participants applying 1.5% ruxolitinib cream twice a day and ██████ ██████ █ █████ ██████ for those on vehicle cream twice daily³¹ (Table 23).

In cohort B (participants who had not achieved a response greater than or equal to an F-VASI90 at week 52), the median duration of study drug exposure was ██████ days for both treatment groups. Among participants initially treated with vehicle cream and later switched to 1.5% ruxolitinib cream, the median daily amount of ruxolitinib cream applied was ████ g, with a median study drug application compliance rate of ███████ In the group that continued ruxolitinib cream throughout the study, the median daily amount applied was ████ g, with a median study drug compliance rate of ███████³¹ (Table 24).

Table 23: Summary of Patient Exposure in the Cohort A (FAS)

b.i.d. = twice a day; FAS = full analysis set; LTE = long-term extension; SD = standard deviation.

^aThis represents the total group of patients randomized to vehicle cream, which includes those who remained on the vehicle cream for the entire study, and those whose disease relapsed and switched to 1.5% ruxolitinib cream.

^bThese patients were initially randomized to vehicle cream and then were switched onto 1.5% ruxolitinib cream after their disease relapsed.

^cThese patients received 1.5% ruxolitinib cream for the entire study period.

^dThis is the combined group of patients who received 1.5% ruxolitinib cream at any point during the study period, which includes those initially randomized to the vehicle cream and then were switched onto 1.5% ruxolitinib cream after their disease relapsed.

Source: TRuE-V LTE Clinical Study Report.³¹

Table 24: Summary of Patient Exposure in the Cohort B (FAS)

b.i.d. = twice a day; FAS = full analysis set; SD = standard deviation; LTE = long-term extension.

^aPatients randomized to vehicle cream in the double-blind period of the TRuE-V1 or TRuE-V2 trial who crossed over to receive 1.5% ruxolitinib cream after 24 weeks.

^bPatients who received 1.5% ruxolitinib cream since study start.

Source: TRuE-V LTE Clinical Study Report.³¹

Concomitant Medications

Concomitant medications used in the TRuE-V LTE study are listed in Table 25 by WHO drug class. In cohort A, medications used by 10% or more of participants included other viral vaccines, thyroid hormones and anilides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, propionic acid derivatives, and progestogens and estrogens in fixed combinations. The most frequently reported concomitant medications by WHO drug term were tozinameran (█████) and paracetamol (█████). Other medications used by greater than or equal to ██ of participants included elasomeran, ethinyl estradiol or levonorgestrel, ibuprofen, levothyroxine, salbutamol, vitamin B12, and other unspecified vitamins.³¹

Table 25: Most Commonly Used Concomitant Medications During the TRUE-V LTE Study

b.i.d. = twice a day; HMG-CoA = 3-hydroxy-3-methyl glutaryl coenzyme A; LTE = long-term extension.

^aPatients randomized to vehicle cream in the double-blind period of the TRuE-V1 or TRuE-V2 trial who crossed over to receive 1.5% ruxolitinib cream after 24 weeks.

^bPatients who received 1.5% ruxolitinib cream since study start.

Source: TRuE-V LTE Clinical Study Report.³¹

In cohort B, medications used by 10% or more of participants included other viral vaccines, thyroid hormones and anilides, propionic acid derivatives, and vitamin D and analogues. Additional medications used by at least 5% of participants included ascorbic acid, colecalciferol, other unspecified vitamins, elasomeran, levothyroxine, metformin, and vitamin D. The most frequently used medications were similar between participants initially randomized to vehicle cream and those randomized to 1.5% ruxolitinib cream in the parent study and were generally consistent with prestudy medication use.³¹

Efficacy

Primary End Point — Time to Relapse (Less Than an F-VASI75)

