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

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ClinicalTrials.gov Identifier: NCT02125604
Recruitment Status : Completed
First Posted : April 29, 2014
Results First Posted : April 18, 2017
Last Update Posted : April 18, 2017
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Relapsing-Remitting Multiple Sclerosis Drug: dimethyl fumarate Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 214 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Open-Label, Single-Arm Study to Evaluate Gastrointestinal Tolerability in Subjects With Relapsing-Remitting Multiple Sclerosis Receiving Dimethyl Fumarate (TOLERATE)
Study Start Date : June 2014
Actual Primary Completion Date : February 2016
Actual Study Completion Date : March 2016

Resource links provided by the National Library of Medicine


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
  • Tecfidera
  • DMF




Primary Outcome Measures :
  1. Number of Participants Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Overall Gastrointestinal Symptom Scale (MOGISS) [ Time Frame: Up to Week 12 ]
    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.

  2. Number of Participants Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Acute Gastrointestinal Symptom Scale (MAGISS) [ Time Frame: Up to Week 12 ]
    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.

  3. Worst Severity Of Gastrointestinal-Related Events In Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS [ Time Frame: Up to Week 12 ]
    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.

  4. Worst Severity Of Gastrointestinal-Related Events In Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MAGISS [ Time Frame: Up to Week 12 ]
    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.

  5. Duration of Gastrointestinal-Related Events in Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS [ Time Frame: Up to Week 12 ]
    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.

  6. Duration of Gastrointestinal-Related Events in Participants Who Utilize Symptomatic Therapy During the 12-Week Treatment Period, MAGISS [ Time Frame: Up to Week 12 ]
    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.


Secondary Outcome Measures :
  1. Percentage of Participants Who First Took Symptomatic Therapy for Gastrointestinal-Related Events at Weeks 4, 8, and 12 [ Time Frame: Week 4, Week 8, Week 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.

  2. Number of Participants Who Used Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category [ Time Frame: Up to Week 12 ]
    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.

  3. Duration of Use of Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category [ Time Frame: Up to Week 12 ]
    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'.

  4. Percentage of Participants Who Required Dimethyl Fumarate Dose Reduction In Response To Gastrointestinal-Related Events [ Time Frame: Up to Week 12 ]
    Dose reductions are defined as participants who take any dimethyl fumarate 120 mg or 0 mg since initiation of dimethyl fumarate 240 mg.

  5. Percentage of Participants Who Discontinued Dimethyl Fumarate Due To Gastrointestinal-Related Treatment-Emergent Adverse Events [ Time Frame: Up to Week 12 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02125604


Locations
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Germany
Research Site
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
Sponsors and Collaborators
Biogen
Investigators
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Study Director: Medical Director Biogen

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Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02125604    
Other Study ID Numbers: 109MS407
2013-001486-17 ( EudraCT Number )
First Posted: April 29, 2014    Key Record Dates
Results First Posted: April 18, 2017
Last Update Posted: April 18, 2017
Last Verified: March 2017
Keywords provided by Biogen:
Gastrointestinal event
Additional relevant MeSH terms:
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Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Dimethyl Fumarate
Dermatologic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs