Effect of Dimethyl Fumarate vs Interferon β-1a in Patients With Pediatric-Onset Multiple Sclerosis: The CONNECT Randomized Clinical Trial

Abstract

Importance: With few approved multiple sclerosis therapies in the pediatric population, there is a need for further approved treatment options. Limited data exist for dimethyl fumarate (DMF) treatment in pediatric-onset multiple sclerosis (POMS).

Objective: To compare the efficacy, safety, and tolerability of DMF vs intramuscular interferon β-1a (IFNβ-1a) in POMS.

Design, setting, and participants: The CONNECT study was an active-controlled, open-label, rater-blinded 96-week randomized clinical trial in patients with POMS aged 10 to less than 18 years treated between August 2014 and November 2020. Data were analyzed from January through October 2021.

Interventions: Patients were randomized to DMF or IFNβ-1a.

Main outcomes and measures: The primary end point was the proportion of patients free of new or newly enlarging (N or NE) T2 hyperintense lesions at week 96 among trial completers. Secondary end points included number of N or NE T2 lesions, proportion of patients free of relapse, annualized relapse rate (ARR), and safety. The estimated proportion of participants who were relapse free up to week 96 was calculated based on the Kaplan-Meier method. Adjusted ARR was obtained from a negative binomial regression adjusted for baseline relapse rate, baseline Expanded Disability Status Scale (EDSS) score, and age group.

Results: Among 150 patients with POMS in the intention-to-treat (ITT) population (median [range] age, 15 [10-17] years; 101 [67.3%] female patients), 78 individuals received DMF and 72 individuals received IFNβ-1a. At week 96, the proportion of patients with no N or NE T2 hyperintense lesions among 103 trial completers was 16.1% (95% CI, 8.0%-27.7%) for DMF vs 4.9% (95% CI, 0.6%-16.5%) for IFNβ-1a, and in a sensitivity analysis among the ITT population, the proportions were 10 patients receiving DMF (12.8%) vs 2 patients receiving IFNβ-1a (2.8%). The estimated proportion of patients who remained relapse free at week 96 was 66.2% for DMF vs 52.3% for IFNβ-1a. Adjusted ARR (95% CI) at week 96 was 0.24 (95% CI, 0.15-0.39) for DMF vs 0.53 (95% CI, 0.33-0.84) for IFNβ-1a; the rate ratio for DMF vs IFNβ-1a was 0.46 (95% CI, 0.26-0.80; P = .006). The number of treatment-emergent adverse events (TEAEs; 74 patients [94.9%] vs 69 patients [95.8%]), serious TEAEs (18 patients [23.1%] vs 21 patients [29.2%]), and treatment discontinuations due to TEAEs (5 patients [6.4%] vs 8 patients [11.1%]) was similar for DMF vs IFNβ-1a.

Conclusions and relevance: This study found that more pediatric patients with POMS treated with DMF were free of new or newly enlarging T2 lesions and that the adjusted ARR was lower among these patients compared with those treated with interferon β-1a. DMF was well tolerated.

Trial registration: ClinicalTrials.gov Identifier: NCT02283853.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vermersch reported receiving personal fees from AB Science, Sanofi-Genzyme, Biogen, Merck, Imcyse, Celgene-BMS, Novartis, and Teva and grants from Sanofi-Genzyme and Merck outside the submitted work. Mr Scaramozza reported being an employee and shareholder of Biogen outside the submitted work. Dr Alroughani reported receiving personal fees from Biogen, Novartis, Sanofi, Roche, and Merck outside the submitted work. Dr Deiva reported serving as principal investigator for the CONNECT study for Biogen during the conduct of the study and serving as principal investigator and consultant for Novartis, Sanofi, Roche, Alexion, and Viela outside the submitted work. Dr Pozzilli reported receiving grants from Roche and Biogen and personal fees from Janssen, Novartis, Merck, Bristol Myers Squibb, and Almirall outside the submitted work. Dr Lyons reported serving as an employee of Biogen. Dr Pultz reported being an employee of Biogen during the conduct of the study. Dr Liu reported being an employee of and owning stock in Biogen outside the submitted work. Dr Badwan reported being an employee and shareholder of Biogen outside the submitted work. Dr Franchimont reported being an employee and shareholder of Biogen during the conduct of the study and outside the submitted work and serving on the board of directors for OMass Therapeutics outside the submitted work. Dr Hanna reported being an employee of and holding stocks and shares in Biogen. Dr Maghzi reported being an employee and shareholder of Biogen outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Patient Disposition

The number of individuals screened and excluded prior to randomization is not available.

Figure 2.. New or Newly Enlarging (N or NE) T2 Lesion and Adjusted Annualized Relapse Rate (ARR) Outcomes

A, The proportions of patients from the completers population with no N or NE hyperintense T2 lesions at week 96 relative to baseline, with Clopper-Pearson exact 95% CIs, are shown. B, The adjusted mean number of N or NE T2 hyperintense lesions at week 96 relative to baseline and percent reduction of T2 hyperintense lesions were estimated from a negative binomial regression model, adjusted for age group and baseline number of T2 hyperintense lesions, in the intention-to-treat population with week 96 magnetic resonance imaging measurements. C, Adjusted ARR and 95% CI were estimated from a negative binomial regression model adjusted for the baseline relapse rate, baseline Expanded Disability Status Scale score, and age group in the intention-to treat population. DMF indicates dimethyl fumarate; IFNβ-1a, interferon β-1a.