The majority of patients who achieved complete or near-complete repigmentation of the face (cohort A, patients who had achieved greater than or equal to F-VASI90 at week 52) in the parent studies did not relapse (less than an F-VASI75) while on study. The median time to relapse (less than an F-VASI75) was not evaluable (NE) for either the ruxolitinib cream group (95% CI, NE to NE) or the vehicle cream treatment group (95% CI, 238.0 to NE) due to the small number of patients who experienced disease relapse (Table 26 and Figure 3).³¹ Fewer patients experienced disease relapse in the ruxolitinib cream group (14.5%) compared with the vehicle cream group (28.6%), and the risk of relapse was lower for patients who continued to apply ruxolitinib cream beyond week 52 compared with patients who applied vehicle cream after week 52 (HR = 0.422; 95% CI, 0.180 to 0.990; P = 0.0414).³¹

Table 26: Summary and Analysis of Time to Relapse (Less Than an F-VASI75) (ITT Extension Population)

b.i.d. = twice a day; CI = confidence interval; F-VASI = Facial Vitiligo Area Scoring Index; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; HR = hazard ratio; ITT = intention to treat; NE = not evaluable.

Note: Relapse was defined as a loss of response, assessed as improvement in the F-VASI score at baseline (day 1 of the parent study) to less than 75%.

^aCox regression model stratified by stratification factor (treatment assignment in the parent studies) was conducted to compare the difference in hazard rate between the treatment and vehicle cream. The P value was based on the log-rank test stratified by randomization stratification factor between treatment and vehicle cream.

Source: TRuE-V LTE Clinical Study Report.³¹

Figure 3: Kaplan-Meier Curve of the Time to Relapse (ITT Extension Population)

BID = twice a day; CI = confidence interval; ITT = intention to treat; NE = not evaluable.

Note: Relapse is defined as a loss of an F-VASI75 response, assessed as percentage improvement in the F-VASI score at baseline (day 1 of the parent study) to less than 75%.

Source: TRuE-V LTE Clinical Study Report.³¹

Key Secondary End Points

Time to Maintain F-VASI90 Response

The majority of patients who achieved a complete or near-complete repigmentation of the face (cohort A, patients who had achieved a response of greater than or equal to an F-VASI90 at week 52) in the parent studies maintained this level of repigmentation with continued application of ruxolitinib cream beyond week 52. Of the cohort of patients who received vehicle cream, 55.4% lost their F-VASI90 response.³¹ The median time to loss of an F-VASI90 in the group of patients who received the vehicle cream was 195.0 days (95% CI, 113.0 days to 372.0 days). Of the cohort of patients who applied ruxolitinib cream in the double-blind period then continued treatment with ruxolitinib and achieved an F-VASI90 response, 23.6% lost their F-VASI90 response³¹ (Table 27). The median time to loss of an F-VASI90 response in this cohort was not evaluable.³¹ The risk of losing an F-VASI90 response was lower for patients who continued to use ruxolitinib cream compared with patients who applied the vehicle cream (HR = 0.316; 95% CI, 0.165 to 0.606; P = 0.0003).³¹

Figure 4: Kaplan-Meier Curve for Maintenance of an F-VASI90 Response (ITT Extension Population)

BID = twice a day; CI = confidence interval; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; ITT = intention to treat; NE = not evaluable.

Note: Loss of adequate response is defined as a loss of F-VASI90 response, assessed as percentage improvement in the Facial Vitiligo Area Scoring Index score at baseline (day 1 of the parent study) to less than 90%. The hazard ratio stratification factor was the initial treatment assigned in the parent studies.

Source: TRuE-V LTE Clinical Study Report.³¹

Table 27: Summary and Analysis of Time to Maintain an F-VASI90 Response (ITT Extension Population)

b.i.d. = twice a day; CI = confidence interval; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; HR = hazard ratio; ITT = intention to treat; NE = not evaluable.

Note: Loss of adequate response is defined as a loss of F-VASI90 response, assessed as percentage improvement in the Facial Vitiligo Area Scoring Index score at baseline (day 1 of the parent study) to less than 90%.

^aA Cox regression model stratified by stratification factor (treatment assignment in the parent studies) was conducted to compare the difference in hazard rate between treatment and vehicle cream. The P value was based on the log-rank test stratified by randomization stratification factor between treatment and vehicle cream.

