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Clinical Trial
. 2020 Feb 1;156(2):131-143.
doi: 10.1001/jamadermatol.2019.3617.

Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial

Margitta Worm  1 , Eric L Simpson  2 , Diamant Thaçi  3 , Robert Bissonnette  4 , Jean-Philippe Lacour  5 , Stefan Beissert  6 , Makoto Kawashima  7 , Carlos Ferrándiz  8 , Catherine H Smith  9 , Lisa A Beck  10 , Kuo-Chen Chan  11 , Zhen Chen  11 , Bolanle Akinlade  11 , Thomas Hultsch  12 , Heribert Staudinger  13 , Abhijit Gadkari  11 , Laurent Eckert  14 , John D Davis  11 , Manoj Rajadhyaksha  11 , Neil M H Graham  11 , Gianluca Pirozzi  13 , Neil Stahl  11 , George D Yancopoulos  11 , Marius Ardeleanu  11
Affiliations
Clinical Trial

Efficacy and Safety of Multiple Dupilumab Dose Regimens After Initial Successful Treatment in Patients With Atopic Dermatitis: A Randomized Clinical Trial

Margitta Worm et al. JAMA Dermatol. .

Abstract

Importance: The dupilumab regimen of 300 mg every 2 weeks is approved for uncontrolled, moderate to severe atopic dermatitis (AD).

Objective: To assess the efficacy and safety of different dupilumab regimens in maintaining response after 16 weeks of initial treatment.

Design, setting, and participants: The Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (LIBERTY AD SOLO-CONTINUE) was a randomized, double-blind, phase 3 clinical trial conducted from March 25, 2015, to October 18, 2016, at 185 sites in North America, Europe, Asia, and Japan. Patients with moderate to severe AD who received dupilumab treatment and achieved an Investigator's Global Assessment score of 0 or 1 or 75% improvement in Eczema Area and Severity Index scores (EASI-75) at week 16 in 2 previous dupilumab monotherapy trials (LIBERTY AD SOLO 1 and 2) were rerandomized in SOLO-CONTINUE. After completing SOLO-CONTINUE, patients were followed up for up to 12 weeks or enrolled in an open-label extension. Data were analyzed from December 5 to 12, 2016.

Interventions: High-responding patients treated with dupilumab in SOLO were rerandomized 2:1:1:1 to continue their original regimen of dupilumab, 300 mg, weekly or every 2 weeks or to receive dupilumab, 300 mg, every 4 or 8 weeks or placebo for 36 weeks.

Main outcomes and measures: Percentage change in EASI score from baseline during the SOLO-CONTINUE trial, percentage of patients with EASI-75 at week 36, and safety.

Results: Among the 422 patients (mean [SD] age, 38.2 [14.5] years; 227 [53.8%] male), continuing dupilumab treatment once weekly or every 2 weeks maintained optimal efficacy, with negligible change in percent EASI improvement from SOLO 1 and 2 baseline during the SOLO-CONTINUE trial (-0.06%; P < .001 vs placebo); percent change with the other regimens dose-dependently worsened (dupilumab every 4 weeks, -3.84%; dupilumab every 8 weeks, -6.84%; placebo, -21.67%). More patients taking dupilumab weekly or every 2 weeks (116 of 162 [71.6%]; P < .001 vs placebo) maintained EASI-75 response than those taking dupilumab every 4 weeks (49 of 84 [58.3%]) or every 8 weeks (45 of 82 [54.9%]) or those taking placebo (24 of 79 [30.4%]). Overall adverse event incidences were 70.7% in the weekly or every 2 weeks group, 73.6% in the every 4 weeks group, 75.0% in the every 8 weeks group, and 81.7% in the placebo group. Treatment groups had similar conjunctivitis rates. Treatment-emergent antidrug antibody incidence was lower with more frequent dupilumab dose regimens (11.3% in the placebo group and 11.7%, 6.0%, 4.3%, and 1.2% in the dupilumab every 8 weeks, every 4 weeks, every 2 weeks, and weekly groups, respectively).

Conclusions and relevance: In this trial, continued response over time was most consistently maintained with dupilumab administered weekly or every 2 weeks. Longer dosage intervals and placebo resulted in a diminution of response for both continuous and categorical end points. No new safety signals were observed. The approved regimen of 300 mg of dupilumab every 2 weeks is recommended for long-term treatment.

