A 104-Week Study of Ritlecitinib Oral Capsules in Adults With Nonsegmental Vitiligo (Active and Stable) Tranquillo 2

Study Overview
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Brief Summary
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The purpose of this study is to learn about the safety and effects of the study medicine ritlecitinib for the possible treatment of nonsegmental vitiligo. Vitiligo causes white patches on your skin when the cells that give your skin color are destroyed. Nonsegmental means that it can affect both sides of the body such as both knees and both hands. Ritlecitinib has been tested in earlier clinical studies and has a favorable safety profile. At present there are no approved medications taken by mouth to treat nonsegmental vitiligo. This study is seeking participants who: Are 18 years of age or older. are confirmed to have nonsegmental vitiligo for at least 3 months. Are willing to stop all other treatments that they may be taking for vitiligo. In this study participants will be chosen by chance, like drawing names out of a hat to receive 1 of 3 treatments: •Part I where two different amounts of ritlecitinib (50 mg and 100 mg) are taken once daily. It will be compared to placebo. Placebo is a dummy capsule. It doesn't have any medicine used in the study. Participants receiving placebo who have not responded to treatment after 52 weeks will be given 100 milligrams or 50 milligrams of ritlecitinib for the remaining 52 weeks of the study. • In Part II, participants will only receive 100 milligrams of ritlecitinib. About 1000 participants will take part in Part I and around 450 in Part II globally. The study will compare the experiences of people receiving ritlecitinib to those of the people who do not. This will help see if ritlecitinib is safe and effective. People in Part I will be in this study for about 26 months and people in Part II will be in this study for about 14 months. During the study, participants in part I will need to visit the study site at least 17 times. In part II, participants will visit at least 11 times. Participants will undergo various tests and procedures such as: vitiligo rating, physical examinations, hearing tests, blood tests, x-ray, ECG, photographs of areas with vitiligo. Participants will be asked to complete questionnaires about their vitiligo.

Detailed Description
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Study B7981080 is a Phase 3 randomized, double-blind, multicenter study with a 52-week placebo-controlled period (Part Ia) followed by a double-blind 52-week extension period (Part Ib) that includes randomized dose-up/down titration and a de novo 52-week non-randomized open-label cohort (Part II), investigating the efficacy, safety, and tolerability of ritlecitinib 100 mg QD and 50 mg QD compared with placebo in adult participants with nonsegmental active or stable vitiligo

Official Title
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A PHASE 3 RANDOMIZED, DOUBLE-BLIND, 52-WEEK PLACEBO-CONTROLLED MULTI-CENTER STUDY WITH A DOUBLE-BLIND 52-WEEK EXTENSION PERIOD WITH RANDOMIZED DOSE UP/DOSE DOWN TITRATION INVESTIGATING THE EFFICACY, SAFETY, AND TOLERABILITY OF RITLECITINIB IN ADULT PARTICIPANTS WITH NONSEGMENTAL VITILIGO

Conditions
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Stable Nonsegmental Vitiligo, Active Nonsegmental Vitiligo

Intervention / Treatment
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* Drug: Ritlecitinib
* Drug: Ritlecitinib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants aged 18 years (or the minimum age of consent in accordance with local regulations) or older (no upper age limit) at Screening. • Meeting reproductive criteria for female participants. Disease Characteristics: Eligible participants must have at both Screening and BL: A clinical diagnosis of nonsegmental vitiligo for at least 3 months; and BSA involvement 4% to 60% inclusive, excluding involvements at palms of the hands, soles of the feet, or dorsal aspect of the feet and BSA ≥0.5% involvement on the face. Face is defined as including the area on the forehead to the original hairline, on the cheek to the jawline vertically to the jawline and laterally from the corner of the mouth to the tragus. Face will not include scalp, ears, neck, or surface area of the lips, but will include the nose and the eyelids; and F-VASI ≥0.5 and T-VASI ≥3; and Either active or stable nonsegmental vitiligo at Screening and BL visits. All participants who do not have the features of active vitiligo (defined below) will be classified as having stable disease. Active vitiligo is defined as: Participants will be classified as having active vitiligo based on the presence of at least one active lesion at BL defined as one of the following: New/extending lesions(s) in