Trial Design and Oversight

In this international, randomized, double-blind, placebo-controlled, phase 3 trial, we assessed the efficacy and safety of dupilumab in patients with oral glucocorticoid–dependent severe asthma. Patients completed an oral glucocorticoid dose-adjustment period lasting 3 to 10 weeks, followed by 1:1 randomization to receive dupilumab or placebo for a 24-week intervention period. The 24-week intervention period consisted of a 4-week induction period, during which the adjusted oral glucocorticoid dose was continued; a 16-week period of reduction in oral glucocorticoid use (weeks 4 to 20), during which the glucocorticoid dose was adjusted down every 4 weeks according to a protocol-prespecified algorithm; and a 4-week maintenance period, during which patients continued the glucocorticoid dose that was established at week 20; the 24-week intervention period was followed by a 12-week evaluation period (Fig. S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org). Full details regarding the trial design are provided in Section 2 in the Supplementary Appendix; the protocol (with the statistical analysis plan) is also available at NEJM.org. Eligible patients who completed the trial regimen were permitted to enter a long-term, open-label extension study.

The protocol was developed by the sponsors (Sanofi and Regeneron Pharmaceuticals). Data were collected by the investigators and analyzed by the sponsors. The trial was conducted in accordance with the Declaration of Helsinki, with the Good Clinical Practice guidelines of the International Conference on Harmonisation, and with applicable regulatory requirements. An independent data and safety monitoring committee conducted blinded monitoring of patients’ safety data (Section 2 in the Supplementary Appendix). The local institutional review board or ethics committee at each center oversaw trial conduct and documentation. All the patients provided written informed consent before participating in the trial. Patients younger than 18 years of age provided assent according to the ethics committee–approved standard practice for pediatric patients at each participating center.

All the authors participated in the interpretation of the data and provided input into the drafting of the manuscript, critical feedback, and final approval for submission of the manuscript for publication. The authors take responsibility for the accuracy and completeness of the data and analyses and vouch for the fidelity of the trial to the protocol. All the investigators had confidentiality agreements with the sponsors. The drafts of the manuscript were prepared with the assistance of a medical writer paid by the sponsors.

Patients

Patients 12 years of age or older who had had physician-diagnosed asthma for 1 year or more according to the Global Initiative for Asthma 2014 guidelines12 and who had been receiving treatment with regular systemic glucocorticoids in the previous 6 months (5 to 35 mg per day of prednisone or prednisolone or equivalent) were eligible to participate. During the 4 weeks before screening, their treatment had to also include a high-dose inhaled glucocorticoid (fluticasone propionate at a total daily dose of >500 μg or equipotent equivalent) in combination with up to two controllers (i.e., a long-acting β 2 -agonist or leukotriene-receptor antagonist) for at least 3 months. Eligible patients had to have a forced expiratory volume in 1 second (FEV 1 ) before bronchodilator use of 80% or less of the predicted normal value (or ≤90% of the predicted normal value in adolescents),13 FEV 1 reversibility of at least 12% and 200 ml, or airway hyperresponsiveness documented in the 12 months before screening visit 1. Patients were recruited with no minimum requirement regarding a baseline blood or sputum eosinophil count or any other type 2 biomarkers (i.e., Fe NO or IgE). A complete list of the inclusion and exclusion criteria is provided in Section 3 in the Supplementary Appendix.

Trial Regimens and Procedures

Patients were randomly assigned in a 1:1 ratio to receive subcutaneous dupilumab (at a dose of 300 mg, after the receipt of a 600-mg loading dose on day 1) as add-on therapy or matched placebo every 2 weeks. Randomization was conducted by means of interactive voice–Web response technology, and patients were stratified according to the adjusted oral glucocorticoid dose (≤10 mg per day vs. >10 mg per day of prednisone or prednisolone) and country. In patients who had been using other oral glucocorticoids, these agents were switched to a clinically comparable dose of prednisone or prednisolone during the screening period.

The adjusted oral glucocorticoid dose was defined as the lowest dose that a patient could receive without having an increase of 0.5 (i.e., the minimal clinically important difference) or more in the 5-item Asthma Control Questionnaire (ACQ-5) score (global scores range from 0 to 6, with higher scores indicating less asthma control),14,15 a severe exacerbation, or any clinically significant event leading to an upward adjustment in the oral glucocorticoid dose. During the dose-reduction phase, the oral glucocorticoid dose was reduced every 4 weeks to minimize the risk of clinically significant events and carryover effects from the previous dose. No dose adjustments were allowed beyond week 20 except for safety reasons. Background asthma controllers were continued at a stable dose, and the use of a short-acting β 2 -agonist was permitted as needed for asthma symptoms. Full details of the methods are provided in the protocol.