Trial registration: ClinicalTrials.gov identifier: NCT02395133.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Worm reported receiving honoraria for consulting and lecture activity from Regeneron Pharmaceuticals, Inc and Sanofi during the conduct of the study and outside the submitted work and receiving personal fees from Regeneron Pharmaceuticals, Inc, Sanofi, ALK-Abello, Allergopharma GmbH & Co, Allergy Therapeutics Plc, HAL Allergy B.V., LEO Pharma, Mylan Germany GmbH, and Novartis outside the submitted work. Dr Simpson reported grants, personal fees, and nonfinancial support from Regeneron Pharmaceuticals, Inc, during the conduct of the study; grants and personal fees from AbbVie, Eli Lilly, Galderma, LEO Pharma, Pfizer, Genentech, MedImmune, and Anacor; grants from Kyowa Hakko Kirin, Chugai, Merck, Novartis, Tioga Vanda, Amgen, and Celgene; and personal fees from Sanofi Genzyme, Boehringer Ingelheim, Dermavant, Forte Bio Rx, Menlo Therapeutics, Pierre Fabre Dermo Cosmetique, Valeant, and Roivant outside the submitted work. Dr Thaçi reported receiving grants and personal fees from Sanofi and Regeneron Pharmaceuticals, Inc during the conduct of the study and grants and personal fees from AbbVie, Novartis, Pfizer, LEO Pharma, Eli Lilly, Almirall, Janssen-Cilag, Bristol-Myers Squibb, and Dignity and grants from Morphosis outside the submitted work. Dr Bissonnette reported serving as an investigator, consultant, advisory board member, and speaker for and/or receiving honoraria from Antiobix, Aquinox Pharma, Asana, Astellas, Brickell Biotech, Dermavant, Dermira, Dignity Sciences, Galderma, Glenmark, GSK-Stiefel, Hoffman-La Roche Ltd., Kiniksa, LEO Pharma, Neokera, Pfizer Inc, Regeneron Pharmaceuticals, Inc, Sienna, and Vitae and being a shareholder in Innovaderm Research. Dr Lacour reported receiving grants and personal fees from Regeneron Pharmaceuticals, Inc and personal fees from Sanofi during the conduct of the study and grants and personal fees from Novartis, Lilly, Galderma, Boehringer Ingelheim, Celgene, and LEO Pharma and grants from Janssen, AbbVie, Amgen, and Pfizer outside the submitted work. Dr Beissert reported being an investigator with Regeneron Pharmaceuticals, Inc during the conduct of the study; serving on the member advisory board for AbbVie, Celgene, Novartis, BMS, MSD, Actelion, Janssen-Cilag, LEO Pharma, UCB Pharma, Menlo and Therapeutics; and receiving speaker honorarium from AbbVie, Celgene, Novartis, Actelion, Janssen-Cilag, and La Roche-Posay. Dr Smith reported receiving departmental funding for commercially sponsored clinical trials that involved dupilumab from Regeneron Pharmaceuticals, Inc, Pfizer, Roche, AbbVie and Novartis. Dr Beck reported receiving grants from Regeneron Pharmaceuticals, Inc during the conduct of the study and grants and personal fees from Regeneron Pharmaceuticals, Inc, AbbVie, Pfizer, and LEO Pharma, personal fees from Sanofi, Allakos, Arena Pharma, AstraZeneca, Connect Biopharma, Novan, Incyte, Lilly, Novartis, UCB, and Vimalan outside the submitted work. Dr Chen reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Akinlade reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Hultsch reported being a full-time employee at Sanofi when the clinical studies were performed. Dr Staudinger reported being an employee of and holding stock and/or stock options in Sanofi Genzyme during the conduct of the study and outside the submitted work. Dr Gadkari reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc during the conduct of the study and outside the submitted work. Dr Eckert reported being an employee of and holding stock or stock options in Sanofi during the conduct of the study and outside the submitted work. Dr Davis reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc, Inc during the conduct of the study and outside the submitted work. Dr Rajadhyaksha reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc during the conduct of the study. Dr Graham reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc. Dr Pirozzi reported being an employee of and holding stock or stock options in Sanofi outside the submitted work. Dr Stahl reported receiving being and employee and shareholder of Regeneron Pharmaceuticals, Inc during the conduct of the study. Dr Yancopoulos reported being an employee, shareholder, and member of the board of directors of Regeneron Pharmaceuticals, Inc during the conduct of the study. Dr Ardeleanu reported being an employee and shareholder of Regeneron Pharmaceuticals, Inc during the conduct of the study and outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
aThere were 53 placebo-treated patients from the Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 1) and Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 2) who met the eligibility criteria; for the purposes of maintaining blinding, these patients were assigned to a separate placebo cohort, not randomized in Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (SOLO-CONTINUE), and therefore not included in these analyses. Two randomized patients (placebo and dupilumab every 8 weeks) withdrew before receiving the study drug. Two patients were erroneously randomized (placebo and dupilumab weekly or every 2 weeks); they had not achieved 75% improvement in Eczema Area and Severity Index scores or Investigator’s Global Assessment scores of 0 or 1 at SOLO week 16 and were excluded from per-protocol efficacy analyses but were included in the primary (intention-to-treat) analyses. bOne patient withdrew consent shortly after randomization and was not entered in the end of treatment page of the electronic data capture; therefore, this individual was not counted in the subcategories for reason for discontinuing study treatment. cThe categories with 1 patient overall were grouped together, including the categories of patient had been taking oral corticosteroids; therefore, study drug injection could not be administered at week 36 and early rollover into protocol of the open-label extension study.
Figure 2.
Figure 2.. Maintenance of Improvement in Clinical and Patient-Reported Outcomes and Rescue Medication Use in the Study to Confirm the Efficacy and Safety of Different Dupilumab Dose Regimens in Adults With Atopic Dermatitis (SOLO-CONTINUE)
Outcome measures included the Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and Hospital Anxiety and Depression Scale (HADS) scores. A, Least squares (LS) mean percent change in EASI score from baseline of Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 1) or Study of Dupilumab Monotherapy Administered to Adult Patients With Moderate-to-Severe Atopic Dermatitis (SOLO 2) baseline during SOLO-CONTINUE: difference between SOLO-CONTINUE baseline and week 36. B, The LS mean percent change in Peak Pruritus NRS score from SOLO baseline during SOLO-CONTINUE: difference between SOLO-CONTINUE baseline and week 35. C, The LS mean change in POEM score from SOLO-CONTINUE baseline to week 36. D, The LS mean change in DLQI score from SOLO-CONTINUE baseline to week 36. E, The LS mean change in HADS score from SOLO-CONTINUE baseline to week 36. F, Cumulative percentage of patients using rescue medication from baseline in to week 36 in SOLO-CONTINUE. A-E, Negative values indicate a diminution of response. Error bars indicate SEs.
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