PLACEBO-CONTROLLED SAFETY STUDY OF RITLECITINIB (PF-06651600) IN ADULTS WITH ALOPECIA AREATA

Study Overview
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Brief Summary
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This is a global Phase 2a randomized, double-blind, placebo-controlled study to evaluate the safety and tolerability of ritlecitinib in adults aged 18 to ≤50 years of age with ≥25% scalp hair loss due to Alopecia Areata (AA).

Official Title
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A PHASE 2a, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY INVESTIGATING THE SAFETY OF RITLECITINIB (PF-06651600) IN ADULT PARTICIPANTS WITH ALOPECIA AREATA

Conditions
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Alopecia Areata

Intervention / Treatment
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* Drug: PF-06651600
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of alopecia areata, including alopecia totalis and alopecia universalis. At least 25% hair loss due to alopecia areata Must have normal hearing and normal brainstem auditory evoked potentials (BAEPs) Must have a normal neurological exam; can have a stable unilateral median neuropathy or ulnar neuropathy Signed informed consent Stable regimen for other medications before and during the study Exclusion Criteria: Other significant medical conditions Occupational or recreational noise exposure History of peripheral neuropathy or first degree relative with a hereditary peripheral neuropathy HbA1c > or = 7.5% at Screening Recurrent or disseminated Herpes Zoster Active or chronic infection; or infection requiring hospitalization or IV antimicrobials within 6 months Active or latent (insufficiently treated) Hepatitis Active or latent (insufficiently treated) TB Concomitant medications associated with peripheral neurologic or hearing loss Protocol specific laboratory abnormalities

