Treatment of Alopecia Areata (AA) With Dupilumab in Patients With and Without Atopic Dermatitis (AD)

Study Overview
=================
Brief Summary
-----------------
Alopecia areata is a medical condition, in which the hair falls out in patches. The hair can fall out on the scalp or elsewhere on the face and body. Alopecia areata is an autoimmune skin disease, which means that the immune system is recognizing the hair follicles as foreign and attacking them, causing round patches of hair loss. It can progress to total scalp hair loss (alopecia totalis) or complete body hair loss (alopecia universalis). The scalp is the most commonly affected area, but the beard or any hair-bearing site can be affected alone or together with the scalp. Alopecia areata occurs in males and females of all ages, and is a highly unpredictable condition that tends to recur. Alopecia areata can cause significant distress to both patients and their families. In this study, the aim is to assess the effects of dupilumab in patients with alopecia areata.

Detailed Description
-----------------
The purpose of this study is to assess whether dupilumab can be a helpful treatment for alopecia areata. This is a randomized, double-blind, placebo-controlled pilot study of a total of 54 subjects with moderate to severe alopecia areata involving 30-100% of the scalp. The researchers expect one third of these subjects to have concomitant alopecia areata (AA) and atopic dermatitis (AD). The researchers' experience in AD, and past experience in psoriasis showed that biomarker studies in skin tissues are critical to the understanding of key pathogenic pathways that are upregulated in each disease and how well they are suppressed with effective treatment. These mechanistic studies coupled with clinical trials are key in the disease to shed light on important disease mechanisms, and to explain which molecules are suppressed by each therapeutic target. Data shows that IL-13 is significantly upregulated in both AD and AA lesions compared to nonlesional skin. It is very important to associate the clinical responses with suppression of this cytokine and related molecules as well as other pathway cytokines in skin tissues. Both the whole genomic profiling and individual molecular and cellular markers are very important in order to understand how well anti-IL-13 will change/suppress AA-associated pathways and compare with those that will be suppressed in AD. Since this study is designed to gain basic knowledge rather than to yield information directly related to patient care, the results are not entered in the participants' medical records. If, at a later date, correlations of in-vitro tests and the patients' clinical situation suggest that the results do bear on the patients' health, an amended protocol will be submitted to the IRB so that results can be made available to the medical record.

Official Title
-----------------
Defining Reversal of Alopecia Areata (AA) Phenotype With Dupilumab in Patients With and Without Associated Atopic Dermatitis (AD)

