Ritlecitinib for Cicatricial Alopecia

Study Overview
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Brief Summary
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Alopecia could be subdivided into two main groups of diseases: non-scarring alopecia, such as male pattern baldness, or alopecia areata (AA), in which hair follicles are preserved, yet quiescent, and scarring alopecia, also known as cicatricial alopecia (CA), in which hair follicles are irreversibly destroyed. CA leads to scarred areas, most commonly on the scalp, that cannot re-grow hair. Despite being a long-term condition, that often has significant impact on patients' well-being, available effective treatments for these diseases are lacking. In addition, the molecular abnormalities causing CA are largely unknown. The research team will be administering a new investigational drug (a JAK3/TEC inhibitor), ritlecitinib, which has shown statistically significant improvement in scalp hair loss for AA patients in a proof of concept and phase 2b/3 studies (B7981015 AA study). This is an open-label clinical trial. CA patients will be asked to provide small samples of skin and blood throughout the treatment period, to find out how they respond to the drug, and to attempt to better understand these diseases.

Official Title
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A Pilot Study to Assess Safety and Biomarker Responses of Ritlecitinib (JAK3/TEC Inhibitor) in Cicatricial Alopecia

Conditions
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Cicatricial Alopecia

Intervention / Treatment
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* Drug: PF-06651600