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm: PF-06651600<br>ritlecitinib 200 milligram (mg) once per day (QD) (four 50 mg tablets) for 4 weeks then ritlecitinib 50 mg tablet QD through month 24. At Month 9, participants assigned to this treatment arm will also receive 3 tablets of placebo for 4 weeks to maintain the blind with the other arm. After month 24, participants switch to 50 mg capsules, 1 QD, up to month 60. | Drug: PF-06651600<br>* 50 mg tablet, dosed as 200 mg QD or 50 mg QD 50 mg capsule, dosed as 50 mg QD<br>* Other names: ritlecitinib;|
| Other: Control Arm (Placebo) followed by active therapy extension<br>matching comparator: placebo QD (4 tablets x 4 weeks then 1 tablet x 8 months) then ritlecitinib 200 mg QD (four 50 mg tablets) for 4 weeks then ritlecitinib 50 mg tablet QD through month 24. After month 24, participants switch to 50 mg capsules, 1 QD, up to month 60. | Drug: Placebo<br>* tablet, dosed as 4 tablets QD or 1 tablet QD<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in I-V Interwave Latency on Brainstem Auditory Evoked Potentials (BAEP) at a Stimulus Intensity of 80 Decibels (dB) From the Right Side at Month 9 | BAEP interwave I-V latency (in milliseconds) was the primary endpoint for this study. High-intensity stimulation (80dB) was used. Participants had BAEP evaluations performed at the same evaluation center, by the same audiology professional using the same equipment, during the study. Audiology and BAEP evaluations were done on the same day, with audiology assessment first. If they could not be done on the same day, assessments had to be within 7 days of each other. A central reader was used for BAEP to confirm that locally read BAEP waves were labelled appropriately and at their peak so that latency were accurate. Central reading also ensured consistency in BAEP interpretation. | Baseline, Month 9 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Change From Baseline in I-V Interwave Latency on BAEP at a Stimulus Intensity of 80 dB From the Left Side at Month 9 | BAEP interwave I-V latency was the primary endpoint for this study. High-intensity stimulation (80dB) was used. Participants had BAEP evaluations performed at the same evaluation center, by the same audiology professional using the same equipment, during the study. Audiology and BAEP evaluations were done on the same day, with audiology assessment first. If they could not be done on the same day, assessments had to be within 7 days of each other. A central reader was used for BAEP to confirm that locally read BAEP waves were labelled appropriately and at their peak so that latency were accurate. Central reading also ensured consistency in BAEP interpretation. | Baseline, Month 9 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in I-V Interwave Latency on BAEP at 80 dB From the Right Side at Month 6 | High-intensity stimulation (80dB) was used. Participants had BAEP evaluations performed at the same evaluation center, by the same audiology professional using the same equipment, during the study. Audiology and BAEP evaluations were done on the same day, with audiology assessment first. If they could not be done on the same day, assessments had to be within 7 days of each other. A central reader was used for BAEP to confirm that locally read BAEP waves were labelled appropriately and at their peak so that latency were accurate. Central reading also ensured consistency in BAEP interpretation. | Baseline, Month 6 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Change From Baseline in I-V Interwave Latency on BAEP at 80 dB From the Left Side at Month 6 | High-intensity stimulation (80dB) was used. Participants had BAEP evaluations performed at the same evaluation center, by the same audiology professional using the same equipment, during the study. Audiology and BAEP evaluations were done on the same day, with audiology assessment first. If they could not be done on the same day, assessments had to be within 7 days of each other. A central reader was used for BAEP to confirm that locally read BAEP waves were labelled appropriately and at their peak so that latency were accurate. Central reading also ensured consistency in BAEP interpretation. | Baseline, Month 6 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Change From Baseline in Percentage of Intraepidermal Nerve Fiber (IENF) With Axonal Swelling in Skin Punch Biopsies at Month 9 | The endpoint axonal dystrophy referred to the percentage of IENF with axonal swellings. Axonal swellings were evaluated in peripheral skin punch biopsies from the distal part of lower extremities. Axonal swellings were counted by axon. Any IENF with single or multiple swellings was counted as a single event, ie, a single axon with axonal swellings. For each participant, data were reported as the percentage of IENF with any number of swellings. IENF was assessed at Day 1 and Month 9. Participants who had entered the Active Therapy Extension Phase at Month 6 had a skin punch biopsy taken at Month 6 for IENF assessments instead of at Month 9. The skin biopsy was collected before the start of Active Therapy Extension Phase. | Baseline, Month 9 (Month 6 for the 2 participants who entered the Active Therapy Extension Phase at Month 6). Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase. | 
| Change From Baseline in Intraepidermal Nerve Fiber Density (IENFD) in Skin Punch Biopsies at Month 9 | IENFD was evaluated in peripheral skin punch biopsies from the distal part of lower extremities. IENFD was measured by counting the number of fibers and fiber branches that independently crossed the dermal-epidermal barrier (basement membrane). Secondary branching was excluded from quantification and fragments were not counted. The length of the histology section was measured (mm) and the linear epidermal nerve fiber density was reported as number of intraepidermal nerve fibers/mm. | Baseline, Month 9 (Month 6 for the 2 participants who entered the Active Therapy Extension Phase at Month 6). Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase. | 
