Gastrointestinal Tolerability Study Of Dimethyl Fumarate In Participants With Relapsing-Remitting Multiple Sclerosis In Germany (TOLERATE)

A Multicenter, Open-Label, Single-Arm Study to Evaluate Gastrointestinal Tolerability in Subjects With Relapsing-Remitting Multiple Sclerosis Receiving Dimethyl Fumarate (TOLERATE)

The primary objective of this study is to evaluate the effect of symptomatic therapies on gastrointestinal-related events reported by participants with relapsing-remitting multiple sclerosis initiating therapy with BG00012 (dimethyl fumarate, DMF) in the clinical practice setting.

The secondary objectives of this study in this study population are as follows: to evaluate gastrointestinal-related events requiring symptomatic therapy and the role of those therapies over time; to evaluate gastrointestinal-related events that lead to a physician's decision to manage the events with BG00012 dose modification; and to evaluate gastrointestinal-related events that lead to BG00012 discontinuation after the use of symptomatic therapy.

Study Overview

• Status: Completed
• Conditions: Relapsing-Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: dimethyl fumarate

• Study Type: Interventional
• Enrollment (Actual): 214
• Phase: Phase 4

Contacts and Locations

Study Locations

• Germany
  • Augsburg, Germany
    • Research Site
  • Bamburg, Germany
    • Research Site
  • Bayreuth, Germany
    • Research Site
  • Berlin, Germany
    • Research Site
  • Bochum, Germany
    • Research Site
  • Bonn, Germany
    • Research Site
  • Erbach, Germany
    • Research Site
  • Erlangen, Germany
    • Research Site
  • Freiburg, Germany
    • Research Site
  • Hamburg, Germany
    • Research Site
  • Leipzig, Germany
    • Research Site
  • Marburg, Germany
    • Research Site
  • Minden, Germany
    • Research Site
  • Mittweida, Germany
    • Research Site
  • Munchen, Germany
    • Research Site
  • Munster, Germany
    • Research Site
  • Osnabruck, Germany
    • Research Site
  • Potsdam, Germany
    • Research Site
  • Siegen, Germany
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion Criteria:

• Have a confirmed diagnosis of relapsing-remitting multiple sclerosis according to the current McDonald Criteria and satisfy the therapeutic indication as described in the official local registration for Tecfidera (dimethyl fumarate)
• Naïve to dimethyl fumarate and fumaric acid esters

Key Exclusion Criteria:

• Female subjects who are currently pregnant or breastfeeding or who are considering becoming pregnant while in the study
• History of significant gastrointestinal disease (e.g., irritable bowel disease, peptic ulcer disease, history of major gastrointestinal surgeries), or chronic use of gastrointestinal-related symptomatic therapy as determined by the Investigator (or ≥ 7 consecutive days of gastrointestinal-related symptomatic therapy
• Known active malignancies
• History of anaphylaxis or severe allergic reactions or known drug hypersensitivity
• Current use of B vitamin supplements
• In the opinion of the Investigator, blood test values suggestive of a low lymphocyte count or renal or hepatic impairment, as described in the product label precautions for use

