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

PurposeDelayed-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.MethodsPatients 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.FindingsThe 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.ImplicationsThese 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: NCT00420212; NCT00451451.     

Effect of Bismuth Subsalicylate on Gastrointestinal Tolerability in Healthy Volunteers Receiving Oral Delayed-release Dimethyl Fumarate: PREVENT,a Randomized,Multicenter, Double-blind,Placebo-controlled Study

Purpose

Flushing and gastrointestinal (GI) events are commonly associated with the use of delayed-release dimethyl fumarate (DMF) treatment for relapsing multiple sclerosis.

Patients With High-disease-activity Relapsing-Remitting Multiple Sclerosis in Real-world Clinical Practice: A Population-based Study in Sweden

PurposeThis study aims to compare the disease progression and disease-modifying treatment–switching patterns between patients with high-disease-activity (HDA) relapsing-remitting multiple sclerosis (RRMS) and patients with low-disease-activity (LDA) RRMS in real-world clinical practice.MethodsThe confirmed disease progression and time to switch of 6647 patients from the Swedish multiple sclerosis registry were analyzed using a marginal structural model that compared patients with relapsing HDA (HDA-R) and lesion HDA (HDA-L) following definitions in European labels of disease-modifying therapies with patients with LDA. Time to milestone and stratified drug cohort analyses were used for internal validation.FindingsA total of 262 patients with LDA, 985 patients with HDA-R, and 683 patients with HDA-L were included in the primary analysis. The HDA-R subgroup had statistically significant greater risk of disease progression (hazard ratio = 1.23; 95% CI, 1.03–1.46) and no difference in time to switch compared with the LDA subgroup. The HDA-L subgroup had statistically significant shorter time to switch (hazard ratio = 1.47; 95% CI, 1.31–1.66) and no difference in disease progression compared with the LDA subgroup.ImplicationsCompared with past research on HDA RRMS grounded mainly in randomized controlled trials of individual disease-modifying therapies, the main contribution of this study is that HDA, as identified by relapses, in real-world clinical settings has a clearer association with disease progression than HDA identified by new magnetic resonance imaging lesions. Taking into account that the HDA-L subgroup had a shorter time to switch, there is evidence of an unmet need for effective treatments in clinical practice for both the HDA-R and HDA-L subgroups.     

Patients' Self-Assessment of the Symptoms and Impact of Opioid-Induced Constipation: Results From a Prospective Observational Cohort Study of Japanese Patients With Cancer

ContextMany patients who have cancer consider opioid-induced constipation (OIC) to be a burdensome side effect of opioid treatment.ObjectivesTo evaluate patient-reported outcomes in Japanese patients with cancer pain and OIC.MethodsThis prospective observational study evaluated OIC incidence for two weeks in patients with cancer after they initiated strong opioid therapy. Rome IV diagnostic criteria, a physician's diagnosis, spontaneous bowel movements, Bowel Function Index score, and patients' daily self-assessments were used. Changes from baseline in Patient Assessment of Constipation Symptoms and Patient Assessment of Constipation Quality of Life (PAC-QOL) scores were compared between patients with and without OIC. Patients and health care providers (HCPs) completed study-specific questionnaires regarding OIC burden, treatment satisfaction, and patient-provider communications.ResultsAmong 212 enrolled patients, the incidence of OIC was 47.6% by patients' self-assessments, with a cumulative incidence of 30.2% by Day 3 and 43.5% by Day 7. Patient Assessment of Constipation Symptoms and PAC-QOL overall scores from patients with OIC worsened significantly from baseline compared with patients without OIC by all diagnostic criteria, except for spontaneous bowel movement frequency for PAC-QOL. Patients and HCPs were generally satisfied with OIC treatment; however, 53.5% of patients and approximately 40.0% of HCPs reported that OIC affected pain management. Most patients and HCPs reported that OIC conditions were sufficiently or essentially communicated.ConclusionAfter starting opioid therapy, patients recognized OIC onset and its impact on cancer pain management, highlighting the need for effective patient-provider communications, diagnosis, and treatment of OIC to improve QOL for patients with cancer receiving opioid analgesics.     

Dosage and Effectiveness of Aerobic Training on Cardiorespiratory Fitness,Functional Capacity,Balance, and Fatigue in People With Multiple Sclerosis: A Systematic Review and Meta-Analysis

ObjectivesTo evaluate the benefits of aerobic training (AT) programs on cardiorespiratory fitness, functional capacity, balance, and fatigue in individuals with multiple sclerosis (MS) and to identify the optimal dosage of AT programs for individuals with MS via a systematic review with meta-analysis.Data sourcesTwo electronic databases were searched until March 2020 (PubMed-Medline and Web of Science).Study SelectionStudies examining the effect of AT program on cardiorespiratory fitness, functional capacity, balance, and fatigue were included.Data ExtractionAfter applying the inclusion and exclusion criteria, we included 43 studies. A total sample of 1070 individuals with MS (AT group, n=680; control group, n=390) were analyzed.Data SynthesisThe AT group demonstrated a significant increase in cardiorespiratory fitness (standardized mean difference [SMD], 0.29; P=.002), functional capacity (timed Up and Go Test: SMD, –1.14; P<.001; gait speed: SMD, –1.19; P<.001; walking endurance: SMD, 0.46; P<.001), and balance (SMD, 3.49; P<.001) after training. Fatigue perception also decreased (SMD, –0.45; P<.001). However, no significant differences were observed when compared with the control group in either cardiorespiratory fitness (SMD, 0.14; P=.19) or fatigue perception. Nevertheless, we observed significant differences between the AT and control groups in balance (P=.02), gait speed (P=.02), and walking endurance (P=.03), favoring the participants who performed AT. Regarding the subgroup analysis, no significant differences were observed between subgroups in any of the variables studied except for gait speed, for which a greater increase in posttraining was observed when the AT program applied the continuous method (χ²=7.75; P=.005) and the exercises were performed by walking (χ²=9.36; P=.002).ConclusionsAerobic training improves gait speed, walking endurance, and balance. Cardiorespiratory fitness and fatigue perception also improved after AT, but we found no differences with the control group. In addition, subgroup analysis suggested that training using continuous and walking methods could optimize gait speed.