Safety and Efficacy of ARQ-252 Cream 0.3% in Subjects With Non-Segmental Facial Vitiligo

Study Overview
=================
Brief Summary
-----------------
This study will assess the safety and efficacy of ARQ-252 cream in combination with NB-UVB phototherapy treatment in individuals with non-segmental facial vitiligo.

Detailed Description
-----------------
This study is a Phase 2a, parallel group, double blind, vehicle-controlled study of the safety and efficacy of ARQ-252 0.3% cream in combination with NB-UVB phototherapy treatment in subjects with non-segmental facial vitiligo.

Official Title
-----------------
A Phase 2a, Proof of Concept, 24-Week, Parallel Group, Double Blind, Vehicle-Controlled Study of the Safety and Efficacy of ARQ-252 Cream 0.3% in Subjects With Non-Segmental Facial Vitiligo

Conditions
-----------------
Vitiligo

Intervention / Treatment
-----------------
* Drug: ARQ-252 cream 0.3%
* Drug: ARQ-252 Vehicle cream
* Device: NB-UVB phototherapy active treatment
* Device: NB-UVB phototherapy sham treatment


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject is legally competent to sign and give informed consent. Males and females ages 18 years and older (inclusive) Clinical diagnosis of non-segmental vitiligo involving face. A Facial Vitiligo Area Severity Index [F-VASI] score of ≥ 0.25 at baseline. Vitiligo of the face involving at least ≥ 0.25% body surface area (BSA) involvement (ie, one quarter of one handprint). Subjects may have non-facial vitiligo elsewhere which will not be included in the minimum BSA. The maximum BSA (total body inclusive of the face, whether or not in areas to be treated in this study) permitted is 15%. Subjects with vitiligo on the hands, forearms, or elbows agree to treat these areas in addition to the face, with investigational product and phototherapy. Subject agrees to discontinue all agents used to treat vitiligo from screening through the final safety follow-up visit. Over-the-counter preparations deemed acceptable by the Investigator and camouflage makeups are permitted. Female subject of childbearing potential (FOCBP) must have a negative serum pregnancy test at Screening and negative urine pregnancy test at Baseline (Visit 2). For FOCBP involved in any sexual intercourse that could lead to pregnancy: the subject must agree to use a highly effective contraceptive method for at least 4 weeks prior to Day 1. Additionally, from Day 1 until at least 4 weeks after the last investigational product administration, these subjects must agree to use at least 1 highly effective contraceptive method in addition to 1 barrier method. Female subject of non-childbearing potential must either be post-menopausal with spontaneous amenorrhea for at least 12 months prior to baseline (post-menopausal status will be confirmed with FSH testing) or have undergone surgical sterilization. Males, if engaging in sexual intercourse with a female who is pregnant or a female of child-bearing potential, must agree to use a condom every time during the study and every time subsequently until 4 weeks beyond the last dose of investigational product. Males must agree not to donate sperm from the first dose of investigational product until 4 weeks after the last dose of investigational product. Subject is in good health as judged by the Investigator, based on medical history, physical examination, 12-lead electrocardiogram (ECG), serum chemistry labs, hematology values, and urinalysis. Exclusion Criteria: Subjects who have ever used skin bleaching treatments for treatment of vitiligo or other pigmented areas, eg, depigmenting agents such as monobenzyl ether of hydroquinone, including Benoquin® (Monobenzone) Use of any other prior and concomitant therapy that is a contraindication to phototherapy or may otherwise interfere with the objective of the study as per discretion of the Investigator, such as drugs that cause photosensitivity or skin pigmentation (eg, antibiotics such as tetracyclines, antifungals) within 8 weeks of Baseline (Visit 2). More than 33% leukotrichia