Clinical trial NCT02755649: A Study to Assess the Efficacy and Safety of Dupilumab in Participants 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
Official title: A Phase 3 Study Investigating the Efficacy, Safety, and Tolerability of Dupilumab Administered to Adult Patients With Severe Atopic Dermatitis Who Are Not Adequately Controlled With or Are Intolerant to Oral Cyclosporine A, or When This Treatment is Not Medically Advisable
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Atopic Dermatitis
Lead sponsor: Regeneron Pharmaceuticals
Sponsor class: INDUSTRY
Collaborators: name: Sanofi
First posted: 2016-04-29
Enrollment: 325
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The main objective of the trial is 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 Cyclosporine A (CSA), or when this treatment is currently not medically advisable.

The secondary objective is 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.


Eligibility criteria: Inclusion Criteria:

1. Male or female, 18 years or older
2. Severe, Chronic AD, (according to American Academy of Dermatology Consensus Criteria \[Eichenfield 2014\]) for whom treatment with potent TCS is indicated
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:

   1. 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
   2. 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)

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:

    1. A positive tuberculin skin test at the screening visit
    2. A positive blood QuantiFERON®-TB or T-Spot test at the screening visit
    3. 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

Primary outcomes:
measure: Percentage of Participants With Eczema Area and Severity Index (EASI) 75 (≥75% Improvement From Baseline) at Week 16
timeFrame: Baseline, Week 16
Secondary outcomes:
measure: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Score at Week 16
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in Weekly Average of Peak Pruritus Numerical Rating Scale (NRS) at Week 16
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in SCORing Atopic Dermatitis (SCORAD) Score at Week 16
timeFrame: Baseline, Week 16
measure: Percentage of Participants With Improvement (Reduction ≥4 Points) of Weekly Average of Peak Daily Pruritus NRS From Baseline to Week 16
timeFrame: Baseline to Week 16
measure: Change From Baseline in Percent Body Surface Area (BSA) Involvement With Atopic Dermatitis (AD) at Week 16
timeFrame: Baseline, Week 16
measure: Percentage of Participants With Investigator Global Assessment (IGA) 0 or 1 (on the 0 to 4 IGA Scale) and a Reduction From Baseline of ≥2 Points at Week 16
timeFrame: Baseline, Week 16
measure: Change From Baseline in the Dermatology Life Quality Index (DLQI) at Week 16
timeFrame: Baseline, Week 16
measure: Change From Baseline in the Patient Oriented Eczema Measure (POEM) at Week 16
timeFrame: Baseline, Week 16
measure: Percentage of Participants With Eczema Area and Severity Index (EASI) Score (≥75% Improvement From Baseline) at Week 16 for Participants With Prior CSA Use
timeFrame: Baseline, Week 16
measure: Change From Baseline in Mean Weekly Dose of Topical Corticosteroid (TCS) Use During Treatment Period
timeFrame: Baseline to week 16
measure: Change From Baseline in Total Hospital Anxiety and Depression Scale (HADS) Score at Week 16
timeFrame: Baseline, Week 16
measure: Percentage of Participants Achieving SCORAD 50 (≥50% Improvement From Baseline) at Week 16
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in the Total Global Individual Signs Score (GISS) at Week 16 (Erythema, Infiltration/ Papulation, Excoriations, Lichenification)
timeFrame: Baseline, Week 16
measure: Percent Change From Baseline in Weekly Average of Peak Pruritus Numerical Rating Scale (NRS) Score at Week 2
timeFrame: Baseline, Week 2
measure: Percentage of Participants With Skin Infection Treatment Emergent Adverse Events (TEAEs) (Excluding Herpetic Infections) From Baseline Through Treatment Period
timeFrame: Baseline to Week 16
measure: Percentage of Participants Having at Least One Serious Treatment Emergent Adverse Event (TEAE) Through Treatment Period
timeFrame: Baseline to Week 16
measure: Percentage of Participants Having at Least One Treatment-Emergent Adverse Event (TEAE) Leading to Treatment Discontinuation Through Treatment Period
timeFrame: Baseline to Week 16
measure: Percentage of Participants With Treatment-Emergent Adverse Events Through Treatment Period
timeFrame: Baseline to Week 16
Other outcomes:
Locations:
city: Vienna
country: Austria
facility: Site 1
city: Vienna