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA Subjects of any gender, age 18 years or older, at the time of informed consent at Screening Subjects who are willing and able to adhere to the study visit schedule and comply with protocol requirements. Subject self-reports a history of at least 6 months of CA (LPP/FFA or CCCA). Diagnosis will be made clinically (according to the LPPAI37, FFASI36 and/or CHLG38). Subject has a negative Tuberculin purified protein derivative (PPD) or QuantiFERON TB-Gold test (QFT) at screening or within the last 12 months. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP) OR; Is a WOCBP (all female participants, regardless of whether or not they have experienced/reported menarche, are considered WOCBP unless they are permanently sterile or confirmed infertile). A WOCBP who is sexually active must use a contraceptive method that is highly effective, with a failure rate of <1%, during the intervention period and for at least 28 days after the last dose of study intervention. And if a WOCBP, must have a negative highly sensitive serum pregnancy test at the screening visit and a negative urine pregnancy test at baseline performed before the first dose of study intervention. Subject is judged to be in otherwise good overall health following a detailed medical and medication history, physical examination, and laboratory testing. EXCLUSION CRITERIA Subject's cause of hair loss is indeterminable and/or they have concomitant causes of alopecia, such pregnancy-related, drug-induced, telogen effluvium, or advanced androgenetic alopecia. Subject has a history of CA for ≥ 7 years since their disease onset, severe fibrosing disease, or very rapid hair loss at screening (de novo patients only). Subject has a history of moderate to severe keloids on the scalp, as determined by clinical examination at screening. Other scalp disease that may impact assessment (e.g., scalp psoriasis, dermatitis, etc.). Subject is pregnant or breastfeeding. Participation in other studies involving investigational drug(s) within 4 weeks or within 5 half-lives (if known), whichever is longer, prior to study entry and/or during study participation (de novo patients only). Active systemic diseases that may cause hair loss (e.g., systemic lupus erythematosus, thyroiditis, systemic sclerosis, etc.). Any Psychiatric condition in the opinion of the investigator precludes participation in the study. Subjects with a Columbia Suicide Severity Rating Scale (C-SSRS) score of yes on questions 4 and/or 5 at Visit 2 (Baseline). 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 (particularly thyroid disease which can be associated with hair loss), 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, the subject is inappropriate for entry into this study, or unwilling/unable to comply with STUDY PROCEDURES. History of thromboembolic events including DVT and PE or history of inherited coagulopathies. Any present malignancies or history of malignancies with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in situ. History of any lymphoproliferative disorder such as Epstein Barr Virus (EBV) related lymphoproliferative disorder, history of lymphoma, history of leukemia, or signs and symptoms suggestive of current lymphatic or lymphoid disease. History (single episode) of disseminated herpes zoster or disseminated herpes simplex, or a recurrent (more than one episode of) localized, dermatomal herpes zoster. History of systemic infection requiring hospitalization, parenteral antimicrobial therapy, or as otherwise judged clinically significant by the investigator within 6 months prior to Day 0. Active acute or chronic infection requiring treatment with oral antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 4 weeks prior to Day 0 or superficial skin infection within 1 week prior to Day 0. Significant trauma or major surgery within 1 month of signing informed consent. Considered in imminent need for surgery or with elective surgery scheduled to occur during the study. Active hepatitis B, hepatitis C, human immunodeficiency virus (HIV), or positive HIV serology at the time of screening for subjects determined by the investigators to be at high-risk for this disease. ANY of the following abnormalities in the clinical laboratory tests at screening, as assessed by the study-specific laboratory and confirmed by a single repeat, if deemed necessary: Absolute neutrophil count of <1.2 x 109/L (<1200/mm3); Hemoglobin <11.0 g/dL or hematocrit <33%; Platelet count of <150 x 109/L (<150,000/mm3); Absolute lymphocyte count of <0.80 x 109 /L (<800/mm3); Estimated Glomerular Filtration Rate (eGFR) less than 60 mL/ml/min/1.73m2 based on CKD-Epi 2021 (creatine equation); Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) values >2 times the ULN; Total bilirubin greater than or equal to 1.5 times the ULN; participants with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is less than or equal to ULN. Have an active history of alcohol or substance abuse within 1 year prior to Day 0. Donation of blood in excess of 500 mL within 8 weeks prior to Day 0. Subject has received a live attenuated vaccine ≤ 6 weeks prior to study screening. Subject has any uncertain or clinically significant laboratory abnormalities that may affect interpretation of study data or endpoints, at determined by the PI. History of adverse systemic or allergic reactions to components of study drug. Use of systemic immunosuppressive medications, including, but not limited to, cyclosporine, systemic corticosteroids, mycophenolate mofetil, azathioprine, methotrexate, within 8 weeks prior to baseline visit. Use of other non-biologic systemic agent for CA, including, 5α-reductase inhibitors, hydroxychloroquine, or retinoids, within 4 weeks prior to baseline visit. Use of an intralesional corticosteroids or oral JAK inhibitor (tofacitinib, ruxolitinib, or any JAK1/TYK2 product) within 4 weeks