Effectiveness of Delayed-release Dimethyl Fumarate on Clinical and Patient-reported Outcomes in Patients With Relapsing Multiple Sclerosis Switching From Glatiramer Acetate: RESPOND, a Prospective Observational Study.

PURPOSE: The goal of this study was to evaluate clinical outcomes and patient-reported outcomes (PROs) over 12 months in patients with relapsing multiple sclerosis (RMS) who switched from glatiramer acetate (GA) to delayed-release dimethyl fumarate (DMF) 240 mg BID after suboptimal response to GA in real-world clinical practice. METHODS: The RESPOND (Effectiveness of DMF and Its Impact on PROs in Suboptimal GA Responders With RMS) study was a Phase IV, prospective, multicenter, open-label, single-arm, 12-month observational trial. The study was conducted in the United States at 63 sites between August 2013 and February 2016. Patients diagnosed with RMS who experienced a suboptimal response to GA (defined as perceived suboptimal efficacy, intolerance, or poor adherence to GA) were eligible for enrollment. DMF treatment was initiated within 60 days of enrollment. The primary objective was to estimate the annualized relapse rate (ARR) at 12 months based on data collected from medical records and compare it with the 12 months before DMF initiation. Secondary objectives of the study included assessing the change in PRO scores from baseline to 12 months; PROs were recorded before and at 6 and 12 months after DMF initiation. FINDINGS: Of the 318 patients included in the analysis population, 247 (78%) completed treatment. Mean (SD) time on GA treatment before switching to DMF was 51.3 months (49.1 months). The ARR (95% CI) reported for the 12 months before DMF initiation was 0.49 (0.42-0.57) compared with 0.11 (0.07-0.17) at 12 months after DMF initiation, representing a 78% reduction in ARR (P < 0.0001). Statistically significant improvements from baseline were observed for multiple PROs, including the 36-item Short Form Health Survey physical and mental component summaries (P = 0.0201 and P = 0.0014, respectively), the 5-item Modified Fatigue Impact Scale (P = 0.0002), the 14-item Treatment Satisfaction Questionnaire for Medication (P < 0.0001), and the 7-item Beck Depression Inventory (P = 0.0117). IMPLICATIONS: DMF may be an effective treatment option in patients with RMS who experience a suboptimal response to GA. The results should be interpreted with caution due to the observational nature of the study and the lack of a control group. Other limitations of the study include a potential bias due to regression to the mean and lack of randomization. ClinicalTrials.gov identifier: NCT01903291.

Clinical outcomes in patients with relapsing-remitting multiple sclerosis who switch from natalizumab to delayed-release dimethyl fumarate: A multicenter retrospective observational study (STRATEGY).

BACKGROUND: Delayed-release dimethyl fumarate (DMF) may be a therapeutic option for patients with relapsing-remitting multiple sclerosis (RRMS) who are treated with natalizumab and require a change in therapy. However, there is limited information regarding predictors of favorable treatment outcomes in patients switching from natalizumab to DMF. Clinical practices and sequencing protocols vary. Herein, we present the clinical results, including annualized relapse rate (ARR) and risk of relapse, of a phase 4 retrospective observational study of patients with RRMS who switched from natalizumab to DMF in a community practice setting (STRATEGY). METHODS: STRATEGY was performed through a single time point medical record abstraction; no study visits or procedures were required. Key inclusion criteria included age ≥ 18 years, RRMS diagnosis (McDonald criteria, 2010 revised), ≥ 12 months of continuous treatment with natalizumab monotherapy before DMF initiation, and initiation of DMF ≥ 12 months before enrollment. Patients were eligible to enroll regardless of current DMF use. RESULTS: A total of 530 patients at 45 US sites enrolled, and 506 met the inclusion criteria and were included in the modified evaluable population for analysis. Mean (SD) age at DMF initiation was 47.0 (10.9) years, with a mean (SD) of 12.7 (7.2) years since MS diagnosis. The mean (SD) duration of natalizumab treatment was 3.4 (1.9) years, and the mean (SD) washout from natalizumab discontinuation to DMF initiation (n = 502) was 101.6 (164.0) days. Overall risk of relapse 12 months after DMF initiation was 19.6%. Overall unadjusted ARR was higher during the 12 months following initiation of DMF treatment compared with the 12 months following initiation of natalizumab treatment (rate ratio, 2.32 [95% CI, 1.69-3.18]; p < 0.0001), but was lower compared with that observed in the year before initiation of natalizumab (rate ratio, 0.51 [95% CI, 0.40-0.64]; p < 0.0001). At 1 year following initiation of DMF treatment, the relapse rate was lower for patients who did not experience a relapse during 1 year following initiation of natalizumab treatment than for those who did (rate ratio for relapse rate, 0.47 [95% CI, 0.16-1.38]; p = 0.1664). The relapse rate for patients who did not relapse during natalizumab treatment was significantly lower with a washout period of ≤ 90 days as compared with a washout period of > 90 days (rate ratio for relapse rate, 0.49 [95% CI, 0.26-0.90]; p = 0.0216). A total of 42 (8%) patients reported ≥ 1 adverse event leading to DMF discontinuation during the study; the most commonly reported events were gastrointestinal disorders (n = 21; 4%). CONCLUSIONS: Results from this multicenter retrospective observational study suggest that DMF may be an effective treatment option for patients who discontinue natalizumab in routine clinical practice. ARR was lower in patients who initiated DMF within 90 days of natalizumab discontinuation compared with patients who initiated DMF after 90 days of natalizumab discontinuation. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02159573.