Source: TRuE-V LTE Clinical Study Report.³¹

Additional Secondary End Points

Vitiligo Area Scoring Index

Proportions of patients achieving an F-VASI 50, F-VASI75, or F-VASI90: In cohort B, at week 104, for those who continued using 1.5% ruxolitinib cream, 86.4%, 66.1%, and 33.9% achieved an F-VASI50, F-VASI75, or F-VASI90, respectively. Among those initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during the TRuE-V LTE study, the respective rates were 69.9%, 47.3%, and 28.0%.³¹

Proportions of patients achieving T-VASI75: In cohort A, the proportions of participants continuing on 1.5% ruxolitinib cream who achieved a T-VASI75 were 42.1% at week 52 and 55.3% at week 104. Among participants using vehicle cream, 38.6% achieved a T-VASI75 at week 52 and 39.1% at week 104.

In cohort B at week 52, for those who continued using 1.5% ruxolitinib cream, 12.2% achieved a T-VASI75, and by week 104, 30.5% achieved this threshold. Among participants initially randomized to the vehicle cream who switched to 1.5% ruxolitinib cream during the TRuE-V LTE study, 3.4% achieved a T-VASI75 at week 52 and 18.3% at week 104.³¹

Vitiligo Noticeability Scale

Proportions of patients achieving a VNS of “a lot less noticeable” or “no longer noticeable”: In cohort A, the proportions of participants receiving blinded treatment who reported a VNS score of 4 (a lot less noticeable) or 5 (no longer noticeable) remained generally stable compared to week 52. Among participants receiving 1.5% ruxolitinib cream, 50.0% reported a score of 4 or 5 at week 104, compared to 42.1% at week 52. Among participants receiving the vehicle cream, 56.5% reported a score of 4 or 5 at week 104, compared to 49.1% at week 52.³¹

In cohort B, the proportion of participants achieving a VNS score of 4 or 5 for those who continued using 1.5% ruxolitinib cream remained generally stable (43.3% at week 104 versus 35.3% at week 52). The VNS score of 4 or 5 increased from week 52 to week 104 for those initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during the TRuE-V LTE study (30.1% at week 104 versus 11.9% at week 52).³¹

Dermatology Life Quality Index and Children’s Dermatology Life Quality Index

█████ ███ ██ █████ ███████ ██ ██████ ██ ████ █████ ██████ ███ ████ ████████ ██████ ████████ ██ ████ ██ ██████ ███ ███████ █████████ ██████ ███ ████████████ ██ ██████ █ ███ ████ ██ ███████ █████████ ███ ████████████ ██ ██████.

For cohort A, irrespective of treatment group, participants had mean total scores between ████ and ████ throughout the 52-week treatment period. At week 104 in cohort A, the mean changes from week 52 in total score were █████ in the 1.5% ruxolitinib cream treatment group and ████ in the vehicle cream twice a day treatment group.³¹

For cohort B, irrespective of initial randomization, participants had mean total scores between ████ and ████ throughout the 52-week treatment period. At week 104 in cohort B, the mean changes from week 52 in the total score were █████ for participants initially randomized to 1.5% ruxolitinib cream in the parent study and █████ for participants initially randomized to vehicle cream and then switched to 1.5% ruxolitinib cream.³¹

Change From Baseline in CDLQI (Aged Younger Than 16 Years)

CDLQI scores were reported for a small number of participants: 9 participants in cohort A (6 applying 1.5% ruxolitinib cream and 3 applying vehicle cream) and 26 participants in cohort B (all applying 1.5% ruxolitinib cream twice a day). Due to the small sample size, no definitive conclusions could be drawn from the data.

