Study of Montelukast on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis Receiving Tecfidera (MITIGATE)

A Multicenter, Double- Blind, Placebo- Controlled Study of Montelukast on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis Receiving Tecfidera® (Dimethyl Fumarate) Delayed Release Capsules

The primary objective of this study is to evaluate whether montelukast can reduce the severity of gastrointestinal (GI) events, measured by the Gastrointestinal Symptom Rating Scale (GSRS), after oral administration of dimethyl fumarate (DMF) in participants with relapsing forms of Multiple Sclerosis (MS). The secondary objectives of this study are as follows: To evaluate whether montelukast after oral administration of DMF in participants with relapsing forms of MS decreases discontinuations due to GI events and reduces the number of participants taking symptomatic therapies for GI events; To investigate the effect of montelukast on the incidence of flushing events after oral administration of 240 mg DMF in participants with relapsing forms of MS.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Placebo; Drug: dimethyl fumarate; Drug: montelukast

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Jonesboro, Arkansas, United States, 72401
      • Research Site
  • California
    • Carmichael, California, United States, 95608
      • Research Site
    • La Jolla, California, United States, 92037
      • Research Site
    • La Mesa, California, United States, 91942
      • Research Site
    • Pomona, California, United States, 91767
      • Research Site
    • Simi Valley, California, United States, 93065
      • Research Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Research Site
    • Colorado Springs, Colorado, United States, 80907
      • Research Site
  • Connecticut
    • Fairfield, Connecticut, United States, 06824
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20057
      • Research Site
  • Florida
    • Jacksonville, Florida, United States, 32216
      • Research Site
    • Naples, Florida, United States, 34102
      • Research Site
    • Ormond Beach, Florida, United States, 32174-3102
      • Research Site
    • Sunrise, Florida, United States, 33351
      • Research Site
  • Georgia
    • Rome, Georgia, United States, 30165-1625
      • Research Site
    • Smyrna, Georgia, United States, 30269
      • Research Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
    • Flossmoor, Illinois, United States, 60422
      • Research Site
  • Indiana
    • Indianapolis, Indiana, United States, 46256
      • Research Site
  • Kentucky
    • Louisville, Kentucky, United States, 40207
      • Research Site
  • Maine
    • Scarborough, Maine, United States, 04074
      • Research Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48334
      • Research Site
  • Missouri
    • Chesterfield, Missouri, United States, 63017
      • Research Site
    • Kansas City, Missouri, United States, 64111
      • Research Site
    • Saint Louis, Missouri, United States, 63104
      • Research Site
  • New Jersey
    • Freehold, New Jersey, United States, 07728
      • Research Site
  • New York
    • Amherst, New York, United States, 14226
      • Research Site
    • New York, New York, United States, 10029
      • Research Site
    • Patchogue, New York, United States, 11772
      • Research Site
  • North Carolina
    • Hendersonville, North Carolina, United States, 28792
      • Research Site
    • Raleigh, North Carolina, United States, 27607-6010
      • Research Site
    • Sanford, North Carolina, United States, 27330
      • Research Site
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Dayton, Ohio, United States, 45417
      • Research Site
    • Dayton, Ohio, United States, 45459
      • Research Site
    • Uniontown, Ohio, United States, 44685
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73109
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97225
      • Research Site
    • Tualatin, Oregon, United States, 97062
      • Research Site
  • Pennsylvania
    • Dickson City, Pennsylvania, United States, 18519
      • Research Site
    • Greensburg, Pennsylvania, United States, 15601
      • Research Site
    • Hershey, Pennsylvania, United States, 17033
      • Research Site
    • Wilkes-Barre, Pennsylvania, United States, 18711
      • Research Site
  • Tennessee
    • Nashville, Tennessee, United States, 37215
      • Research Site
  • Texas
    • Dallas, Texas, United States, 75214
      • Research Site
    • Round Rock, Texas, United States, 78681
      • Research Site
  • Virginia
    • Alexandria, Virginia, United States, 22310
      • Research Site
    • Newport News, Virginia, United States, 23601
      • Research Site
  • Washington
    • Seattle, Washington, United States, 98122
      • Research Site
  • Wisconsin
    • Madison, Wisconsin, United States, 53705
      • 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:

• Reside in the United States and have a confirmed diagnosis of a relapsing form of MS and satisfy the therapeutic indication as described in the local label
• As perceived by the Investigator, have the ability to comply with all requirements of the study protocol and to operate the eDiary required to record GI-related events
• Female participants of childbearing potential who are not surgically sterile must practice effective contraception during their participation in the study and be willing and able to continue contraception for 30 days after they complete or withdraw from the study. All men must practice effective contraception, and they should not donate sperm throughout the study and for at least 90 days after their last dose of study treatment.

Key Exclusion Criteria:

• History of significant GI disease (for example, irritable bowel disease, peptic ulcer disease, history of major GI surgery, eosinophilic GI disease, or food allergies)
• Chronic use (≥7 consecutive days) of bismuth subsalicylate, simethicone, calcium carbonate, loperamide, proton-pump inhibitors, or ondansetron within 1 month prior to the Screening Visit
• Use of the following medications: montelukast, immunotherapy, mast cell stabilizers, or parenteral, inhaled, or oral steroids up to 1 month prior to the Screening Visit. Use of these medications is also not permitted for the duration of the study (except for the use of montelukast as per study protocol) and will lead to discontinuation
• Have one or more major comorbidities that, in the opinion of the Investigator, may affect the outcome of the study
• History of malignancy (except for basal cell carcinoma that had been completely excised prior to study entry), severe allergic or anaphylactic reactions or known drug hypersensitivity, abnormal laboratory results indicative of any significant disease, and/or a major disease that would preclude participation in a clinical study

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DMF plus montelukast; DMF as described in the United States Prescribing Information (USPI) plus 10mg montelukast tablet once daily according to the prevailing product label (Singulair)	Drug: dimethyl fumarate; Starting dose of 120 mg twice daily orally After 7 days, maintenance dose of 240 mg twice daily orally; Other Names: BG00012; DMF; Tecfidera; Drug: montelukast; As described in the treatment arm; Other Names: Singulair
Experimental: DMF plus placebo; DMF as described in the USPI plus matched placebo	Drug: Placebo; Matched placebo; Drug: dimethyl fumarate; Starting dose of 120 mg twice daily orally After 7 days, maintenance dose of 240 mg twice daily orally; Other Names: BG00012; DMF; Tecfidera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the GSRS From Day 0 to Day 10	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). Worsening in severity was defined as a positive average change from baseline (Day 0) to Day 10 in the GSRS score. Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 was the last day when the threshold was reached, prior to the first dose. Average change is the sum of changes from baseline in GSRS score over the first 10 days divided by the total of days with a GSRS score.	Baseline (Day 0), Day 10 (10 days after Day 0)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average Change From Baseline in GSRS Overall Score at Day 1 to Day 10	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). This endpoint reports the average change from baseline (Day 0) at Day 1 to Day 10. Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 was the last day when the threshold was reached, prior to the first dose. A negative change from baseline indicates that symptoms decreased.	Baseline (Day 0), Day 1 (1 day after Day 0), Day 10 (10 days after Day 0)
Average Change From Baseline in GSRS Overall Score at Day 1 to Week 10	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). This endpoint reports the average change from baseline (Day 0) between Day 1 and Week 10. Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 was the last day when the threshold was reached, prior to the first dose. A negative change from baseline indicates that symptoms decreased.	Baseline (Day 0), Day 1 (1 day after Day 0), Week 10 (10 weeks after Day 0)
Time to First Worsening From Baseline in GSRS Overall Score at Day 1 to Day 10	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 was the last day when the threshold was reached, prior to the first dose.. Time to the first worsening was defined as the number of days from Day 1 to the first date with a worsened GSRS score. Censoring occurred at Day 10.	Baseline (Day 0), Day 1 (1 day after Day 0) to Day 10 (10 days after Day 0)
Time to Recovery to Baseline GSRS Score From Last Occurrence of Worst GSRS Score at Day 1 to Week 8	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). Recovery was defined as a GSRS score less than or equal to the Day 0 score. Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 was the last day when the threshold was reached, prior to the first dose. Time to recovery was defined as the date of recovery minus the date of the last occurrence of the worst score.	Baseline (Day 0), Day 1 (1 Day after Day 0) to Week 8 (8 weeks after Day 0)
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). This endpoint reports the average change from baseline (Day 0) between Day 1 and the specified time point. Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 was the last day when the threshold was reached, prior to the first dose. A negative change from baseline indicates that symptoms decreased.	Baseline (Day 0), Day 1 (1 Day after Day 0), Weeks 1 to 8 (1-8 weeks after Day 0)
Average Change From Baseline in GSRS Overall Score at Day 0 to 72 Hours From the Initiation of Randomized Study Treatment	The GSRS is a weekly recall scale that was modified for daily recall. The 15-question GSRS is summarized with a 7-point Likert scale: no discomfort at all=0; minor discomfort=1; mild discomfort=2; moderate discomfort=3; moderately severe discomfort=4; severe discomfort=5 and very severe discomfort=6. The overall GSRS score is a mean score that ranges from 0 (no symptoms) to 6 (the worst possible symptoms). This endpoint reports the average change from baseline (Day 0) at Day 1 to Day 3. Day 0: the day before a participant started randomized treatment (if the GI threshold was reached 1 day previously) or the first day of randomized treatment if the threshold was reached that day. If the threshold was reached >1 day previously, then Day 0 is the last day when the threshold was reached, prior to the first dose. A negative change from baseline indicates that symptoms decreased.	Baseline (Day 0), Day 3 (72 hours after Day 0)
Percentage of Participants Who Required GI Symptomatic Therapy During the Study	Symptomatic therapies were not permitted during the first 10 days after starting montelukast or placebo. From Day 10 onward, participants were allowed to use the following symptomatic therapies to treat DMF-related GI events: bismuth subsalicylate, simethicone, calcium carbonate, loperamide, proton-pump inhibitors and ondansetron.	Day 10 to Week 10
Percentage of Participants Who Discontinued DMF Therapy Due to GI-Related Adverse Events (AEs) From Day 0 to Week 10	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. Participants used an electronic diary to record GI-related events. GI-related AEs included diarrhea, nausea, upper abdominal pain, abdominal pain, and dyspepsia.	Day 0 to Week 10
Percentage of Participants Who Experienced AEs Related to Flushing	An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and that did not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. Flushing-related AEs included flushing and hot flush. Only events with an onset date on or after the date of first DMF dose (up to 27 days before Day 0) are presented. This includes events present before and subsequently worsened after the first dose of DMF.	Day of first DMF dose (up to 27 days before Day 0) to Week 10

Collaborators and Investigators

• Sponsor: Biogen

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2015
• Primary Completion (Actual): February 16, 2017
• Study Completion (Actual): April 27, 2017

Study Registration Dates

• First Submitted: April 2, 2015
• First Submitted That Met QC Criteria: April 2, 2015
• First Posted (Estimate): April 7, 2015

Study Record Updates

• Last Update Posted (Actual): March 31, 2020
• Last Update Submitted That Met QC Criteria: March 20, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Immunosuppressive Agents; Immunologic Factors; Hormones, Hormone Substitutes, and Hormone Antagonists; Dermatologic Agents; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Montelukast; Dimethyl Fumarate
• Other Study ID Numbers: 109MS414