Number Needed to Treat in Multiple Sclerosis Clinical Trials.

Clinicians are expected to select a therapy based on their appraisal of evidence on benefit-to-risk profiles of therapies. In the management of relapsing-remitting multiple sclerosis (RRMS), evidence is typically expressed in terms of risk (proportion) of event, risk reduction, relative and hazard rate reduction, or relative reduction in the mean number of magnetic resonance imaging lesions. Interpreting treatment effect using these measures from a RRMS clinical trial is fairly reliable; however, this might not be the case when treatment effect is expressed in terms of the number needed to treat (NNT). The objective of this review is to discuss the utility of NNT in RRMS trials. This article presents an overview of the methodological definition and characteristics of NNT as well as the relative merit of NNT use in RRMS controlled clinical trials, where endpoints are typically time-to-event and frequency of recurrent events. The authors caution against using NNT in multiple sclerosis, a clinically heterogeneous disease that can change course and severity unpredictably. The authors also caution against the use of NNT to interpret results in comparative trials where the absolute risk difference is not statistically significant, computing NNT using the time-to-event endpoint at intermediate time points, computing NNT using the annualized relapse rate, and comparing NNT across trials.

Efficacy and Tolerability of Delayed-release Dimethyl Fumarate in Black, Hispanic, and Asian Patients with Relapsing-Remitting Multiple Sclerosis: Post Hoc Integrated Analysis of DEFINE and CONFIRM.

INTRODUCTION: Clinical course and treatment response may vary according to race/ethnicity in multiple sclerosis (MS) patients. Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated significant efficacy and a favorable benefit-risk profile in relapsing-remitting MS (RRMS) patients in the 2-year phase III DEFINE/CONFIRM studies. METHODS: In this post hoc analysis of integrated data from DEFINE/CONFIRM, we assessed clinical efficacy and safety/tolerability in black, Hispanic, and Asian patients treated with DMF 240 mg twice daily (approved dosage) or placebo. Eligible patients were 18-55 years of age with an Expanded Disability Status Scale score of 0-5.0. In the integrated intention-to-treat population, 769 and 771 patients were treated with DMF or placebo, respectively, of whom 10 and 19 were black, 31 and 23 were Hispanic, and 66 and 70 were Asian. RESULTS: In the black, Hispanic, and Asian subgroups, DMF was associated with lower annualized relapse rates at 2 years compared with placebo [rate ratio (95% confidence interval (CI)), 0.05 (0.00-1.07); 0.31 (0.10-0.95); and 0.64 (0.30-1.34), respectively]. The percentage of black, Hispanic, and Asian patients with 12-week confirmed disability progression was lower with DMF (43%, 8%, and 20%, respectively) compared with placebo [57%, 30%, and 25%, respectively; hazard ratio (95% CI), 0.53 (0.02-1.39); 0.17 (0.00-0.60); and 0.71 (0.32-1.58), respectively]. The safety/tolerability profile of DMF was generally consistent with that in the overall population of DEFINE/CONFIRM. The incidence of adverse events leading to treatment discontinuation in black, Hispanic, and Asian patients was 2/10, 2/31, and 3/66, respectively, with DMF, and 2/19, 1/23, and 8/70, respectively, with placebo. CONCLUSION: DMF may be an efficacious treatment with a favorable benefit-risk profile in black, Hispanic, and Asian patients with RRMS. Further clinical studies are needed to characterize differences in MS presentation and treatment outcomes across ethnic and racial groups. FUNDING: Biogen. TRIAL REGISTRATION: DEFINE: ClinicalTrials.gov identifier NCT00420212; CONFIRM ClinicalTrials.gov identifier NCT00451451.

Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM.

PURPOSE: In Phase III studies (DEFINE [Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS]/CONFIRM [Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis]), delayed-release dimethyl fumarate (DMF) demonstrated significant efficacy and a favorable benefit-risk profile in patients with relapsing-remitting multiple sclerosis (RRMS). Post hoc analyses of integrated data from DEFINE/CONFIRM were conducted to evaluate the effect of DMF in patients previously treated with interferon (IFN) beta. METHODS: Patients (age 18-55 years; Expanded Disability Status Scale score, 0-5.0) were randomized to receive DMF 240 mg BID or TID, placebo, or glatiramer acetate (CONFIRM only) for up to 2 years. Previous IFN users received at least 1 IFN treatment >3 months before randomization. Data for DMF 240 mg BID (approved dosing regimen) are reported. FINDINGS: In the integrated intention-to-treat population, 172 and 169 patients receiving DMF or placebo, respectively, had received ≥1 prior IFN. In this subgroup, significant reductions with DMF versus placebo were observed for the annualized relapse rate (rate ratio, 0.55 [95% CI, 0.40-0.77]), new/newly enlarging T2-hyperintense lesions (lesion mean ratio, 0.16 [95% CI, 0.09-0.29]), odds of having more gadolinium-enhancing lesions (odds ratio, 0.17 [95% CI, 0.07-0.44]), and new T1-hypointense lesions (lesion mean ratio, 0.25 [95% CI, 0.14-0.45]). Median Expanded Disability Status Scale scores remained stable during the study period. Adverse events associated with DMF included flushing and gastrointestinal events. IMPLICATIONS: In this post hoc analysis in patients with previous IFN treatment, DMF demonstrated significant efficacy over 2 years versus placebo and an adverse event profile consistent with the overall population of DEFINE/CONFIRM. ClinicalTrials.gov identifiers: DEFINE, NCT00420212; and CONFIRM, NCT00451451.

Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies.

PURPOSE: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) has been reported to have clinical and neuroradiologic efficacy in people with relapsing-remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. An integrated analysis of data from DEFINE and CONFIRM was conducted to estimate more precisely the therapeutic effects of delayed-release DMF. Here we describe the impact of RRMS on health-related quality of life (HRQoL) at baseline and assess the effects of delayed-release DMF on prespecified HRQoL end points over 2 years. METHODS: Patients with RRMS were randomly assigned to receive delayed-release DMF 240 mg PO BID or TID or matching placebo for up to 2 years (96 weeks). As a tertiary end point in both studies, patient-reported HRQoL was assessed using the Physical and Mental Component Summaries (PCS and MCS, respectively) of the 36-item Short Form Health Survey (SF-36); global assessment of well-being, as measured on a visual analog scale (VAS); and the EuroQoL-5D (EQ-5D) VAS, administered at baseline and at weeks 24, 48, and 96. Higher scores suggested better HRQoL. FINDINGS: The integrated analysis included 2301 patients treated with delayed-release DMF BID (n = 769) or TID (n = 761) or placebo (n = 771). The mean PCS and MCS scores at baseline were lower overall compared with those reported in the general US population and were ≥5 points lower (a clinically meaningful difference) in patients with a baseline Expanded Disability Status Scale (EDSS) score of ≥2.5 compared with those in patients with a baseline EDSS score of 0. At 2 years, mean PCS and MCS scores were increased from baseline in the patients treated with delayed-release DMF, whereas the mean PCS and MCS scores were decreased from baseline in the placebo group; the difference in PCS and MCS scores was significant for the delayed-release DMF BID and TID groups compared with placebo. SF-36 subscale scores generally remained stable or were improved relative to baseline in patients treated with delayed-release DMF and decreased in patients receiving placebo; improvements were significant for delayed-release DMF BID and TID versus placebo on most subscales. Compared with that in the placebo group, the proportions of patients in the delayed-release DMF groups exhibiting a ≥5-point improvement in SF-36 score were significantly higher. The following factors were found to be predictive of improved PCS and MCS scores at 2 years: delayed-release DMF treatment, lower baseline EDSS score, age ≤40 years (PCS only), and corresponding lower baseline PCS or MCS score. Changes from baseline in VAS and EuroQoL-5D scores were generally consistent with changes in SF-36 scores. IMPLICATIONS: These HRQoL benefits parallel the improvements in clinical and magnetic resonance imaging end points with delayed-release DMF, suggesting that delayed-release DMF treatment improves patient-perceived health status as well as neurologic and physical functioning. ClinicalTrials.gov identifiers: NCT0042012; NCT00451451.