prior to the baseline visit (de novo patients only). Subject has used topical corticosteroids, and/or tacrolimus, and/or pimecrolimus or cyclosporine within 1 week before the baseline visit. Subject has been previously treated with biological drugs in the last 12 weeks for other indications. Subjects previously tested with a positive or indeterminable PPD or QFT result, including subjects that completed standard tuberculosis therapy. Screening 12-lead ECG that demonstrates clinically significant abnormalities requiring treatment, e.g. acute myocardial infarction, serious tachy or brady arrhythmias or that are indicative of serious underlying heart disease (e.g. cardiomyopathy, major congenital heart disease, low voltage in all leads, Wolff-Parkinson-White syndrome and other clinically relevant abnormalities which may affect participant safety or interpretation of study results. A history of additional risk factors for Torsades de Pointes (TdP) (e.g. heart failure, hypokalemia, family history of long QT syndrome). If QTcF exceeds 450 ms, or QRS exceeds 120 ms, the ECG should be repeated 2 more times and the average of 3 QTc or QRS values should be used to determine the participants' eligibility. Participants with average screening value QTcF > 450 ms should be excluded. The use of prohibited and permitted CYP3A substrates are provided in Appendix 2.1 and 2.2, respectively and medications that prolong the QT/QTcF interval in Appendix 3. Have hearing loss with progression over the previous 5 years, or 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 acute, fluctuating, or progressive.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06651600 (Ritlecitinib)<br>200 mg once-daily for 8 weeks and then 100 mg once daily for the remaining 40 weeks | Drug: PF-06651600<br>* tablets containing active drug (a combined JAK3/TEC inhibitor)<br>* Other names: Ritlecitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treatment-Emergent Adverse Events | The adverse event will be described and categorized as Treatment-emergent, Serious, abnormal in vital signals, and abnormalities in laboratory parameters. | Week 48 | 
| Severity of Treatment-Emergent Adverse Events | The adverse event will be categorized according to CTCAE guidelines when applicable | Week 48 | 
| Change in Ct values of mRNA levels of CCL5 gene | Changes in mRNA Levels of CCL5 gene expression in skin biopsies quantified by normalized Ct values obtained by quantitative real-time PCR assay, measured at baseline and week 24. The unit of the outcome is called Ct value and it represents the number of amplification cycles to reach a level of fluorescence in the experiment. The Ct value is directly associated to the level of expression of a gene | Baseline to Week 24 | 
| Change in Ct values of mRNA levels of CCL5 gene | Changes in mRNA Levels of CCL5 gene expression in skin biopsies quantified by normalized Ct values obtained by quantitative real-time PCR assay, measured at baseline and week 48. The unit of the outcome is called Ct value and it represents the number of amplification cycles to reach a level of fluorescence in the experiment. The Ct value is directly associated to the level of expression of a gene. | Baseline to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Ct values of mRNA levels of CXCR3 | Changes in mRNA Levels of CXCR3 gene expression in skin biopsies quantified by normalized Ct values obtained by quantitative real-time PCR assay, measured at baseline and week 24. The unit of the outcome is called Ct value and it represents the number of amplification cycles to reach a level of fluorescence in the experiment. The Ct value is directly associated to the level of expression of a gene. | Baseline to Week 24 | 
| Ct value of mRNA levels of CXCR3 | Changes in mRNA Levels of CXCR3 gene expression in skin biopsies quantified by normalized Ct values obtained by quantitative real-time PCR assay, measured at baseline and week 48. The unit of the outcome is called Ct value and it represents the number of amplification cycles to reach a level of fluorescence in the experiment. The Ct value is directly associated to the level of expression of a gene. | Baseline to Week 48 | 
| The Frontal Fibrosis Alopecia Severity Index (FFASI) | The Frontal Fibrosis Alopecia Severity Index utilizes clinical images of the entire hairline from a total score of 0-84, with higher score indicating more severity. | Baseline | 
| The Frontal Fibrosis Alopecia Severity Index (FFASI) | The Frontal Fibrosis Alopecia Severity Index utilizes clinical images of the entire hairline, from a total score of 0-84, with higher score indicating more severity. | Week 24 | 
| The Frontal Fibrosis Alopecia Severity Index (FFASI) | The Frontal Fibrosis Alopecia Severity Index utilizes clinical images of the entire hairline, from a total score of 0-84, with higher score indicating more severity. | Week 48 | 
| The Lichen Planopilaris Activity Index (LPPAI) | The Lichen Planopilaris Activity Index is a numeric composite index that aggregates symptoms and signs of pruritus, pain, burning, scalp erythema , perifollicular erythema, perifollicular scale , pull test and spreading. Symptoms and signs are measured in a 4-point scale (0-absent, 1-mild, 2-moderate and 3-severe). Full range from 0-10, higher score indicates more severity. | Baseline | 
| The Lichen Planopilaris Activity Index (LPPAI) | The Lichen Planopilaris Activity Index is a numeric composite index that aggregates symptoms and signs of pruritus, pain, burning, scalp erythema , perifollicular erythema, perifollicular scale , pull test and spreading. Symptoms and signs are measured in a 4-point scale (0-absent, 1-mild, 2-moderate and 3-severe). Full range from 0-10, higher score indicates more severity. | Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FFA, frontal fibrosing alopecia, lichen planopilaris, LPP, central centrifugal, scarring alopecia, CCCA