Gastrointestinal Tolerability of Delayed-Release Dimethyl Fumarate in a Multicenter, Open-Label Study of Patients with Relapsing Forms of Multiple Sclerosis (MANAGE)

Abstract

Background: In phase 3 trials, delayed-release dimethyl fumarate (DMF; also known as gastroresistant DMF) demonstrated efficacy in relapsing-remitting multiple sclerosis (MS). Gastrointestinal (GI) events were associated with DMF treatment. The single-arm, open-label MANAGE study examined the incidence, severity, duration, and management of GI events in adults with relapsing MS initiating DMF treatment in clinical practice in the United States shortly after marketing approval.

Patients and methods: Patients (N = 233) took DMF for up to 12 weeks and recorded information regarding GI events using an eDiary and numerical rating scales.

Results: Overall, 54.1% of patients used symptomatic therapy and had GI symptoms. The incidence of GI events was highest in the first month of treatment. The duration of GI events varied by event type, and severity was generally mild to moderate. Decreased severity was seen in patients treated with antacids, bismuth subsalicylate, acid-secretion blockers, antidiarrheals, and antiemetics. Less than 10% of patients were using symptomatic therapy for GI events by week 12 of DMF treatment. A modest reduction in severe GI events was observed in patients who regularly took DMF with food compared with patients who did not. The incidence of GI-related events was comparable in patients with or without a history of GI abnormalities and in patients who did or did not use alcohol or tobacco.

Conclusions: Gastrointestinal events associated with DMF are generally transient, mild to moderate in severity, and manageable. Symptomatic therapy and dosing with food may mitigate these events.

Figures

Figure 1.

A, Frequency of overall gastrointestinal (GI) events (assessed by the Modified Overall Gastrointestinal Symptom Scale [MOGISS]) and acute upper and lower GI events (assessed by the Modified Acute Gastrointestinal Symptom Scale) in the safety population, users of GI symptomatic therapy, and nonusers of GI symptomatic therapy across the 12-week study. B, Frequency of overall GI events (assessed by the MOGISS) in the safety population, users of GI symptomatic therapy, and nonusers of GI symptomatic therapy by study week. The denominator for the percentages is the safety population.

Figure 2.

Median duration of acute upper and lower gastrointestinal (GI) events (assessed by the Modified Acute Gastrointestinal Symptom Scale) in the safety population, users of GI symptomatic therapy, and nonusers of GI symptomatic therapy. For patients with more than one GI-related event during a visit interval, the average duration for the visit interval was used.

Figure 3.

A, Mean (SD) worst severity scores for overall gastrointestinal (GI) events (assessed by the Modified Overall Gastrointestinal Symptom Scale [MOGISS]) and acute upper and lower GI events (assessed by the Modified Acute Gastrointestinal Symptom Scale) in the safety population, users of GI symptomatic therapy, and nonusers of GI symptomatic therapy. B, Distribution of worst severity scores for overall GI events (assessed by the MOGISS) in the safety population, users of GI symptomatic therapy, and nonusers of GI symptomatic therapy. Severity was rated on a 10-point numerical rating scale, where 0 = no events, 1 to 3 = mild events, 4 to 6 = moderate events, 7 to 9 = severe events, and 10 = extreme events.