A study to assess the efficacy and safety of Dupilumab in patients with severe atopic dermatitis (AD) that are not controlled with oral cyclosporine A (CSA) or for those who cannot take oral CSA because it is not medically advisable

Phase 1

Conditions: Atopic dermatitis
MedDRA version: 20.0Level: LLTClassification code 10003639Term: Atopic dermatitisSystem Organ Class: 100000004858
Therapeutic area: Diseases [C] - Skin and Connective Tissue Diseases [C17]

Registration Number: EUCTR2015-002653-35-PL

Lead Sponsor: Regeneron Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 330

Inclusion Criteria

1. Male or female, 18 years or older
2. Severe, Chronic AD, (according to American Academy of Dermatology Consensus Criteria [Eichenfield 2014])
3. EASI score =20 at the screening and baseline visits
4. IGA score =3 (on the 0 to 4 IGA scale) at the screening and baseline visits
5. =10% body surface area (BSA) of AD involvement at the screening and baseline visits
6. Documented recent history (within 6 months before the screening visit) of inadequate response to treatment with TCS
7. Have applied a stable dose of topical emollient (moisturizer) twice daily for at least the 7 consecutive days immediately before the baseline visit
8. Documented history by a physician of either:
A. No prior CSA exposure and not currently a candidate for CSA treatment due to:
• medical contraindications (eg, uncontrolled hypertension on medication), or
• use of prohibited concomitant medications (eg, statins, digoxin, macrolide
• antibiotics, barbiturates, anti-seizure, nonsteroidal anti-inflammatory drugs,
• diuretics, angiotensin-converting-enzyme inhibitors, St John’s Wort, etc), or
• increased susceptibility to CSA-induced renal damage (elevated creatinine) and
• liver damage (elevated function tests), or
• increased risk of serious infections, or
• hypersensitivity to CSA active substance or excipients,
OR
B. Previously exposed to CSA, and CSA treatment should not be continued or restarted due to:
• intolerance and/or unacceptable toxicity (eg, elevated creatinine, elevated liver function tests, uncontrolled hypertension, paraesthesia, headache, nausea, hypertrichosis, etc), or
• inadequate response to CSA (defined as flare of AD on CSA tapering after a maximum of 6 weeks of high dose [5 mg/kg/day] to maintenance dose [2 to 3 mg/kg/day] or a flare after a minimum of 3 months on maintenance dose). Flare is defined as increase in signs and/or symptoms leading to escalation of therapy, which can be an increase in dose, a switch to a higher-potency class of TCS, or the start of another systemic non-steroidal immunosuppressive drug. Or
• requirement for CSA at doses >5 mg/kg/day, or duration beyond those specified in the prescribing information (>1 year).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 130

Exclusion Criteria

1. Participation in a prior dupilumab clinical study
2. Treatment with an investigational drug within 8 weeks or within 5 half-lives (if known), whichever is longer, before the screening visit
3. Hypersensitivity and/or intolerance to corticosteroids or to any other ingredients contained in the TCS product used in the study
4. Systemic CSA, systemic corticosteroids, or phototherapy within 4 weeks prior to screening, and azathioprine (AZA), methotrexate (MTX), mycophenolate mofetil (MMF), or Janus kinase (JAK) inhibitors within 8 weeks prior to screening
5. Treatment with TCI within 1 week before the screening visit
6. Treatment with biologics as follows:
• Any cell-depleting agents including but not limited to rituximab: within 6 months before the screening visit, or until lymphocyte count returns to normal, whichever is longer
• Other biologics: within 5 half-lives (if known) or 16 weeks prior to the screening visit, whichever is longer
7. Regular use (more than 2 visits per week) of a tanning booth/parlor within 4 weeks of the screening visit
8. Treatment with a live (attenuated) vaccine within 12 weeks before the screening
9. Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiparasitics, antiprotozoals, or antifungals within 2 weeks before the screening
or superficial skin infections within 1 week before the screening visit. NOTE: patients may be rescreened no sooner than 2 weeks after infection resolves.
10. Known or suspected history of immunosuppression, including history of invasive opportunistic infections (eg, tuberculosis [TB], histoplasmosis, Listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite infection resolution; or unusually frequent, recurrent, or prolonged infections, per investigator judgment
11. Presence of any 1 of the following TB criteria:
a. A positive tuberculin skin test at the screening visit
b. A positive blood QuantiFERON®-TB or T-Spot test at the screening visit
c. Chest x-ray (posterior-anterior and lateral views) at screening or within 3 months before the screening visit (radiology report must be available) with results consistent with prior TB infection (including but not limited to apical scarring, apical fibrosis, or multiple calcified granuloma). This does not include non-caseating granulomata.
NOTE: Any of these 3 TB tests will be performed on a country-by-country basis according to local guidelines only if required by regulatory authorities or ethics boards.
12. History of human immunodeficiency virus (HIV) infection or positive HIV serology at screening
13. Positive hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBc Ab), or hepatitis C antibody (HCV Ab) at the screening visit

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To evaluate the efficacy of 2 dose regimens of dupilumab compared to placebo, administered with concomitant topical corticosteroids (TCS), in adult patients with severe AD who are not adequately controlled with, or are intolerant to, oral CSA, or when this treatment is currently not medically advisable.;Secondary Objective: To assess the safety and tolerability of 2 dose regimens of dupilumab compared to placebo, administered with concomitant TCS, in adult patients with severe AD who are not adequately controlled with, or are intolerant to, oral CSA, or when this treatment is currently not medically advisable.;Primary end point(s): The primary endpoint in the study is the proportion of patients with EASI 75 (=75% improvement from baseline) at week 16<br>;Timepoint(s) of evaluation of this end point: At week 16.

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): The secondary endpoints are:<br><br>Efficacy<br>- Proportion of patients with EASI 75 (=75% improvement from baseline) at week 16 for patients with prior CSA use<br>- Proportion of patients with IGA 0 or 1 (on the 0 to 4 IGA scale) and a reduction from baseline of =2 points at week 16<br>- Percent change from baseline to week 16 in the pruritus NRS<br>- Percent change from baseline to week 16 in the SCORAD<br>- Change in Quality of Life Measures<br><br>Safety and Tolerability<br>- Incidence of treatment-emergent serious adverse events (TESAEs) from baseline through the on-treatment period<br>- Overall incidence of TEAEs from baseline through the on-treatment period;Timepoint(s) of evaluation of this end point: Week 16

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