in facial lesions (assessed via dermatoscope). Other forms of vitiligo (eg, segmental vitiligo); or other skin depigmentation disorder that would confound study assessments. Use of oral or systemic immunomodulating medications (eg, corticosteroids, azathioprine, methotrexate, cyclosporine) within 8 weeks of Baseline (Visit 2). Use of prescription or over-the-counter topical treatments that may affect vitiligo (eg, corticosteroids, tacrolimus/pimecrolimus, retinoids, vitamin D derivates, psoralens) within 4 weeks prior to Baseline (Visit 2). Use of any biological or experimental therapy for vitiligo within 24 weeks of Baseline (Visit 2) (or 5 half-lives, whichever is longer). Use of phototherapy (including laser and tanning beds) within 8 weeks prior to Baseline (Visit 2). Previous oral or topical JAK inhibitor therapy within 24 weeks prior to Baseline (Visit 2), and/or prior non-response to oral or topical JAK inhibitor therapy for vitiligo History of melanocyte-keratinocyte transplantation procedure (MKTP) or other surgical treatment for vitiligo. Contraindication to phototherapy, such as photosensitivity disorder (eg, lupus, polymorphic light eruption, solar urticaria, dermatomyositis) or use of photosensitizing or phototoxic medications. Subjects with clinically significant abnormal thyroid-stimulating hormone or free T4 at screening, or otherwise uncontrolled thyroid function at screening as determined by the investigator (Note: If the subject has a history of thyroid disease and is on treatment, the participant must be on a stable thyroid regimen for at least 3 months prior to baseline) History of chronic alcohol or drug abuse within 6 months prior to baseline. Subjects with a cytopenia at screening, defined as follows: Leukocytes < 3 × 10^9/L (2.5 × 10^9/L for subjects who are African-American), Neutrophils < lower limit of normal (<1.5x10^9/L), Lymphocytes < 0.8 × 10^9/L, Hemoglobin < 10 g/dL, Platelets < 100 × 10^9/L. Subjects with current or a history of non-skin cancer within 5 years with the exception carcinoma in situ of the cervix. Subjects with greater than 3 adequately treated nonmetastatic basal cell carcinomas (BCC) or squamous cell carcinomas (SCC) within 12 months prior to Baseline (Visit 2), or a previous history of multiple BCC or SCC on any area of the body, which may pose additional risks from participation in the study, in the opinion of the Investigator. Subjects with previous history of melanoma anywhere on the body, or basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or actinic keratosis (AK) on the face, neck, hands, forearms, or elbows. Subjects that have received live vaccine therapy less than 4 weeks prior Baseline (Visit 2), or anticipate receiving a live or live-attenuated vaccination during the course of the study, have received immunosuppressive drugs less than 4 weeks prior Baseline, or have known infection with mycobacterium tuberculosis, hepatitis B or C, or HIV, or have a diagnosis of an immunodeficiency disorder. Subject had a major surgery within 4 weeks prior to Baseline or has a major surgery planned during the study. Subjects with severe renal insufficiency (as evidenced by estimated glomerular filtration rate <40 mL/min) or with severely impaired liver function (Child-Pugh Class C), ALT or AST ≥ 2 × ULN, total bilirubin > 1.5 x ULN, or total bilirubin > ULN and ≤ 1.5 x ULN AND direct bilirubin is > 35% of total bilirubin, ALP ≥ 2x ULN Subjects with known or suspected hypersensitivity to component(s) of the investigational product. Pregnant or lactating women or women planning to become pregnant during the study and / or within 28 days following the last dose of investigational product. Subjects who cannot discontinue the use of strong systemic Cytochrome P-450 CYP3A4 inducers e.g., efavirenz, nevirapine, glucocorticoids, barbiturates (including phenobarbital), phenytoin, rifampin and carbamazepine for 2 weeks prior to Baseline and during the study period. Subjects who cannot discontinue the use of strong systemic Cytochrome P-450 CYP3A4 inhibitors e.g., indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, fluconazole, nefazodone, saquinavir, suboxone and telithromycin for 2 weeks prior to Baseline and during the study period.