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

Primary Purpose

Relapsing-Remitting Multiple Sclerosis

Status
Completed
Phase
Phase 4
Locations
Germany
Study Type
Interventional
Intervention
dimethyl fumarate
Sponsored by
Biogen
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Relapsing-Remitting Multiple Sclerosis focused on measuring Gastrointestinal event

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Research Site
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Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Dimethyl Fumarate

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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.
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.
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.
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.
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.

Secondary Outcome Measures

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.
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.
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'.
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.
Percentage of Participants Who Discontinued Dimethyl Fumarate Due To Gastrointestinal-Related Treatment-Emergent Adverse Events

Full Information

First Posted
April 25, 2014
Last Updated
March 7, 2017
Sponsor
Biogen
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1. Study Identification

Unique Protocol Identification Number
NCT02125604
Brief Title
Gastrointestinal Tolerability Study Of Dimethyl Fumarate In Participants With Relapsing-Remitting Multiple Sclerosis In Germany
Acronym
TOLERATE
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 Type
Interventional

2. Study Status

Record Verification Date
March 2017
Overall Recruitment Status
Completed
Study Start Date
June 2014 (undefined)
Primary Completion Date
February 2016 (Actual)
Study Completion Date
March 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biogen

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Relapsing-Remitting Multiple Sclerosis
Keywords
Gastrointestinal event

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
214 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dimethyl Fumarate
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
dimethyl fumarate
Other Intervention Name(s)
BG00012, Tecfidera, DMF
Intervention Description
capsules administered according to the prevailing product label
Primary Outcome Measure Information:
Title
Number of Participants Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Overall Gastrointestinal Symptom Scale (MOGISS)
Description
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.
Time Frame
Up to Week 12
Title
Number of Participants Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Acute Gastrointestinal Symptom Scale (MAGISS)
Description
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.
Time Frame
Up to Week 12
Title
Worst Severity Of Gastrointestinal-Related Events In Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS
Description
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.
Time Frame
Up to Week 12
Title
Worst Severity Of Gastrointestinal-Related Events In Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MAGISS
Description
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.
Time Frame
Up to Week 12
Title
Duration of Gastrointestinal-Related Events in Participants Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS
Description
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.
Time Frame
Up to Week 12
Title
Duration of Gastrointestinal-Related Events in Participants Who Utilize Symptomatic Therapy During the 12-Week Treatment Period, MAGISS
Description
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.
Time Frame
Up to Week 12
Secondary Outcome Measure Information:
Title
Percentage of Participants Who First Took Symptomatic Therapy for Gastrointestinal-Related Events at Weeks 4, 8, and 12
Description
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.
Time Frame
Week 4, Week 8, Week 12
Title
Number of Participants Who Used Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category
Description
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.
Time Frame
Up to Week 12
Title
Duration of Use of Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category
Description
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'.
Time Frame
Up to Week 12
Title
Percentage of Participants Who Required Dimethyl Fumarate Dose Reduction In Response To Gastrointestinal-Related Events
Description
Dose reductions are defined as participants who take any dimethyl fumarate 120 mg or 0 mg since initiation of dimethyl fumarate 240 mg.
Time Frame
Up to Week 12
Title
Percentage of Participants Who Discontinued Dimethyl Fumarate Due To Gastrointestinal-Related Treatment-Emergent Adverse Events
Time Frame
Up to Week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Biogen
Official's Role
Study Director
Facility Information:
Facility Name
Research Site
City
Augsburg
Country
Germany
Facility Name
Research Site
City
Bamburg
Country
Germany
Facility Name
Research Site
City
Bayreuth
Country
Germany
Facility Name
Research Site
City
Berlin
Country
Germany
Facility Name
Research Site
City
Bochum
Country
Germany
Facility Name
Research Site
City
Bonn
Country
Germany
Facility Name
Research Site
City
Erbach
Country
Germany
Facility Name
Research Site
City
Erlangen
Country
Germany
Facility Name
Research Site
City
Freiburg
Country
Germany
Facility Name
Research Site
City
Hamburg
Country
Germany
Facility Name
Research Site
City
Leipzig
Country
Germany
Facility Name
Research Site
City
Marburg
Country
Germany
Facility Name
Research Site
City
Minden
Country
Germany
Facility Name
Research Site
City
Mittweida
Country
Germany
Facility Name
Research Site
City
Munchen
Country
Germany
Facility Name
Research Site
City
Munster
Country
Germany
Facility Name
Research Site
City
Osnabruck
Country
Germany
Facility Name
Research Site
City
Potsdam
Country
Germany
Facility Name
Research Site
City
Siegen
Country
Germany

12. IPD Sharing Statement

Learn more about this trial

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

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