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A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries.

ABSTRACT: BACKGROUND:Delayed-release dimethyl fumarate (DMF) has demonstrated efficacy and a favorable benefit-risk profile in phase 2 and 3 studies that enrolled predominantly white patients with relapsing-remitting multiple sclerosis (RRMS). In this study (APEX, Part I), we evaluated the efficacy/safety outcomes of DMF in a predominantly East Asian population of patients with RRMS. METHODS:In this 24-week, randomized, double-blind, placebo-controlled phase 3 study, 225 patients, 142 of which were East Asian (63.4%), were enrolled: Japan (n?=?114), South Korea (n?=?20), Taiwan (n?=?8), the Czech Republic (n?=?42), and Poland (n?=?40). Key exclusion criteria included diagnosis of neuromyelitis optica spectrum disorder. Stratified by country, patients were randomized 1:1 to receive DMF 240?mg twice daily or placebo. Clinical assessments, including neurological examination and EDSS scoring, were conducted at baseline and at weeks 12 and 24. RESULTS:A total of 213 patients (95.1%) completed the study. From weeks 12?-?24, the total number of new gadolinium-enhancing (Gd+) lesions was reduced by 84% (p?

SUBMITTER: Saida T

PROVIDER: S-EPMC6322309 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries.

Saida Takahiko T Yamamura Takashi T Kondo Takayuki T Yun Jang J Yang Minhua M Li Jie J Mahadavan Lalitha L Zhu Bing B Sheikh Sarah I SI

BMC neurology 20190107 1

<h4>Background</h4>Delayed-release dimethyl fumarate (DMF) has demonstrated efficacy and a favorable benefit-risk profile in phase 2 and 3 studies that enrolled predominantly white patients with relapsing-remitting multiple sclerosis (RRMS). In this study (APEX, Part I), we evaluated the efficacy/safety outcomes of DMF in a predominantly East Asian population of patients with RRMS.<h4>Methods</h4>In this 24-week, randomized, double-blind, placebo-controlled phase 3 study, 225 patients, 142 of wh ...[more]

PMID: 30616596

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Project description:Background:Gastrointestinal (GI) events are common adverse events (AEs) associated with delayed-release dimethyl fumarate (DMF), an approved treatment for relapsing-remitting multiple sclerosis (RRMS). The objective of the TOLERATE study was to evaluate GI tolerability and GI mitigation via symptomatic therapies in patients initiating DMF in a real-world clinical setting in Germany. Methods:TOLERATE was a multicentre, open-label, single-arm study performed at 25 German sites. Endpoints were frequency, severity, duration (all primary) and mitigation of GI-related events (secondary). Patients were instructed to take DMF according to the prescribing information for up to 12 weeks and to document GI events and intake of GI-symptomatic therapy on numerical rating scales, using eDiaries. Results:A total of 211 patients were included in the safety population (71% female; mean age 40 ± 11 years). Of these, 185 patients (87.7%) reported GI-related events, out of which nearly half received GI-symptomatic therapy (84/185; 45.4%). The most frequently reported GI events were upper abdominal pain, flatulence and nausea. GI-related events peaked during the first 3 weeks of therapy and rapidly decreased thereafter. The severity of GI events over 12 weeks according to the Modified Overall Gastrointestinal Symptom Scale were mild to moderate in the majority of patients reporting GI-related events and taking symptomatic GI medication (53.6%). Only 10% of all patients discontinued study treatment due to AEs in general, while 6.6% discontinued due to GI-related events. The severity of GI-related events decreased over time in patients who received symptomatic treatment with one or more medications (e.g. acid secretion blockers, antidiarrhoeals or antiemetics). Conclusion:Gastrointestinal events associated with delayed-release DMF were mainly mild to moderate in severity. Prevalence of GI events peaked during the first 3 weeks of therapy and rapidly faded thereafter. Although 44.9% of patients experiencing GI events used common GI symptomatic therapies, only 6.6% of patients discontinued DMF because of GI events, suggesting that GI events could be managed well with common symptomatic therapy.

Project description:IntroductionWe report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported.MethodsIncidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0-2 /DMF for years 3-9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed.ResultsOf 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0-2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6-0.8 and 0.9-2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was -1.32% (range -1.60% to -1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 109/L at discontinuation (n = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation.ConclusionsSustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS.Trial registrationClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM).

Project description:Multiple sclerosis (MS) shares an immune-mediated origin with psoriasis. Long-term safety and efficacy data generated in Europe from usage of fumaric acid formulations in the latter disease constituted grounds to investigate their effects in MS patients. Dimethyl fumarate (DMF) was found to be the active principle in those formulations and in vitro studies have demonstrated that DMF has immune-modulatory properties exerted through abilities to divert cytokine production toward a Th2 profile, both on lymphocytes and microglial cells. More importantly, DMF was discovered to impact the anti-oxidative stress cell machinery promoting the transcription of genes downstream to the activation of the nuclear factor (erythroid derived 2)-like2 (NRF2). DMF exposure increases the cytosol concentrations of NRF2, which besides immune regulatory effects, has the potential for cytoprotection on glial cells, oligodendrocytes and neurons. Extensive and rigorous clinical trials have assessed the efficacy and safety of DMF at the dose of 240 mg twice and three times a day in relapsing-remitting MS patients during one phase IIb and two phase III trials. Robust, positive results were obtained across a number of clinical and paraclinical parameters. In one study (DEFINE), the relative reductions of the adjusted annualized relapse rate of the low and high dose regimens in comparison with placebo were 53% and 48%, respectively (p < 0.001 for both comparisons). In the other trial (CONFIRM), DMF decreased the annualized relapse rate in comparison with placebo by 44% in the lower and by 51% in higher dosage group (also p < 0.001). The number and size of lesions as detected by magnetic resonance imaging were also significantly decreased in comparison with the patients receiving DMF at every dosage. Multiple post hoc and subgroup analyses corroborated the clinical data, rendering DMF an appealing medication whose potential for impacting the degenerative aspects of MS remains to be explored.

Project description:IntroductionClinical 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.MethodsIn 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.ResultsIn 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.ConclusionDMF 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.FundingBiogen.Trial registrationDEFINE: ClinicalTrials.gov identifier NCT00420212; CONFIRM ClinicalTrials.gov identifier NCT00451451.

Dataset Information

A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries.

Publications

A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from East Asia and other countries.

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