Conditions
-----------------
Alopecia Areata

Intervention / Treatment
-----------------
* Drug: Dupilumab
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female subjects who are at least 18 years old at the time of informed consent. Subject is able to understand and voluntarily sign an informed consent document prior to participation Subject is able to adhere to the study visit schedule and other protocol requirements. Females of childbearing potential (FCBP) must have a negative pregnancy test at Screening and Baseline. While on investigational product and for at least 28 days after taking the last dose of investigational product (IP), FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below: Option 1: Any one of the following highly effective methods: hormonal contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation; or partner's vasectomy; OR Option 2: Male or female condom (latex condom or non-latex condom NOT made out of natural [animal] membrane [for example, polyurethane]); PLUS one additional barrier method: (a) diaphragm with spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with spermicide. If subject is a female of non-childbearing potential, she must have documented history of infertility, be in a menopausal state for one year, or had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy. Subject has a history of at least 6 months of moderate to severe AA (≥ 30% scalp involvement) as measured using the SALT score; OR subject has ≥ 95% loss of scalp hair for enrollment as AA totalis (AT) or universalis (AU) subtypes. AT and AU will be limited to 50% of the total number of subjects enrolled. One-third of subjects must have active AD skin or a concomitant history of AD at the time of the Screening and Baseline visits. Subject has a negative Tuberculin purified protein derivative (PPD) or QuantiFERON TB-Gold test (QFT) prior to baseline. Subjects with a positive or indeterminable PPD or QFT result must have a documented negative workup for tuberculosis and/or completed standard tuberculosis therapy. Subjects must meet the following laboratory criteria: White blood cell count ≥ 3000/mm3 (≥ 3.0 x 109/L) and < 14,000/mm3 (≤ 14 x 109/L). Platelet count ≥ 100,000/μL (≥ 100 x 109/L). Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L). AST (SGOT) and ALT (SGPT) ≤ 2 x upper limit of normal (ULN). If the initial test shows ALT or AST > 2 times the ULN, one repeat test is allowed during the Screening Phase. Total bilirubin ≤ 2 mg/dL (34 μmol/L). If the initial test shows total bilirubin > 2 mg/dL (34 μmol/L), one repeat test is allowed during the Screening Phase. Hemoglobin ≥ 10 g/dL (≥ 6.2 mmol/L). 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 is pregnant or breastfeeding. Subject's cause of hair loss is indeterminable and/or they have concomitant causes of alopecia, such traction, cicatricial, pregnancy-related, drug-induced, telogen effluvium, or advanced androgenetic alopecia (i.e. Ludwig Type III or Norwood-Hamilton Stage ≥ V). Subject has a history of AA with no evidence of hair regrowth for ≥ 10 years since their last episode of hair loss. Subject has an active bacterial, viral, or helminth parasitic infections; OR a history of ongoing, recurrent severe infections requiring systemic antibiotics Subject with a known or suspected underlying immunodeficiency or immune-compromised state as determined by the investigator. Subject has a concurrent or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, intestinal, metabolic, endocrine, pulmonary, cardiovascular, or neurological disease. 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. Subject has a suspected or active lymphoproliferative disorder or malignancy; OR a history of malignancy within 5 years before the Baseline assessment, except for completely treated in situ non-melanoma skin and cervical cancers without evidence of metastasis. Subject has received a live attenuated vaccine ≤ 30 days prior to study randomization. Subject has any uncertain or clinically significant laboratory abnormalities that may affect interpretation of study data or endpoints. Subject has any other medical or psychological condition that, in the opinion of the investigator, may present additional unreasonable risks as a result of their participation in the study and/or interfere with clinic visits and necessary study assessments. History of adverse systemic or allergic reactions to any component of the study drug. Severe, untreated asthma or a history of life-threatening asthma exacerbations while on appropriate anti-asthmatic mediations. Use of systemic immunosuppressive medications, including, but not limited to, cyclosporine, systemic or intralesional corticosteroids, mycophenolate mofetil, azathioprine, methotrexate, tacrolimus, or ultraviolet (UV) phototherapy with/without Psoralen Ultraviolet A (PUVA) therapy within 4 weeks prior to randomization. Use of an oral JAK inhibitor (tofacitinib, ruxolitinib) within 12 weeks prior to the Baseline visit. Subject has used topical corticosteroids, and/or tacrolimus, and/or pimecrolimus within 1 week before the Baseline visit. Subject has been previously treated with dupilumab. Subject currently uses or plans to use anti-retroviral therapy at any time during the study.