At week 104 in cohort A, the mean change from week 52 in CDLQI score was ████ in participants who applied 1.5% ruxolitinib cream and ████ in participants who applied vehicle cream.³¹

At week 104 in cohort B (participants who had not achieved a response greater than or equal to an F-VASI90 at week 52), the mean changes from week 52 in CDLQI score were █████ in participants initially randomized to 1.5% ruxolitinib cream in the parent study and █████ in participants initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during TRuE-V LTE study.³¹

Vitiligo-Specific Quality of Life

There was no clear pattern of change in VitiQoL total or subscale scores for participants in cohort A who were receiving blinded treatment during the 52-week treatment period. At week 104 in cohort A, the mean changes from week 52 in total score were █████ in the 1.5% ruxolitinib cream twice a day treatment group and ████ in the vehicle cream twice a day treatment group.³¹

Participants in cohort B (participants who had not achieved a response greater than or equal to an F-VASI90 at week 52) who continued to apply 1.5% ruxolitinib cream showed improvement in VitiQoL total scores relative to week 52; at week 104, the mean changes from week 52 were █████ for participants initially randomized to 1.5% ruxolitinib cream in the parent study and █████ for participants initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during the LTE study.³¹

Exploratory End Points

Time to Regain F-VASI Response

The median time to regain an F-VASI75 for patients randomized to vehicle cream in cohort A (patients who had achieved a response greater than or equal to an F-VASI90 at week 52) who experienced disease relapse (less than an F-VASI75) and received open-label rescue treatment was 85.0 days (95% CI, 43.0 days to 106.0 days) (Figure 5).³¹ Although some patients randomized to 1.5% ruxolitinib cream in cohort A experienced disease relapse, the majority (5 of 8 patients [62.5%]) regained an F-VASI75 with continued application of ruxolitinib cream; the median time to regain an F-VASI75 was 205.0 days (95% CI, 27.0 days to NE).³¹

The median time to regain an F-VASI90 for patients randomized to the vehicle cream in cohort A who experienced disease relapse and received open-label rescue treatment was 106.0 days (95% CI, 50.0 days to NE)³¹ (Figure 6). For patients randomized to ruxolitinib cream in cohort A who experienced disease relapse and continued to apply ruxolitinib cream, the median time to regain an F-VASI90 was 205.0 days (95% CI, 36.0 days to NE).³¹

Figure 5: Kaplan-Meier Curve of the Time to Regain an F-VASI75 Response (RES)

BID = twice a day; CI = confidence interval; F-VASI75 = 75% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; NE = not evaluable.

Note: The hazard ratio stratification factor was the initial treatment assigned in the parent studies.

Source: TRuE-V LTE Clinical Study Report.³¹

Figure 6: Kaplan-Meier Curve of the Time to Regain F-VASI90 Response (RES)

BID = twice a day; CI = confidence interval; F-VASI90 = 90% or more improvement from baseline on the Facial Vitiligo Area Scoring Index; NE = not evaluable.

Note: The hazard ratio stratification factor was the initial treatment assigned in the parent studies.

Source: TRuE-V LTE Clinical Study Report.³¹

Harms

An overall summary of TEAEs for participants in TRuE-V LTE (cohorts A and B) is presented in Table 28.

The overall incidences of TEAEs (all causality) and application site reactions for cohort A were higher among patients who applied ruxolitinib cream (55.2% and █████ respectively) compared with the vehicle cream treatment group (36.2% and ████, respectively).

One participant treated with 1.5% ruxolitinib cream in cohort A (1.7%) had a serious TEAE, and no participant had a TEAE with a fatal outcome or a TEAE leading to study drug discontinuation.³¹

The overall incidences of TEAEs and application site reactions in cohort B were 50.9% and ████, respectively, among patients who continued receiving 1.5% ruxolitinib cream, compared to 50.0% and ████ for participants initially randomized to vehicle cream who switched to 1.5% ruxolitinib cream during the LTE study.³¹ The incidence of serious TEAEs was 3.1% in patients treated with 1.5% ruxolitinib cream and 3.4% in those initially treated with vehicle cream. The only TEAE leading to discontinuation of the study drug in cohort B was ████ ███████ accident (in 1 participant) that the investigator assessed as unlikely to be related to the study drug.³¹

Table 28: Summary of Harms From TRuE-V LTE Study (FAS)