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

NCT ID: NCT02755649

Last Updated: 2020-08-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 325 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-01-31
• Study Completion Date: 2017-03-31

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.

Conditions

Atopic Dermatitis

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Placebo QW + TCS

Participants received one subcutaneous (SC) injection of dupilumab matching placebo once per week (QW) (following two SC injections on day 1) from Week 1 to Week 15. All participants were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, participants could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Participants who did not enter the OLE study were followed for up to an additional 12 weeks for safety (\[Week 28, end of study (EOS) period\]).

Group Type: EXPERIMENTAL

Matching Placebo

Intervention Type: DRUG

Dupilumab 300 mg Q2W + TCS

Participants received one subcutaneous (SC) injection of dupilumab 300 mg every 2 weeks (Q2W) from Week 1 to Week 15 (following a SC loading dose of 600 mg on day 1). During weeks in which dupilumab was not administered, participants received matching placebo. All participants were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, participants could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Participants who did not enter the OLE study were followed for up to an additional 12 weeks for safety (\[Week 28, end of study (EOS) period\]).

Group Type: EXPERIMENTAL

Dupilumab

Intervention Type: DRUG

Dupilumab 300 mg QW + TCS

Participants received one subcutaneous (SC) injection of dupilumab 300 mg once per week (QW) (following an SC loading dose of 600 mg on day 1) from Week 1 to Week 15. All participants were required to undergo treatment with topical corticosteroids (TCS) using a standardized regimen that continued through the end of the treatment period (Week 16). Starting at week 16, participants could roll over into an open-label extension (OLE) study (R668-AD-1225), if they were considered eligible. Participants who did not enter the OLE study were followed for up to an additional 12 weeks for safety (\[Week 28, end of study (EOS) period\]).

Group Type: EXPERIMENTAL

Dupilumab

Intervention Type: DRUG

Interventions

Dupilumab

Intervention Type: DRUG

Matching Placebo

Intervention Type: DRUG

Other Intervention Names

DUPIXENT®; REGN668; SAR231893

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Sanofi

INDUSTRY

Sponsor Role: collaborator

Regeneron Pharmaceuticals

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trial Management

Role: STUDY_DIRECTOR

Regeneron Pharmaceuticals

Locations

Site 1

Vienna, , Austria

Site 2

Vienna, , Austria

Brussels, , Belgium

Leuven, , Belgium

Loverval, , Belgium

Site 1

Berlin, , Germany

Site 2

Berlin, , Germany

Site 3

Berlin, , Germany

Site 4

Berlin, , Germany

Site 5

Berlin, , Germany

Site 6

Berlin, , Germany

Site 7

Berlin, , Germany

Bochum, , Germany

Site 1

Dresden, , Germany

Site 2

Dresden, , Germany

Site 3

Dresden, , Germany

Erlangen, , Germany

Frankfurt am Main, , Germany

Site 1

Hamburg, , Germany

Site 2

Hamburg, , Germany

Heidelberg, , Germany

Kiel, , Germany

Langenau, , Germany

Leipzig, , Germany

Lübeck, , Germany

Magdeburg, , Germany

Mahlow, , Germany

Mainz, , Germany

Site 1

München, , Germany

Site 2

München, , Germany

Münster, , Germany

Osnabrück, , Germany

Selters, , Germany

Stuttgart, , Germany

Tübingen, , Germany

Dublin, , Ireland

Amsterdam, , Netherlands

Utrecht, , Netherlands

Site 1

Bialystok, , Poland

Site 1

Bydgoszcz, , Poland

Site 2

Bydgoszcz, , Poland

Gdansk, , Poland

Site 1

Katowice, , Poland

Site 2

Katowice, , Poland

Site 3

Katowice, , Poland

Kielce, , Poland

Site 1

Krakow, , Poland

Site 2

Krakow, , Poland

Site 1

Lodz, , Poland

Site 2

Lodz, , Poland

Site 3

Lodz, , Poland

Lublin, , Poland

Szczecin, , Poland

Site 1

Warsaw, , Poland

Site 2

Warsaw, , Poland

Warsaw, , Poland

Site 1

Wroclaw, , Poland

Site 2

Wroclaw, , Poland

Zgierz, , Poland

Chelyabinsk, , Russia

Kazan', , Russia

Moscow, , Russia

Ryazan, , Russia

Saint Petersburg, , Russia

Košice, , Slovakia

Svidník, , Slovakia

Site 1

Barcelona, , Spain

Site 2

Barcelona, , Spain

Site 1

London, , United Kingdom

Site 2

London, , United Kingdom

Oxford, , United Kingdom

Portsmouth, , United Kingdom

Sheffield, , United Kingdom

Countries

Austria; Belgium; Germany; Ireland; Netherlands; Poland; Russia; Slovakia; Spain; United Kingdom

References

Silverberg JI, Lynde CW, Abuabara K, Patruno C, de Benedetto A, Zhang H, Thomas RB, Bego-Le-Bagousse G, Khokhar FA, Vakil J, Marco AR, Levit NA. Efficacy and Safety of Dupilumab Maintained in Adults >/= 60 Years of Age with Moderate-to-Severe Atopic Dermatitis: Analysis of Pooled Data from Four Randomized Clinical Trials. Am J Clin Dermatol. 2023 May;24(3):469-483. doi: 10.1007/s40257-022-00754-4. Epub 2023 Feb 20.

Reference Type: DERIVED

PMID: 36808602 (View on PubMed)

Paller AS, Silverberg JI, Cork MJ, Guttman-Yassky E, Lockshin B, Irvine AD, Kim MB, Kabashima K, Chen Z, Lu Y, Bansal A, Rossi AB, Shabbir A. Efficacy and Safety of Dupilumab in Patients With Erythrodermic Atopic Dermatitis: A Post Hoc Analysis of 6 Randomized Clinical Trials. JAMA Dermatol. 2023 Mar 1;159(3):255-266. doi: 10.1001/jamadermatol.2022.6192.

Reference Type: DERIVED

PMID: 36723913 (View on PubMed)

Mickevicius T, Pink AE, Bhogal M, O'Brart D, Robbie SJ. Dupilumab-Induced, Tralokinumab-Induced, and Belantamab Mafodotin-Induced Adverse Ocular Events-Incidence, Etiology, and Management. Cornea. 2023 Apr 1;42(4):507-519. doi: 10.1097/ICO.0000000000003162. Epub 2022 Dec 15.

Reference Type: DERIVED

PMID: 36525340 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 34142350 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33453450 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33165005 (View on PubMed)

Eichenfield LF, Bieber T, Beck LA, Simpson EL, Thaci D, de Bruin-Weller M, Deleuran M, Silverberg JI, Ferrandiz C, Folster-Holst R, Chen Z, Graham NMH, Pirozzi G, Akinlade B, Yancopoulos GD, Ardeleanu M. Infections in Dupilumab Clinical Trials in Atopic Dermatitis: A Comprehensive Pooled Analysis. Am J Clin Dermatol. 2019 Jun;20(3):443-456. doi: 10.1007/s40257-019-00445-7.

Reference Type: DERIVED

PMID: 31066001 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 29336016 (View on PubMed)

Other Identifiers

R668-AD-1424

Identifier Type: -

Identifier Source: org_study_id