NOTE: Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dimethyl Fumarate; Dimethyl fumarate administered orally at 120 mg twice daily (BID) for the first 7 days and 240 mg BID thereafter for a total of 12 weeks.	Drug: dimethyl fumarate; capsules administered according to the prevailing product label; Other Names: BG00012; DMF; Tecfidera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Overall Gastrointestinal Symptom Scale (MOGISS)	The MOGISS is a questionnaire about the severity of overall gastrointestinal-related events, including specifically symptoms of nausea, diarrhea, upper abdominal pain, lower abdominal pain, vomiting, indigestion, constipation, bloating, and flatulence for 24 hours before the AM dose. Participants who rated the intensity of symptoms reported on the MOGISS and included each symptomatic therapy used in the eDiary are presented.	Up to Week 12
Number of Participants Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Acute Gastrointestinal Symptom Scale (MAGISS)	The MAGISS is a questionnaire in which participants reported overall acute gastrointestinal-related events, (especially symptoms of nausea, diarrhea, upper abdominal pain, lower abdominal pain, vomiting, indigestion, constipation, bloating, and flatulence) for each 10 hours after the AM and PM doses of study drug. Participants who rated the intensity of gastrointestinal-related events reported on MAGISS, included the duration of the gastrointestinal-related events and each symptomatic therapy used in the eDiary are presented.	Up to Week 12
Worst Severity Of Gastrointestinal-Related Events In Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS	The MOGISS is a questionnaire about overall events related to the gastrointestinal system (including nausea, diarrhea, upper abdominal pain, lower abdominal pain, vomiting, indigestion, constipation, bloating, and flatulence) during the 24 hours prior to each AM dose. MOGISS is based on a 0- to 10-point scale, with 0 representing absence of symptoms and 10 representing the most severe symptoms. The worst overall severity score for gastrointestinal-related events was calculated for each participant for the overall treatment period of 12 weeks, and for each 4-week period therein.	Up to Week 12
Worst Severity Of Gastrointestinal-Related Events In Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MAGISS	The MAGISS is a questionnaire about the overall events related to the gastrointestinal system (including nausea, diarrhea, upper abdominal pain, lower abdominal pain, vomiting, indigestion, constipation, bloating, and flatulence) following drug administration (acute symptoms). MAGISS is based on a 0- to 10-point scale, with 0 representing absence of symptoms and 10 representing the most severe symptoms. The worst overall severity score for gastrointestinal-related events was calculated for each participant for the overall treatment period of 12 weeks, and for each 4-week period therein.	Up to Week 12
Duration of Gastrointestinal-Related Events in Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS	The percentage of days with GI events as reported on MOGISS was calculated for each participant and each analysis period using the following formula: 100 x (# of days with [GI] events / # of days tolerability scale completed). The symptomatic therapy (ST) categories were provided by Biogen Medical team as follows: ST1=anti-acid production; ST2=anti-bloating/anti-constipation agent; ST3=multitarget/ herbal agents; ST4=anti-diarrheal (anti-peristaltic); ST5=analgesic (NSAID); ST6=anti-emetic (central); ST7=anti-emetic (pro-kinetic); ST8=antacid; ST9=other; ST10=laxative (pro-kinetic). Overall GI events were reported in the second day after the dose. Relative day for Overall GI events = assessment date-first dose date.	Up to Week 12
Duration of Gastrointestinal-Related Events in Participants Who Utilize Symptomatic Therapy During the 12-Week Treatment Period, MAGISS	Percentage of days with GI events as reported on MAGISS was calculated for each participant and each analysis period using the following formula: 100 x (# of days with [GI] events / # of days tolerability scale completed). The ST categories were provided by Biogen Medical team as follows: ST1=anti-acid production; ST2=anti-bloating/anti-constipation agent; ST3=multitarget/ herbal agents; ST4=anti-diarrheal (anti-peristaltic); ST5=analgesic (NSAID); ST6=anti-emetic (central); ST7=anti-emetic (pro-kinetic); ST8=antacid; ST9=other; ST10=laxative (pro-kinetic). Overall GI events were reported in the second day after the dose. Relative day for Overall GI events = assessment date-first dose date.	Up to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who First Took Symptomatic Therapy for Gastrointestinal-Related Events at Weeks 4, 8, and 12	The cumulative percentage of dimethyl fumarate-treated participants with relapsing-remitting multiple sclerosis who required symptomatic therapy up to Week 4, Week 8, and Week 12 were estimated using the Kaplan-Meier method.	Week 4, Week 8, Week 12
Number of Participants Who Used Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category	Symptomatic therapies were classified into 10 main categories: anti-acid production (eg, pantoprazole, omeprazole, esomeprazole, ranitidine); anti-bloating/anti-constipation agents (eg, hyoscine butylbromide, sodium picosulfate, Agiolax, dimeticone, lactulose, Movicol, simethicone); multitarget/herbal agents (includes Iberogast, Gaviscon, amaratropfen, Wikalin, Gaviscon & Iberogast, Iberogast & Wikalin); anti-diarrheal (anti-peristaltic; loperamide, racecadotril); analgesic (non-steroidal anti-inflammatory drug [NSAID]; ibuprofen, paracetamol, metamizole); anti-emetic (central; dimenhydrinate, domperidone); anti-emetic (pro-kinetic; metoclopramide); anti-acid (calcium carbonate, magaldrate, sodium hydrogen carbonate, sodium hydroxide/aluminium oxide, Talcid); other (Saccharomyces boulardii, carbon tablet, Lactobacillus acidophilus); laxative (pro-kinetic; bisacodyl). Participants may have taken > 1 symptomatic therapy but were counted only once for the 'All therapies' summary.	Up to Week 12
Duration of Use of Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category	Symptomatic therapies were classified into 10 categories: anti-acid production (eg, pantoprazole, omeprazole, esomeprazole, ranitidine); anti-bloating/anti-constipation agents (eg, hyoscine butylbromide, sodium picosulfate, Agiolax, dimeticone, lactulose, Movicol, simethicone); multitarget/herbal agents (eg, Iberogast, Gaviscon, amaratropfen, Wikalin, Gaviscon & Iberogast, Iberogast & Wikalin); anti-diarrheal (anti-peristaltic; loperamide, racecadotril); analgesic (NSAID; ibuprofen, paracetamol, metamizole); anti-emetic (central; dimenhydrinate, domperidone); anti-emetic (pro-kinetic; metoclopramide); anti-acid (calcium carbonate, magaldrate, sodium hydrogen carbonate, sodium hydroxide/aluminium oxide, Talcid); other (Saccharomyces boulardii, carbon tablet, Lactobacillus acidophilus); laxative (pro-kinetic; bisacodyl). If a participant had multiple different therapies on the same day, the days on symptomatic therapy was calculated as 1 day in 'All therapies'.	Up to Week 12
Percentage of Participants Who Required Dimethyl Fumarate Dose Reduction In Response To Gastrointestinal-Related Events	Dose reductions are defined as participants who take any dimethyl fumarate 120 mg or 0 mg since initiation of dimethyl fumarate 240 mg.	Up to Week 12
Percentage of Participants Who Discontinued Dimethyl Fumarate Due To Gastrointestinal-Related Treatment-Emergent Adverse Events		Up to Week 12

Collaborators and Investigators

• Sponsor: Biogen

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): February 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: April 25, 2014
• First Submitted That Met QC Criteria: April 25, 2014
• First Posted (Estimate): April 29, 2014

Study Record Updates

• Last Update Posted (Actual): April 18, 2017
• Last Update Submitted That Met QC Criteria: March 7, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: Gastrointestinal event
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Dimethyl Fumarate
• Other Study ID Numbers: 109MS407; 2013-001486-17 (EudraCT Number)