the 3 months prior to Screening visit (confirmed by photographs or medical record); Confetti-like lesion(s); Confetti-like depigmentation is characterized by the presence of numerous 1-mm to 5-mm depigmented macules in clusters; Trichrome lesion(s); Trichrome lesions have a hypopigmented zone of varying width between normal and completely depigmented skin, resulting in 3 different hues of skin; Koebner phenomenon/phenomena (excluding Type 1 [history based on isomorphic reaction]). The Koebner phenomenon manifests as depigmentation at sites of trauma, usually in a linear arrangement. Stable vitiligo is defined as: • Participants will be classified as having stable vitiligo based on an absence of signs of active disease. All participants who do not have the features of active vitiligo (defined above) will be classified as having stable disease. Eligibility is determined at Screening and Baseline based on the resulting scores from the local in-person reads of F-VASI, T-VASI, and BSA. Additional inclusion criteria are: If receiving concomitant medications for any reason other than vitiligo, participant must be on a stable regimen, which is defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever is longer) prior to Day 1. Participant must be willing to stay on a stable regimen during the duration of the study. Must agree to stop all other treatments for vitiligo from Screening through the final follow-up visit. Exclusion Criteria: Medical Conditions: Any medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. • Any psychiatric condition including recent or active suicidal ideation or behavior that meets defined criteria. Medical conditions pertaining to vitiligo and other diseases/conditions affecting the skin: Participants that have other types of vitiligo that do not meet criteria for active or stable vitiligo as noted in inclusion criteria (including but not limited to segmental vitiligo and mixed vitiligo). Currently have active forms of other hypopigmentation (including but not limited to Vogt-Koyanagi-Harada disease, malignancy-induced hypopigmentation [melanoma and mycosis fungoides], post-inflammatory hypopigmentation, pityriasis alba [minor manifestation of atopic dermatitis], senile leukoderma [age-related depigmentation], chemical/drug-induced leukoderma, ataxia telangiectasia, tuberous sclerosis, melasma, and congenital hypopigmentation disorder including piebaldism, Waardenburg syndrome, hypomelanosis of Ito, incontinentia pigmenti, dyschromatosis symmetrica hereditarian, xeroderma pigmentosum, and nevus depigmentosus). NOTE: Coexistence of halo nevus/nevi (also known as Sutton nevus/nevi) is permitted. Currently have active forms of inflammatory skin disease(s) or evidence of skin conditions (for example, but not limited to morphea, discoid lupus, leprosy, syphilis, psoriasis, seborrheic dermatitis) at the time of the Screening or BL Visit that in the opinion of the investigator would interfere with evaluation of vitiligo or response to treatment. Leukotrichia in more than 33% of the face surface area affected with vitiligo lesions or leukotrichia in more than 33% of the total body surface area affected with vitiligo lesions. Have a superficial skin infection within 2 weeks prior to first dose on Day 1. NOTE: participants may be rescreened after the infection resolves. General Infection History: Have a history of systemic infection requiring hospitalization, parenteral antimicrobial, antiviral (including biologic treatment), antiparasitic, antiprotozoal, or antifungal therapy, or as otherwise judged clinically significant by the investigator within 6 months prior to Day 1. Have active acute or chronic infection requiring treatment with oral antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to Day 1. NOTE: participants may be rescreened after the infection resolves. Evidence or history of untreated, currently treated or inadequately treated active or latent infection with Mycobacterium tuberculosis. Specific Viral Infection History: History (single episode) of disseminated HZ or disseminated herpes simplex or recurrent (more than one episode of) localized, dermatomal HZ. Infected with HBV or HCV: all participants will undergo screening for HBV and HBC for eligibility. Participants who are positive for HCVAb and HCV RNA will not be eligible for this study. Have a known immunodeficiency disorder (including positive serology for HIV at screening) or a first-degree relative with a hereditary immunodeficiency. Other Medical Conditions: Current or recent history of clinically significant severe, progressive, or uncontrolled renal (including but not limited to active renal disease or recent kidney stones), hepatic, hematological, gastrointestinal, metabolic, endocrine (eg, untreated hypovitaminosis D or