A Pilot Study of the Efficacy and Safety of Dupilumab Versus Placebo in Patients With Netherton Syndrome

Study Overview
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Brief Summary
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To date, there are no effective therapy for the management of Netherton Syndrome (NS) Patients use emollients with a limited efficacy on scaling and no efficacy on skin inflammation and pruritus. They may also use topical corticosteroids or calcineurin inhibitors in case of eczematous lesions. The use of therapies targeting skin inflammation has been reported in a few case reports. Their efficacy is very limited and their uses are limited because of the chronicity of the disease, the impaired skin barrier function and the risk for skin infections and skin cancers. Therefore, there is a huge medical need for novel therapies in NS.The expected consequences of this study are that a 16-week course of dupilumab will be more effective than placebo for the treatment of moderate to severe NS Dupilumab could therefore improve skin condition and quality of life.

Detailed Description
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This is a proof of concept (pilot) double-blind randomized placebo-controlled study evaluating the efficacy and safety of dupilumab for the treatment of NS. Patients will be randomized in a 2:1 ratio to receive dupilumab (2 doses of 300 mg), or placebo, at baseline and then 1 dose of dupilumab 300 mg, or placebo, every 2 weeks until week 14 (total of 8 administrations).Moderate to severe NS were selected in order to be able to measure the improvement of skin condition.

Official Title
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A Randomized Double-blinded Pilot Study of the Efficacy and Safety of Dupilumab Versus Placebo in Patients With Netherton Syndrome

Conditions
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Netherton Syndrome

Intervention / Treatment
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* Drug: Dupilumab Prefilled Syringe
* Other: Placebo Prefilled Syringe


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients affiliated to a social insurance protection regimen. Clinical diagnosis of NS (7) (trichorrhexis invaginata, extensive scaling, skin inflammation, allergic manifestations) and absent or marked reduction of LEKTI staining. Moderate to severe forms: NASA (Netherton Area Severity Assessment score) score ≥ 5/12 at inclusion. Patients able to understand the study procedures including the ability to complete patient-based self-assessment questionnaires. Patients who agree to sign the written informed consent. Exclusion Criteria: Hypersensitivity to dupilumab or its excipients. Modification of the usual treatment (emollients and topical corticosteroids used on a regular basis) within 2 weeks before inclusion. Treatment with topical calcineurin inhibitors 1 week before inclusion. Treatment with oral immunosuppressant (including cyclosporine, methotrexate, azathioprine, mycophenolate mofetil), oral retinoids (acitretin, alitretinoin, isotretinoin) or phototherapy within 4 weeks before inclusion. Treatment with immunomodulating biologics (Tumor Necrosis Factor (TNF) inhibitor) 16 weeks before inclusion. Treatment with another investigational drug within 8 weeks before inclusion. Treatment with a systemic antibiotic within 2 weeks before inclusion. Active skin infection requiring the use of a systemic therapy within 2 weeks before the inclusion. Any other condition that according to the investigator will impair the ability to evaluate treatment effect. Known or suspected history of immunosuppression, including history of invasive opportunistic infections (e.g., tuberculosis, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis). Current infections including infection with helminthes. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed during the study. Women of childbearing age, potentially sexually active, and unwilling to use adequate birth control methods. Mental or physical incapacity to fill in the questionnaires.

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
Interventional Model Description: one arm with dupilumab (2/3 of patients) and one arm with placebo (1/3 of patients)
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dupilumab<br>The patient will receive 2 doses at baseline and then 1 dose every 2 weeks (8 administrations in total) of Dupilumab 300 mg (syringe of 2 mL for subcutaneous administration). | Drug: Dupilumab Prefilled Syringe<br>* administration of dupilumab corresponding to dupilumab arm<br>|
| Placebo Comparator: Placebo<br>The patient will receive 2 doses at baseline and then 1 dose every 2 weeks (8 administrations in total) of placebo (syringe of 2 mL for subcutaneous administration).. | Other: Placebo Prefilled Syringe<br>* administration of placebo corresponding to placebo arm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The severity of the disease of the Netherton Area Severity Assessment score (NASA). | NASA score | Day 0 and week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical efficacy severity of pruritus and pain | NASA score | Day 0, week 2, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 28 | 
| Presence of infections (adverse event) | Number of Bacterial or viral Skin infections | Day 0, week 2, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 28 | 
| Quantity of dermocorticosteroids used between each visit will be evaluated by questioning the patient. | number of tubes multiplied by the weight of one tube | Day 0, week 2, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 28 | 
| QOL score | QOL score | Day 0, Week 16 and 28 | 
| Skin inflammation | number of inflammation markers on biopsies | Day 0 and week 16 | 
| Protease activity | number of protease markers on biopsies | Day 0 and week 16 | 
| Microbiome qualitative and quantitative analysis | number and form of bacteria | Day 0 and week 16 | 
| Transepidermal water loss (TEWL) | Measured by a Tewameter applied on a standardized area in the anterior aspect of the forearm, | Day 0 and Week 16 | 
| Safety of dupilumab | Blood tests performed every month until Week 16 (liver and renal tests, total blood count) | Day 0, week 2, week 4, week 6, week 8, week 10, week 12, week 14, week 16, week 28 |