End Points

The primary efficacy end point was the percentage reduction in the oral glucocorticoid dose from baseline to week 24 while asthma control was maintained. Between weeks 20 and 24 asthma control was considered to be maintained if no clinically significant event (on the basis of investigator judgment) leading to an upward adjustment in the oral glucocorticoid dose occurred. For patients who had an exacerbation, the final oral glucocorticoid dose was considered to be one step higher than the dose they had been receiving at the time of the exacerbation.

Key secondary efficacy end points that were assessed in patients with maintained asthma control were the proportion of patients with a reduction from baseline of at least 50% in the oral glucocorticoid dose and the proportion of patients who had a reduction in the oral glucocorticoid dose to less than 5 mg per day. Other secondary end points included the proportion of patients who had the maximum possible reduction in the oral glucocorticoid dose (in patients who began the trial while they were taking a glucocorticoid dose of 35 mg per day, the dose could not be reduced to <2.5 mg per day), the proportion of patients who no longer used oral glucocorticoids, and the absolute reduction in the oral glucocorticoid dose.

Other efficacy end points included the annualized rate of severe exacerbation events (defined as events leading to hospitalization, an emergency department visit, or treatment for ≥3 days with systemic glucocorticoids at ≥2 times the current dose of oral glucocorticoid) during the 24-week intervention period; the absolute change from baseline in the FEV 1 before bronchodilator use at weeks 2, 4, 8, 12, 16, 20, and 24; and the change from baseline in the ACQ-5 score at week 24.

An exploratory end point of the absolute change from baseline in the Fe NO level (assessed in parts per billion [ppb]) was assessed with the use of a NIOX (Aerocrine) or similar instrument at weeks 2, 4, 8, 12, 16, 20, and 24. The full list of prespecified end points is provided in the protocol.

Statistical Analysis

We estimated that 90 patients randomly assigned to each group would provide the trial with 94% power (with a two-tailed test at an alpha level of 0.05) to detect a between-group difference of 27 percentage points in the percentage reduction in daily glucocorticoid dose,16 assuming a common standard deviation of 50%. The primary end point was assessed with the use of an analysis of covariance model. The model included the percentage reduction in the oral glucocorticoid dose at week 24 as the response variable, with trial group, adjusted oral glucocorticoid dose at baseline, geographic region (pooled countries), and baseline eosinophil subgroups (≥150 or <150 cells per cubic millimeter) as covariates. The between-group difference was tested at the two-sided alpha level of 0.05. For patients who discontinued the trial or had missing data regarding the oral glucocorticoid dose at week 24 in the primary analysis, the missing data were handled with the use of a pattern-mixture model by multiple imputations.

The key secondary and other binary secondary end points were analyzed with the use of logistic-regression models. The annualized rate of severe exacerbations during the 24-week intervention period was analyzed with the use of a negative binomial regression model. A mixed-effects model with a repeated-measures approach was used to analyze the changes from baseline in the FEV 1 before bronchodilator use at various time points during the 24-week intervention period and the change from baseline in the ACQ-5 score at week 24. To control the overall type I error rate among the primary, key secondary, and the other binary secondary end points, multiple comparisons were controlled with the use of a prespecified hierarchical test procedure (Section 4 in the Supplementary Appendix). The other efficacy end points and exploratory end points were not controlled for multiple comparisons and are presented with 95% confidence intervals.

Efficacy analyses were performed in the intention-to-treat population, which included all the patients who underwent randomization; data were analyzed according to the assigned trial group, regardless of the trial regimen received. Primary and key secondary end points, FEV 1 , and rates of severe asthma exacerbations were also analyzed in subgroups of patients according to baseline blood eosinophil levels (≥300 or <300 cells per cubic millimeter and ≥150 or <150 cells per cubic millimeter) and baseline Fe NO level (<25 ppb or ≥25 to <50 ppb or ≥50 ppb) to assess consistency in effects across the different subgroups. The safety population included all the patients who received at least one dose or a partial dose of dupilumab or placebo; data were analyzed according to the regimen received. Adverse events were assessed during the trial period, which was defined as the time from the first administration of the trial regimen to the last administration of the trial regimen plus 98 days or until the patient entered the extension study.

All the analyses were conducted with the use of SAS software, version 9.4 (SAS Institute). The statistical methods are summarized in Section 4 in the Supplementary Appendix.