hypothyroidism), pulmonary, cardiovascular, psychiatric, immunologic/rheumatologic or neurologic disease; or have any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration, or interfere with the interpretation of study results; or in the opinion of the investigator or Pfizer (or designee), the participant is inappropriate for entry into this study, or unwilling/unable to comply with study procedures and lifestyle requirements. History of severe allergic or anaphylactoid reaction to any kinase inhibitor or a known allergy/hypersensitivity to any component (including excipients) of the study intervention. Have hearing loss with progression over the previous 5 years, sudden hearing loss, or middle or inner ear disease such as otitis media, cholesteatoma, Meniere's disease, labyrinthitis, or other auditory condition that is considered current, fluctuating, or progressive. Have a history of any lymphoproliferative disorder such as EBV-related lymphoproliferative disorder, history of lymphoma, history of leukemia, or signs and symptoms suggestive of current lymphatic or lymphoid disease. Abnormal findings on the Screening chest imaging (eg, chest x-ray). Chest imaging may be performed up to 12 weeks prior to screening. Documentation of the official reading must be located and available in the source documentation. Long QT Syndrome, a family history of Long QT Syndrome, or a history of TdP. Have any malignancies or have a history of malignancies with the exception of adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. Significant trauma or major surgery within 1 month of the first dose of study drug or considered in imminent need for surgery or with elective surgery scheduled to occur during the study. Prior/Concomitant Therapy: Have received any of the prohibited treatment regimens specified. Prior/Concurrent Clinical Study Experience: Previous administration with an investigational drug or vaccine that do not affect vitiligo within 4 weeks of Day 1 [Baseline] or within 5 half-lives, whichever is longer. Diagnostic Assessments: Any of the following abnormalities in clinical laboratory tests at Screening, as assessed by the study-specific laboratory and, if deemed necessary, confirmed by a single repeat: Renal impairment Hepatic dysfunction Other laboratory abnormalities Standard 12-lead ECG that demonstrates clinically relevant abnormalities Other Exclusion Criteria: Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members. In South Africa only participants are excluded without one of the following: Document evidence form a health professional of having received varicella vaccination (two doses); or Evidence of prior exposure to VZV based on serological testing (ie a positive VZV IgG Ab result) at Screening.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1- Ritlecitinib 100 milligrams (mg)<br>Randomized to Ritlecitinib 100 mg QD for 52 weeks before progressing into the up/down titration extension period, rerandomized according to responder status. | Drug: Ritlecitinib<br>* 100mg Capsule<br>|
| Experimental: Arm 2- Ritlecitinib 50mg<br>Randomized to Ritlecitinib 50 mg QD for 52 weeks before progressing into the up/down titration extension period, rerandomized according to responder status. | Drug: Ritlecitinib<br>* 50mg Capsule<br>|
| Placebo Comparator: Arm 3- Placebo<br>Randomized to Placebo QD for 52 weeks before progressing into the up/down titration extension period, rerandomized according to responder status. | Drug: Placebo<br>* Matching capsule<br>|
| Experimental: Arm 4- Ritlecitinib 100mg<br>Non-randomized open-label Ritlecitinib 100mg QD for 52 weeks. | Drug: Ritlecitinib<br>* 100mg Capsule<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| US only Co-Primary Endpoints: Response based on Total body Vitiligo Area Scoring Index 75 (T-VASI75) at Week 52 and T-VASI50 at Week 52 | Proportion of participants achieving T-VASI75 (defined as at least 75% improvement in T-VASI from Baseline) and T-VASI50 (defined as at least 50% improvement in T-VASI from Baseline) | 52 Weeks | 
| Global (Other than US): Response based on Facial Vitiligo Area Scoring Index 75 (F-VASI75) at Week 52 | Proportion of participants achieving F-VASI75 (defined as at least 75% improvement in F-VASI from Baseline). | 52 Weeks | 
| Incidence of Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) leading to discontinuation. | To evaluate the safety and tolerability of ritlecitinib in adult participants with non segmental vitiligo | Baseline through 108 weeks | 
| Incidence of Clinically significant laboratory abnormalities. |  | Baseline through 108 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| US-Only: Response based on F-VASI75 at 24, 26 and 52 weeks | Proportion of participants achieving at least a 75% improvement in F-VASI from Baseline. | 24, 36 and 52 Weeks | 