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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>An initial dupilumab dose of 600 mg (two 300 mg subcutaneous injections), followed by dupilumab 300 mg given every week | Drug: Dupilumab<br>* A total of 24 doses<br>* Other names: Dupixent;|
| Placebo Comparator: Placebo<br>Matching placebo in prefilled syringes identical to the dupilumab syringes | Drug: Placebo<br>* A total of 24 doses<br>* Other names: matching placebo;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Severity of Alopecia Tool (SALT) Score at Week 24 | The SALT is a validated instrument for measuring the amount of scalp hair loss at a single point in time The SALT is a validated instrument for measuring the amount of scalp hair loss at a single point in time SALT - Scalp divided into four areas: vertex (40% of scalp surface area), right profile (18% of scalp surface area), left profile (18% of scalp surface area), and posterior scalp (24% of scalp surface area). Percentage of hair loss in these areas is multiplied by percent surface area of the scalp in that area. SALT score is the sum of percentage of hair loss in all areas. SALT scores range from 0 (no hair loss) to 100 (complete scalp hair loss) with lower score indicating better health outcomes/less hair loss. Primary Outcome is baseline minus Week 24 value. | Baseline and 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Week 24 in the SALT Score at Week 48 | SALT - Scalp divided into four areas: vertex (40% of scalp surface area), right profile (18% of scalp surface area), left profile (18% of scalp surface area), and posterior scalp (24% of scalp surface area). Percentage of hair loss in these areas is multiplied by percent surface area of the scalp in that area. SALT score is the sum of percentage of hair loss in all areas. Week 24 minus week 48 value. | Week 24 and 48 weeks | 
| Change From Baseline in the SALT Score at Week 48 | Change in SALT score at Week 48 compared to Baseline. SALT - Scalp divided into four areas: vertex (40% of scalp surface area), right profile (18% of scalp surface area), left profile (18% of scalp surface area), and posterior scalp (24% of scalp surface area). Percentage of hair loss in these areas is multiplied by percent surface area of the scalp in that area. SALT score is the sum of percentage of hair loss in all areas. SALT scores range from 0 (no hair loss) to 100 (complete scalp hair loss) with lower score indicating better health outcomes/less hair loss. Baseline minus week 48 value. | Baseline and 48 weeks | 
| Number of Patients Achieving at Least 50% Improvement in Severity of Alopecia Tool (SALT) Score (SALT-50) at Weeks 24 and 48 Compared to Baseline | Number of subjects achieving SALT-50 score at Weeks 24 and 48 compared to Baseline. SALT - Scalp divided into four areas: vertex (40% of scalp surface area), right profile (18% of scalp surface area), left profile (18% of scalp surface area), and posterior scalp (24% of scalp surface area). Percentage of hair loss in these areas is multiplied by percent surface area of the scalp in that area. SALT score is the sum of percentage of hair loss SALT scores range from 0 (no hair loss) to 100 (complete scalp hair loss) with lower score indicating better health outcomes/less hair loss.in all areas. | weeks 24 and 48 | 
| Number of Patients Achieving at Least 75% Improvement in SALT-75 at Weeks 24 and 48 | Number of patients with Severity of Alopecia Tool (SALT) Score (SALT-75) (> or equal to 75% improvement in SALT score) at Weeks 24 compared to Baseline. SALT - Scalp divided into four areas: vertex (40% of scalp surface area), right profile (18% of scalp surface area), left profile (18% of scalp surface area), and posterior scalp (24% of scalp surface area). Percentage of hair loss in these areas is multiplied by percent surface area of the scalp in that area. SALT score is the sum of percentage of hair loss in all areas. SALT scores range from 0 (no hair loss) to 100 (complete scalp hair loss) with lower score indicating better health outcomes/less hair loss. | Weeks 24 and 48 | 
| Number of Patients Achieving at Least 90% Improvement in Severity of Alopecia Tool (SALT) Score (SALT-90) at Weeks 24 and 48 | The number of patients achieving at least 90% improvement in Severity of Alopecia Tool (SALT) score (SALT-90) at Weeks 24, 48 compared to Baseline | Weeks 24 and 48 | 
| Change in Alopecia Areata Symptom Impact Scale (AASIS) | Change in AASIS at Weeks 24 and 48 compared to Baseline. AASIS is a 13-item instrument, each item scored from 0 to 10 where higher scores correspond to worse symptom impact, full range from 0 to 130. | Weeks 24 and 48 | 
| Change in Alopecia Areata Quality of Life Questionnaire | Change in the Alopecia Areata Quality of Life questionnaire (AA-QoL) at Weeks 24 and 48 compared to baseline. AAQoL is a 21-item instrument scored from 0 (poor) to 100 (good). | Weeks 24 and 48 | 
| Eyelash/Eyebrow Assessment Score Weeks 12, 24, 36, and 48 Compared to Baseline | Change in eyelash and eyebrow scores at Weeks 12, 24, 36, and 48 compared to baseline. The Eyelash/Eyebrow Assessment score based on a 5-point scale, ranging from 0 (none) to 4 (very prominent eyelashes/eyebrows). | Weeks 12, 24, 36, and 48 | 
| Change in EASI Scores From Baseline at Week 24 and 48 | Change from baseline in Eczema Area and Severity Index (EASI) at Weeks 24 and 48. EASI scores range from 0 (no symptoms) to 72 (severe eczema) with lower score indicating better health outcomes/less eczema. | Weeks 24 and 48 | 
| Number of Adverse Events | Safety profile of dupilumab in subjects with AA by reported adverse effects, physical examinations and laboratory parameters | 48 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
alopecia, alopecia areata, alopecia universalis, alopecia totalis, dupixent, dupilumab