EVOLVE-MS-2 (NCT03093324) was a 5-week, randomized, double-blind, head-to-head, phase III study designed to evaluate GI tolerability of DRF 462 mg vs DMF 240 mg administered twice daily in patients with RRMS. Patients utilized two eDiary symptom scales to evaluate the duration and severity of GI symptoms on a daily basis: IGISIS and GGISIS. In addition, AEs were collected by investigators at weekly study visits. The study included a ≤ 4-week screening period, a 5-week double-blind treatment period with two blinded treatment groups, and a 2-week follow-up period (Fig. 1). The screening period included a 1-week lead-in period, prior to randomization, during which patients completed the two self-administered GI symptom scales daily to test for eDiary compliance and/or underlying baseline GI symptoms.
Block randomization was performed using a block size of 4. Patients were randomized 1:1 into one of the two treatment groups, and all patients received two capsules twice daily for all doses to maintain blinding. Patients received either DRF at the approved dose of 231 mg twice daily (administered as one 231-mg capsule and one placebo capsule twice daily) for week 1 followed by DRF 462 mg twice daily (administered as two 231-mg capsules twice daily) for weeks 2–5 (group 1), or DMF at the approved dose of 120 mg twice daily (administered as one 120-mg capsule and one placebo capsule twice daily) for week 1 followed by DMF 240 mg twice daily (administered as one 240-mg capsule and one placebo capsule twice daily) for weeks 2–5 (group 2). The treatment period was double-blind; DMF capsules were over-encapsulated to create the blinded study drug. Patients were instructed to take the study drug with or without food, but to avoid a high-fat and high-calorie meal (defined as > 1000 calories and containing 50 g of fat) to ensure adequate levels of monomethyl fumarate [2, 3]. No dose reductions were permitted during the study. Symptomatic therapies for tolerability events were permitted and recorded as concomitant medications.
The study utilized an adaptive study design, an approach that allows for planned modifications to ongoing trials (such as changes to trial parameters or statistical procedures) using pre-specified interim data analyses, without compromising trial integrity or validity [15, 16]. Adaptive trial design has been used to re-estimate sample size in instances in which variances of the response variables are unknown, as was the case with the novel endpoints used in the EVOLVE-MS-2 study . In this study, it was initially hypothesized that comparing DRF and DMF using the IGISIS intensity scale would detect a difference between the two groups. As there was no previous experience with the IGISIS and GGISIS scales to inform statistical assumptions, a pre-planned unblinded analysis of data was conducted after the first 120 patients were randomized (i.e., part A), in which the objectives were to assess the utility of the GI symptom scales; refine the primary endpoint to select the most sensitive measure for detecting a difference between DRF and DMF; and inform the sample size. From this analysis, the IGISIS endpoint was modified from ≥ 3 to ≥ 2 as the latter was deemed to be the more sensitive indicator. All patients, investigators, and sites remained blinded to the part A data to preserve the integrity of the trial. After the initial 120 patients, the subsequently randomized patients (i.e., part B) were enrolled, bringing the overall planned population to 500 patients. Patients who completed the 5-week treatment period were eligible to enroll in the EVOLVE-MS-1 (ClinicalTrials.gov [NCT02634307]) long-term, open-label, DRF safety study .
Eligible patients were aged 18–65 years, had a confirmed diagnosis of RRMS , and were neurologically stable with no evidence of relapse in the 30 days prior to screening. Patients were not eligible to participate if they had a history of GI surgery (except appendectomy that occurred > 6 months prior to screening); clinically significant recurring or active GI symptoms within 3 months of screening or long-term use of medical therapy to treat GI symptoms within 1 month of screening; or two or more IGISIS intensity scores of ≥ 3 during the 1-week lead-in period prior to randomization. Patients who had previously received fumarate treatment were also prohibited from study enrollment. The study was approved by central and local ethics committees and was conducted in accordance with the International Council on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent.
The primary endpoint was the number of days, relative to exposure, with any IGISIS intensity score ≥ 2 in the overall study population. Secondary endpoints included the number of days, relative to exposure, with: (1) an IGISIS intensity score ≥ 2 in part B only; (2) an IGISIS intensity score ≥ 1 in the overall population; (3) an IGISIS intensity score ≥ 3 in the overall population; (4) a GGISIS symptom intensity score ≥ 1 in the overall population; (5) a GGISIS symptom intensity score ≥ 2 in the overall population; (6) a GGISIS symptom intensity score ≥ 3 in the overall population; and (7) worst (i.e., highest) IGISIS individual symptom intensity score by week during the 5-week treatment period in the overall population.
Pre-specified exploratory endpoints included the number of days relative to exposure with an IGISIS intensity score of ≥ 1 and ≥ 3, or a GGISIS intensity score of ≥ 1, ≥ 2, or ≥ 3, in part B only. Investigator-assessed AEs were summarized.
Gastrointestinal tolerability was assessed using two novel GI symptom scales, IGISIS and GGISIS. The scales were adapted from the Modified Acute Gastrointestinal Symptom Scale (MAGISS) and the Modified Overall Gastrointestinal Symptom Scale (MOGISS) used in trials with DMF, which have been previously described [9, 19]. The IGISIS is a questionnaire designed to capture the incidence, intensity, onset, duration, and functional impact of five key individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea (Fig. S1a in the Electronic Supplementary Material [ESM]). In the DMF pivotal DEFINE/CONFIRM trials, these specific GI symptoms were among the most commonly reported AEs and were the most common GI AEs leading to treatment discontinuation [4, 5, 20]. Patients were instructed to self-administer the IGISIS questionnaire twice per day within 9 h of taking the study drug, using an eDiary. The patient rated the severity of each symptom on a scale of 0 (did not have) to 10 (extreme); for each symptom, patients also recorded duration and rated interference on daily activities using a 5-point Likert scale (Fig. S1a in the ESM).
The GGISIS is designed to assess the overall intensity of five GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea) experienced during the previous 24 h, the level of interference and functional impact on work and daily activities, and how bothersome GI symptoms were for patients. To rate the intensity of GI symptoms and assess how bothersome GI symptoms were, patients completed the questionnaire once per day using a scale of 0 (did not have) to 10 (extreme). Patients also recorded the level of interference and impact of GI symptoms on daily activities and work (Fig. S1b in the ESM).
Safety assessments included AEs (including GI AEs), vital signs, clinical laboratory tests (chemistry, hematology, and urinalysis), and electrocardiogram findings. Adverse events were assessed by the investigator at weekly visits and recorded by severity and relatedness.
Analysis Populations and Statistics
Gastrointestinal tolerability was assessed in all patients who received at least one dose of the study drug and completed at least one post-baseline GI tolerability assessment. Data collected from patients in the overall population were analyzed for the primary endpoint; secondary endpoints assessed data from the overall population, as well as for part B separately.
Based on the pre-planned unblinded analysis of the first 120 patients (part A data), it was assumed that the number of days with an IGISIS intensity score of ≥ 2 relative to exposure in the treatment period would be 2.0 days for DRF and 3.5 days for DMF. Using a negative binomial regression approach with a two-sided α-level of 0.05, it was estimated that an enrollment size of 500 total patients would provide ~ 80% power to detect a ≥ 42% reduction in the relative rate for DRF vs DMF. The number of days with any IGISIS individual symptom intensity score relative to exposure days was analyzed using a negative binomial regression model with treatment as a factor and adjusted for study parts, region, age, and body mass index. The worst IGISIS individual symptom intensity score during the treatment period was summarized by treatment group and analyzed using an analysis of covariance model with treatment as a factor and adjusted for study parts, region, age, and body mass index. Safety analyses were summarized for all patients who received at least one dose of the study drug.