Clinical Trial Results:
A Multicenter, Open-Label, Single-Arm Study to Evaluate Gastrointestinal Tolerability in Subjects with Relapsing-Remitting Multiple Sclerosis Receiving Dimethyl Fumarate (TOLERATE)
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Summary
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EudraCT number |
2013-001486-17 |
Trial protocol |
DE |
Global end of trial date |
11 Mar 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Mar 2017
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First version publication date |
23 Mar 2017
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
109MS407
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02125604 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Biogen
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Sponsor organisation address |
225 Binney Street, United States, Cambridge, Massachusetts, United States, 02142
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Public contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Scientific contact |
Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
11 Mar 2016
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Mar 2016
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
This study was designed to assess the incidence, severity, and duration of GI-related events requiring symptomatic therapies in a clinical practice setting in Germany. 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 led to a physician’s decision to manage the events with BG00012 dose modification; and to evaluate gastrointestinal-related events that led to BG00012 discontinuation after the use of symptomatic therapy.
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Protection of trial subjects |
Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
26 Jun 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 211
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Worldwide total number of subjects |
211
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EEA total number of subjects |
211
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
211
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 214 subjects were screened and enrolled; 3 subjects did not receive study drug (1 withdrew consent and 2 did not meet all inclusion/exclusion criteria). A total of 211 subjects were included in the safety population. | ||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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Dimethyl Fumarate | ||||||||||||||||||
Arm description |
Dimethyl fumarate administered orally at 120 mg BID for the first 7 days and 240 mg BID thereafter for a total of 12 weeks. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
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.
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Investigational medicinal product code |
BG00012
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Other name |
Tecfidera; DMF
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Pharmaceutical forms |
Gastro-resistant capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Subjects received information relating to the timing of dosing,missed doses, and accountability of DMF capsules.
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Baseline characteristics reporting groups
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Reporting group title |
Dimethyl Fumarate
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Reporting group description |
Dimethyl fumarate administered orally at 120 mg BID for the first 7 days and 240 mg BID thereafter for a total of 12 weeks. | ||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Dimethyl Fumarate
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Reporting group description |
Dimethyl fumarate administered orally at 120 mg BID for the first 7 days and 240 mg BID thereafter for a total of 12 weeks. | ||
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End point title |
Number of Subjects Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Overall Gastrointestinal Symptom Scale (MOGISS) [1] | ||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented for this endpoint, per protocol. |
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| Notes [2] - n=subjects with an assessment in given time period |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Subjects Who Utilized Symptomatic Therapy With Gastrointestinal-Related Events During the 12-Week Treatment Period: Modified Acute Gastrointestinal Symptom Scale (MAGISS) [3] | ||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented for this endpoint, per protocol. |
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| Notes [4] - n=subjects with an assessment in given time period |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Worst Severity Of Gastrointestinal-Related Events In Subjects Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS [5] | ||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented for this endpoint, per protocol. |
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| Notes [6] - n=subjects with an assessment in given time period |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Worst Severity Of Gastrointestinal-Related Events In Subjects Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MAGISS [7] | ||||||||||||||||
End point 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.
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented for this endpoint, per protocol. |
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| Notes [8] - n=subjects with an assessment in given time period |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Duration of Gastrointestinal-Related Events in Subjects Who Utilized Symptomatic Therapy During the 12-Week Treatment Period, MOGISS [9] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The percentage of days with GI events as reported on MOGISS was calculated for each subject 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.
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented for this endpoint, per protocol. |
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| Notes [10] - n=subjects with an assessment in given time period; 9999=not applicable (1 subject in this group) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Duration of Gastrointestinal-Related Events in Subjects Who Utilize Symptomatic Therapy During the 12-Week Treatment Period, MAGISS [11] | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Percentage of days with GI events as reported on MAGISS was calculated for each subject 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.
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End point type |
Primary
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End point timeframe |
Up to Week 12
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| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics are presented for this endpoint, per protocol. |
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| Notes [12] - n=subjects with an assessment in given time period; 9999=not applicable (1 subject in this group) |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects Who First Took Symptomatic Therapy for Gastrointestinal-Related Events by Weeks 4, 8, and 12 | ||||||||||||||
End point description |
The cumulative percentage of dimethyl fumarate-treated subjects 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.
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End point type |
Secondary
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End point timeframe |
Week 4, Week 8, Week 12
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| Notes [13] - Subjects who reported taking symptomatic therapy. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Number of Subjects Who Used Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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, magaldrat, sodium hydrogen carbonate, sodium hydroxide/aluminium oxide, Talcid); other (Saccharomyces boulardii, carbon tablet, Lactobacillus acidophilus); laxative (pro-kinetic; bisacodyl). Subjects may have taken > 1 symptomatic therapy but were counted only once for the 'All therapies' summary.
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End point type |
Secondary
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End point timeframe |
Up to Week 12
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Duration of Use of Symptomatic Therapies for Gastrointestinal-Related Events During the 12-Week Treatment Period, by Category | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point 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, magaldrat, sodium hydrogen carbonate, sodium hydroxide/aluminium oxide, Talcid); other (Saccharomyces boulardii, carbon tablet, Lactobacillus acidophilus); laxative (pro-kinetic; bisacodyl). If a subject had multiple different therapies on the same day, the days on symptomatic therapy was calculated as 1 day in 'All therapies'.
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End point type |
Secondary
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End point timeframe |
Up to Week 12
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| Notes [14] - n=subjects with an assessment in given time period; 9999=not applicable (1 subject in group). |
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| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End point title |
Percentage of Subjects Who Required Dimethyl Fumarate Dose Reduction In Response To Gastrointestinal-Related Events | ||||||||
End point description |
Dose reductions are defined as subjects who took any dimethyl fumarate 120 mg or 0 mg since initiation of dimethyl fumarate 240 mg.
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End point type |
Secondary
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End point timeframe |
Up to Week 12
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects Who Discontinued Dimethyl Fumarate due to Gastrointestinal-Related Treatment-Emergent Adverse Events | ||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
Up to Week 12
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Events presented are treatment emergent: reported from time of first dose of dimethyl fumarate through last dose (up to 12 weeks (±5 days) plus 2 weeks (±5 days) follow up.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Dimethyl Fumarate
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Reporting group description |
Dimethyl fumarate administered orally at 120 mg BID for the first 7 days and 240 mg BID thereafter for a total of 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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07 Oct 2013 |
- To update the protocol to reflect the use of electronic patient reported outcomes on hand-held devices instead of paper questionnaires.
- To update DMF storage information for consistency with the drug label – DMF should be protected from light. |
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20 Jul 2015 |
- To update the contact details of the pharmacovigilance provider for this study. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