country: Austria
facility: Site 2
city: Brussels
country: Belgium
city: Leuven
country: Belgium
city: Loverval
country: Belgium
city: Berlin
country: Germany
facility: Site 1
city: Berlin
country: Germany
facility: Site 2
city: Berlin
country: Germany
facility: Site 3
city: Berlin
country: Germany
facility: Site 4
city: Berlin
country: Germany
facility: Site 5
city: Berlin
country: Germany
facility: Site 6
city: Berlin
country: Germany
facility: Site 7
city: Bochum
country: Germany
city: Dresden
country: Germany
facility: Site 1
city: Dresden
country: Germany
facility: Site 2
city: Dresden
country: Germany
facility: Site 3
city: Erlangen
country: Germany
city: Frankfurt am Main
country: Germany
city: Hamburg
country: Germany
facility: Site 1
city: Hamburg
country: Germany
facility: Site 2
city: Heidelberg
country: Germany
city: Kiel
country: Germany
city: Langenau
country: Germany
city: Leipzig
country: Germany
city: Lubeck
country: Germany
city: Magdeburg
country: Germany
city: Mahlow
country: Germany
city: Mainz
country: Germany
city: Muenster
country: Germany
city: Munchen
country: Germany
facility: Site 1
city: Munchen
country: Germany
facility: Site 2
city: Osnabrück
country: Germany
city: Selters
country: Germany
city: Stuttgart
country: Germany
city: Tubingen
country: Germany
city: Dublin
country: Ireland
city: Amsterdam
country: Netherlands
city: Utrecht
country: Netherlands
city: Bialystok
country: Poland
facility: Site 1
city: Bydgoszcz
country: Poland
facility: Site 1
city: Bydgoszcz
country: Poland
facility: Site 2
city: Gdansk
country: Poland
city: Katowice
country: Poland
facility: Site 1
city: Katowice
country: Poland
facility: Site 2
city: Katowice
country: Poland
facility: Site 3
city: Kielce
country: Poland
city: Krakow
country: Poland
facility: Site 1
city: Krakow
country: Poland
facility: Site 2
city: Lodz
country: Poland
facility: Site 1
city: Lodz
country: Poland
facility: Site 2
city: Lodz
country: Poland
facility: Site 3
city: Lublin
country: Poland
city: Szczecin
country: Poland
city: Warsaw
country: Poland
city: Warszawa
country: Poland
facility: Site 1
city: Warszawa
country: Poland
facility: Site 2
city: Wroclaw
country: Poland
facility: Site 1
city: Wroclaw
country: Poland
facility: Site 2
city: Zgierz
country: Poland
city: Chelyabinsk
country: Russian Federation
city: Kazan
country: Russian Federation
city: Moscow
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Kosice
country: Slovakia
city: Svidnik
country: Slovakia
city: Barcelona
country: Spain
facility: Site 1
city: Barcelona
country: Spain
facility: Site 2
city: London
country: United Kingdom
facility: Site 1
city: London
country: United Kingdom
facility: Site 2
city: Oxford
country: United Kingdom
city: Portsmouth
country: United Kingdom
city: Sheffield
country: United Kingdom
Study officials:
affiliation: Regeneron Pharmaceuticals
name: Clinical Trial Management
role: STUDY_DIRECTOR
References:
citation: Griffiths C, de Bruin-Weller M, Deleuran M, Fargnoli MC, Staumont-Salle D, Hong CH, Sanchez-Carazo J, Foley P, Seo SJ, Msihid J, Chen Z, Cyr SL, Rossi AB. Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis and Prior Use of Systemic Non-Steroidal Immunosuppressants: Analysis of Four Phase 3 Trials. Dermatol Ther (Heidelb). 2021 Aug;11(4):1357-1372. doi: 10.1007/s13555-021-00558-0. Epub 2021 Jun 18.
citation: Boguniewicz M, Beck LA, Sher L, Guttman-Yassky E, Thaci D, Blauvelt A, Worm M, Corren J, Soong W, Lio P, Rossi AB, Lu Y, Chao J, Eckert L, Gadkari A, Hultsch T, Ruddy M, Mannent LP, Graham NMH, Pirozzi G, Chen Z, Ardeleanu M. Dupilumab Improves Asthma and Sinonasal Outcomes in Adults with Moderate to Severe Atopic Dermatitis. J Allergy Clin Immunol Pract. 2021 Mar;9(3):1212-1223.e6. doi: 10.1016/j.jaip.2020.12.059. Epub 2021 Jan 13.
citation: Silverberg JI, Simpson EL, Guttman-Yassky E, Cork MJ, de Bruin-Weller M, Yosipovitch G, Eckert L, Chen Z, Ardeleanu M, Shumel B, Hultsch T, Rossi AB, Hamilton JD, Orengo JM, Ruddy M, Graham NMH, Pirozzi G, Gadkari A. Dupilumab Significantly Modulates Pain and Discomfort in Patients With Atopic Dermatitis: A Post Hoc Analysis of 5 Randomized Clinical Trials. Dermatitis. 2021 Oct 1;32(1S):S81-S91. doi: 10.1097/DER.0000000000000698.
citation: de Bruin-Weller M, Graham NMH, Pirozzi G, Shumel B. Could conjunctivitis in patients with atopic dermatitis treated with dupilumab be caused by colonization with Demodex and increased interleukin-17 levels?: reply from the authors. Br J Dermatol. 2018 May;178(5):1220-1221. doi: 10.1111/bjd.16348. Epub 2018 Mar 2. No abstract available.