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This study is a parallel group, double blind, vehicle-controlled study in which subjects with non-segmental vitiligo will be randomized to ARQ-252 0.3% cream BID or vehicle cream BID, and active phototherapy or sham phototherapy for 24 weeks to affected areas of vitiligo on the face, neck, hands, forearms, and elbows, (Up to 15% total body BSA)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active IP and Active Phototherapy<br>ARQ-252 cream 0.3% BID with phototherapy. | Drug: ARQ-252 cream 0.3%<br>* ARQ-252 cream 0.3%<br>Device: NB-UVB phototherapy active treatment<br>* NB-UVB phototherapy active treatment<br>|
| Active Comparator: Active IP and Sham Phototherapy<br>ARQ-252 cream 0.3% BID with sham phototherapy | Drug: ARQ-252 cream 0.3%<br>* ARQ-252 cream 0.3%<br>Device: NB-UVB phototherapy sham treatment<br>* NB-UVB phototherapy sham treatment<br>|
| Placebo Comparator: Vehicle and Active Phototherapy<br>ARQ-252 Vehicle cream BID with active phototherapy | Drug: ARQ-252 Vehicle cream<br>* ARQ-252 Vehicle cream<br>Device: NB-UVB phototherapy active treatment<br>* NB-UVB phototherapy active treatment<br>|
| Placebo Comparator: Vehicle and Sham Phototherapy<br>ARQ-252 Vehicle cream BID with sham phototherapy | Drug: ARQ-252 Vehicle cream<br>* ARQ-252 Vehicle cream<br>Device: NB-UVB phototherapy sham treatment<br>* NB-UVB phototherapy sham treatment<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Facial Vitiligo Area Scoring Index (F-VASI) | The proportion of subjects achieving F-VASI75 (≥ 75% change from baseline in F-VASI score). | Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Facial Vitiligo Area Scoring Index (F-VASI) | Proportion of subjects achieving F-VASI50 (≥ 50% change from baseline in F-VASI score), F-VASI75 (≥ 75% change from baseline in F-VASI score), F-VASI90 (≥ 90% change from baseline in F-VASI score). | Week 4, 8, 12, 16, 20, and 24 | 
| Facial Body Surface Area (F-BSA) | Percent change from baseline in F-BSA affected over time. | Week 4, 8, 12, 16, 20, and 24 | 
| Vitiligo Noticeability Scale (VNS) | Proportion of subjects in each category of the VNS. The VNS is a patient-reported measure of vitiligo treatment success, which has a 5-point scale, with 1 being more noticeable and 5 being no longer noticeable. The VNS will be completed for vitiligo on the face. | Week 4, 8, 12, 16, 20, and 24. | 
| Vitiligo Quality of Life (VitiQOL) | Change from Baseline in the VitiQoL, an instrument consisting of 16-item questionnaire (with a 7-point numerical scale from 0 - Not at all to 6 - All of the time) designed to assess disease specific health-related quality of life (HRQL) in patients suffering from vitiligo and also provide an objective measure of disease status, burden of disease, and treatment outcome. | Baseline, Week 4, 8, 12, 16, 20, and 24 | 
| Patient Global Impression of Change-Vitiligo (PaGIC-V) | Proportion of patients in each PaGIC-V category, a 7-point scale comparing facial vitiligo at baseline with the subject's treated facial vitiligo at the study visit (with 1- very much improved and 7 - very much worse), and time to achieve a PaGIC-V of very much improved or much improved. | Week 4, 8, 12, 16, 20, and 24 | 
| F-VASI | Time to achieve F-VASI50 and time to achieve F-VASI75. | Week 4, 8, 12, 16, 20, and 24 | 
| Facial Static Investigator Global Assessment (FsIGA) | Proportion of subjects with FsIGA, (a four point scale of vitiligo severity for the face only) of clear or almost clear (0 or 1) and time to achieve FsIGA of clear or almost clear (0 or 1). | Week 4, 8, 12, 16, 20, and 24 | 
| FsIGA | FsIGA of clear or almost clear (0 or 1) plus 2-grade improvement from baseline. | Week 4, 8, 12, 16, 20, and 24 | 
| F-VASI Change from Baseline | Percent change from baseline in F-VASI score over time. | Week 4, 8, 12, 16, 20, and 24 |