| US-Only: Response based on T-VASI50 at 24 and 36 weeks | Proportion of participants achieving T-VASI50 (defined as at least 50% improvement in T-VASI from Baseline). | 24 and 36 weeks | 
| Global (Other than US):Patient Global Impression of Severity-Face (PGIS-F) | To assess the effect of ritlecitinib compared to placebo on the PGIS-F at Week 36 and 52 | Week 36 and week 52 | 
| Global (Other than US): Patient Global Impression of Severity-Overall Vitiligo (PGIS-V) | To assess the effect of ritlecitinib compared to placebo on the PGIS-V at Week 36 and 52 | Week 36 and week 52 | 
| Global (Other Than US): Response based on T-VASI50 at Week 52 | Proportion of participants achieving T-VASI50 (defined as at least 50% improvement in T-VASI from Baseline). | Week 52 | 
| Patient Global Impression of Change-Face (PGIC-F) | To assess the effect of ritlecitinib compared to placebo on the PGIC-F at Weeks 36 and 52. | Week 36 and week 52 | 
| Patient Global Impression of Change- Overall vitiligo(PGIC-V) | To assess the effect of ritlecitinib compared to placebo on the PGIC-V at Weeks 36 and 52. | Week 36 and week 52 | 
| Global (Other than US): Response based on F-VASI75 at 24 and 36 weeks | Proportion of participants achieving F-VASI75 (defined as at least 75% improvement in F-VASI from Baseline). | 24 and 36 Weeks | 
| Change from baseline in Dermatology Life Quality Index (DLQI) | To evaluate the change from baseline in DLQI at week 52 | Week 52 | 
| Proportion of participants achieving disease stabilization | The difference in the proportion of participants with stable disease at all timepoints in participants with non segmental vitiligo treated with ritlecitinib 50 mg QD and 100mg compared to placebo | Baseline through week 104 | 
| Response based on T-VASI50 | Proportion of participants achieving T-VASI50 (defined as at least 50% improvement in T-VASI from Baseline) | Baseline through week 4, week 8, week 12, week 48, week 56, week 60, week 64, week 76, week 88 and week 104. | 
| Response based on F-VASI75 | Proportion of participants achieving F-VASI75 (defined as at least 75% improvement in F-VASI from Baseline) | Baseline through week 4, week 8, week 12, week 48, week 56, week 60, week 64, week 76, week 88 and week 104. | 
| Response based on T-VASI75 | Proportion of participants achieving T-VASI75 (defined as at least 75% improvement in T-VASI from Baseline) | Baseline through week 4, week 8, week 12, week 24, week 36, week 48, week 56, week 60, week 64, week 76, week 88 and week 104. | 
| Global (Other than US): Response based on T-VASI75 | Proportion of participants achieving T-VASI75 (defined as at least 75% improvement in T-VASI from Baseline) | Baseline through week 52 | 
| Proportion of participants with sustained improvement in T-VASI | Defined as maintenance of ≥T-VASI50 from Week 36 to Week 52 | Week 36 through week 52 | 
| Proportion of participants with sustained improvement in F-VASI | Defined as maintenance of ≥F-VASI75 from Week 36 to 52 | Week 36 through week 52 | 
| Time to rescue medication use |  | Baseline through week 104 | 
| Percentage change from baseline in F-VASI |  | Baseline through week 104 | 
| Percentage change from baseline in T-VASI |  | Baseline through week 104 | 
| Response based on T-VASI90 | Proportion of participants achieving T-VASI90 (defined as at least 90% improvement in T-VASI from Baseline) | Baseline through week 52 | 
| Response based on T-VASI100 | Proportion of participants achieving T-VASI90 (defined as at least 100% improvement in T-VASI from Baseline) | Baseline through week 52 | 
| Response based on F-VASI50 | Proportion of participants achieving F-VASI50 (defined as at least 50% improvement in F-VASI from Baseline). | Baseline through week 104 | 
| Change from baseline in the Hospital Anxiety and Depression Scale (HADS) | To assess the effect of ritlecitinib compared to placebo on depression and anxiety subscales of the HADS at week 52 | Week 52 | 
| The proportion of patients achieving absence of depression on HADS depression subscale | Response based on a 'normal' subscale score indicative of an absence of depression (in participants with baseline HADS subscale scores indicative of depression) | Week 52 | 
| The proportion of patients achieving absence of anxiety on HADS anxiety subscale | Response based on a 'normal' subscale score indicative of an absence of anxiety (in participants with baseline HADS subscale scores indicative of anxiety) | Week 52 | 
| US-Only: Patient Global Impression of Severity-Face (PGIS-F) | To assess the effect of ritlecitinib compared to placebo on the PGIS-F at 52 | Week 52 | 
| US-Only: Patient Global Impression of Severity-Overall Vitiligo (PGIS-V) | To assess the effect of ritlecitinib compared to placebo on the PGIS-V at 52 | Week 52 |