| Change From Baseline in Amplitude of Wave V on BAEP at a Stimulus Intensity of 80 dB From the Right Side at Month 6 and Month 9 | High-intensity stimulation (80dB) was used. Participants had BAEP evaluations performed at the same evaluation center, by the same audiology professional using the same equipment, during the study. Audiology and BAEP evaluations were done on the same day, with audiology assessment first. If they could not be done on the same day, assessments had to be within 7 days of each other. A central reader was used for BAEP to confirm that locally read BAEP waves were labelled appropriately and at their peak so that amplitude data were accurate. Central reading also ensured consistency in BAEP interpretation. | Baseline, Month 6 and Month 9 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Change From Baseline in Amplitude of Wave V on BAEP at a Stimulus Intensity of 80 dB From the Left Side at Month 6 and Month 9 | High-intensity stimulation (80dB) was used. Participants had BAEP evaluations performed at the same evaluation center, by the same audiology professional using the same equipment, during the study. Audiology and BAEP evaluations were done on the same day, with audiology assessment first. If they could not be done on the same day, assessments had to be within 7 days of each other. A central reader was used for BAEP to confirm that locally read BAEP waves were labelled appropriately and at their peak so that amplitude data were accurate. Central reading also ensured consistency in BAEP interpretation. | Baseline, Month 6 and Month 9 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Number of Participants With Absence of Wave V on BAEP at Stimulus Intensities Ranging From 80 dB to 40 dB From Right Side up to Month 9 | Absence of wave V on BAEP at stimulus intensities ranging from 80dB to 40dB were summarized descriptively using number of participants by treatment group at each intensity level. At Month 9, 1 participant in 200/50 mg had absence of Wave V on BAEP at a stimulus intensity of 40 dB on the right side. The event was unilateral and showed fluctuations in the presence or absence of Wave V at various intensities on repeat assessments starting at Month 6. Hearing sensitivity remained normal from screening through Month 9. The case was reviewed by a panel of neuroaudiology experts who concluded that there was no evidence of neural transmission abnormality in the auditory nerve or auditory brainstem and that the likely explanation for the absence of Wave V was that the evoked response amplitude was too small for it to be identified within the electroencephalogram (EEG). | Baseline, Month 6 and Month 9 | 
| Number of Participants With Absence of Wave V on BAEP at Stimulus Intensities Ranging From 80 dB to 40 dB From Left Side up to Month 9 | Absence of wave V on BAEP at stimulus intensities ranging from 80dB to 40dB were summarized descriptively using number of participants by treatment group at each intensity level. | Baseline, Month 6 and Month 9 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Seriousness of an AE was assessed under the criteria of serious adverse event (SAE). An SAE was defined as any untoward medical occurrence that, at any dose: resulted in death; was life-threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent disability/incapacity; was a congenital anomaly/birth defect, etc. Treatment-emergent events were with onset date occurring during the on-treatment period. Relatedness to study treatment was determined by the investigator. | Approximately 16 months | 
| Number of Participants Who Discontinued From Study Due to Adverse Event (AEs) | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Participants who had an AE record that indicated that the AE caused the participant to be discontinued from the study. Relatedness to study treatment was determined by the investigator. | Approximately 16 months | 
| Number of Participants Who Discontinued Study Drug Due to AE and Continued Study | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. This Outcome Measures presented the number of participants who had an AE record that indicated that action taken with study treatment was drug withdrawn but AE did not cause the participant to be discontinued from study. Relatedness to study treatment was determined by the investigator. | Approximately 16 months | 
| Number of Participants With Temporary Drug Discontinuation Due to AEs | An AE was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants with temporary drug discontinuation due to both all-causality and treatment-related AEs are presented below. Relatedness to study treatment was determined by the investigator. | Approximately 16 months | 
| Number of Participants With Clinically Significant Abnormalities in Vital Signs | Oral, tympanic, or axillary temperature, pulse rate, respiratory rate, and blood pressure (BP) were assessed. BP and pulse measurements were assessed in a chair, back supported and arms bared (free of restrictions such as rolled-up sleeves, etc) and supported at heart level. Measurements were taken on the same arm at each visit (preferably non-dominant) with a completely automated device. Pulse rate was measured at approximately the same time as BP for a minimum of 30 seconds. BP and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (eg, television, cell phones). Participants refrained from smoking or ingesting caffeine during the 30 minutes preceding the measurements. The clinical significance was determined by the investigator. | Approximately 16 months | 
| Number of Participants With Clinically Significant Abnormalities in Clinical Laboratory Values | Safety laboratory assessments included the categories of Hematology, Chemistry, Urinalysis and other tests. The clinical significance was determined by the investigator. | Approximately 16 months | 
| Change From Baseline in Overall Severity of Alopecia Tool (SALT) Scores up to Month 9 | SALT is a quantitative assessment of AA severity based on scalp terminal hair loss. The overall SALT score included hair loss regardless of etiology (ie, scalp hair loss due to both non-AA and AA) and was collected at study visits. The Overall SALT Score ranged from 0 to 100%, with higher scores representing greater amount of hair loss. | Baseline, Months 3, 6 and 9 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Change From Baseline in Alopecia Areata - Severity of Alopecia Tool (AA-SALT) Score up to Month 9 | SALT is a quantitative assessment of AA severity based on scalp terminal hair loss. AA-SALT is the amount of scalp hair loss due to AA. AA SALT score in Placebo-Controlled Phase = overall SALT score - non-AA SALT score (The non-AA SALT score only took into account scalp hair loss other than that due to AA and was required to be assessed only at Month 9 [or Month 6 for those who entered the Active Therapy Extension Phase at Month 6] in Placebo-Controlled Phase). The AA-SALT Score ranged from 0 to 100%, with higher scores representing greater amount of hair loss. | Baseline, Months 3, 6 and 9 (Baseline was defined as the last non-missing measurement obtained before the first dose in the placebo-controlled phase) | 
| Number of Participants With Patient's Global Impression of Change (PGI-C) Response up to Month 9 | The PGI-C asked the participants to evaluate the improvement or worsening of their AA as compared to the start of the study using a single item, Since the start of the study, my alopecia areata has: …. The participants selected one of seven responses ranging from greatly improved to greatly worsened. This Outcome Measure presented the number of participants with PGI-C response which was defined as greatly improved or moderately improved. Participants with missing PGI-C scores were considered as non-responders. | Months 1, 3, 6 and 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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JAK, alopecia totalis, alopecia universalis, hair loss, alopecia, ritlecitinib, PF-06651600, double-blind, placebo-controlled, phase 2a