Trial Outcomes & Findings for Study of Montelukast on Gastrointestinal Tolerability in Patients With Relapsing Forms of Multiple Sclerosis Receiving Tecfidera (NCT NCT02410278)

NCT ID: NCT02410278

Last Updated: 2020-03-31

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 102 participants
• Primary outcome timeframe: Baseline (Day 0), Day 10 (10 days after Day 0)
• Results posted on: 2020-03-31

Participant Flow

Participants were recruited from 50 sites in the United States.

Participants were screened over 2 weeks. Those who met ≥1 of the following criteria were considered screen failures: a score of ≥5 on 1 question for 1 day on the Gastrointestinal Symptom Rating Scale (GSRS), ≥4 or ≥3 on 1 question for 2 or 3 consecutive days, respectively; and eDiary compliance of <75% over 14 days prior to randomization.

Participant milestones

Measure	Dimethyl Fumarate (DMF)- Run-in Period Participants received 120 milligrams (mg) of DMF twice daily by mouth for 7 days and 240 mg twice daily (as described in the USPI) for up to 28 days. Participants who reached the predefined threshold in scores on the GSRS continued to the Study Treatment Period; all other participants were discontinued from the study.	Placebo- Study Treatment Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview.	Montelukast- Study Treatment Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Run-in Period STARTED	102	0	0
Run-in Period Received at Least 1 Dose of DMF	98	0	0
Run-in Period COMPLETED	64	0	0
Run-in Period NOT COMPLETED	38	0	0
Study Treatment Period STARTED	0	31	33
Study Treatment Period Modified Intent-to Treat(mITT)Population	0	30	33
Study Treatment Period Completed Randomized Study Treatment	0	20	29
Study Treatment Period COMPLETED	0	20	29
Study Treatment Period NOT COMPLETED	0	11	4

Reasons for withdrawal

Measure	Dimethyl Fumarate (DMF)- Run-in Period Participants received 120 milligrams (mg) of DMF twice daily by mouth for 7 days and 240 mg twice daily (as described in the USPI) for up to 28 days. Participants who reached the predefined threshold in scores on the GSRS continued to the Study Treatment Period; all other participants were discontinued from the study.	Placebo- Study Treatment Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview.	Montelukast- Study Treatment Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Run-in Period Adverse Event	5	0	0
Run-in Period GSRS Threshold Not Met	30	0	0
Run-in Period Lost to Follow-up	1	0	0
Run-in Period Withdrawal by Subject	1	0	0
Run-in Period Pregnancy	1	0	0
Study Treatment Period Adverse Event	0	6	3
Study Treatment Period Physician Decision	0	0	1
Study Treatment Period Withdrawal by Subject	0	1	0
Study Treatment Period Other	0	3	0
Study Treatment Period GSRS Threshold Not Met	0	1	0

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Measure	MITT- Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.	Total n=63 Participants Total of all reporting groups
Age, Continuous	43.63 years STANDARD_DEVIATION 13.00 • n=30 Participants	44.88 years STANDARD_DEVIATION 10.39 • n=33 Participants	44.29 years STANDARD_DEVIATION 11.63 • n=63 Participants
Sex: Female, Male Female	23 Participants n=30 Participants	27 Participants n=33 Participants	50 Participants n=63 Participants
Sex: Female, Male Male	7 Participants n=30 Participants	6 Participants n=33 Participants	13 Participants n=63 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.

PRIMARY outcome

Timeframe: Baseline (Day 0), Day 10 (10 days after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Percentage of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the GSRS From Day 0 to Day 10	17 percentage of participants	33 percentage of participants

SECONDARY outcome

Timeframe: Baseline (Day 0), Day 1 (1 day after Day 0), Day 10 (10 days after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Average Change From Baseline in GSRS Overall Score at Day 1 to Day 10 Day 0	0.80 units on a scale Standard Deviation 0.569	0.84 units on a scale Standard Deviation 0.576
Average Change From Baseline in GSRS Overall Score at Day 1 to Day 10 Change From Day 1 to Day 10	-0.28 units on a scale Standard Deviation 0.695	-0.23 units on a scale Standard Deviation 0.499

SECONDARY outcome

Timeframe: Baseline (Day 0), Day 1 (1 day after Day 0), Week 10 (10 weeks after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Average Change From Baseline in GSRS Overall Score at Day 1 to Week 10 Day 0	0.80 units on scale Standard Deviation 0.569	0.84 units on scale Standard Deviation 0.576
Average Change From Baseline in GSRS Overall Score at Day 1 to Week 10 Change From Day 1 to Week 10	-0.37 units on scale Standard Deviation 0.67	-0.31 units on scale Standard Deviation 0.55

SECONDARY outcome

Timeframe: Baseline (Day 0), Day 1 (1 day after Day 0) to Day 10 (10 days after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Time to First Worsening From Baseline in GSRS Overall Score at Day 1 to Day 10	10 days Interval 3.0 to The upper limit of the inter-quartile range was not estimated because the Kaplan Meier curve did not cross the 75th percentile threshold during the 10 days of data collection for this outcome measure.	7 days Interval 1.0 to The upper limit of the inter-quartile range was not estimated because the Kaplan Meier curve did not cross the 75th percentile threshold during the 10 days of data collection for this outcome measure.

SECONDARY outcome

Timeframe: Baseline (Day 0), Day 1 (1 Day after Day 0) to Week 8 (8 weeks after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Time to Recovery to Baseline GSRS Score From Last Occurrence of Worst GSRS Score at Day 1 to Week 8	1 days Interval 1.0 to 3.0	1 days Interval 1.0 to 2.0

SECONDARY outcome

Timeframe: Baseline (Day 0), Day 1 (1 Day after Day 0), Weeks 1 to 8 (1-8 weeks after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Day 0	0.80 unit on scale Standard Deviation 0.569	0.84 unit on scale Standard Deviation 0.576
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 1	-0.30 unit on scale Standard Deviation 0.686	-0.21 unit on scale Standard Deviation 0.498
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 2	-0.29 unit on scale Standard Deviation 0.701	-0.25 unit on scale Standard Deviation 0.495
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 3	-0.31 unit on scale Standard Deviation 0.686	-0.26 unit on scale Standard Deviation 0.522
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 4	-0.33 unit on scale Standard Deviation 0.679	-0.26 unit on scale Standard Deviation 0.537
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 5	-0.35 unit on scale Standard Deviation 0.674	-0.28 unit on scale Standard Deviation 0.533
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 6	-0.35 unit on scale Standard Deviation 0.673	-0.29 unit on scale Standard Deviation 0.537
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 7	-0.36 unit on scale Standard Deviation 0.673	-0.30 unit on scale Standard Deviation 0.544
Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 Change from Day 1 to Week 8	-0.36 unit on scale Standard Deviation 0.677	-0.31 unit on scale Standard Deviation 0.548

SECONDARY outcome

Timeframe: Baseline (Day 0), Day 3 (72 hours after Day 0)

Population: The MITT: All participants who were randomized, received at least 1 dose of both DMF treatment and study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period. One participant in the MITT-Montelukast arm did not provide post-baseline data.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Average Change From Baseline in GSRS Overall Score at Day 0 to 72 Hours From the Initiation of Randomized Study Treatment Day 0	0.80 units on scale Standard Deviation 0.569	0.84 units on scale Standard Deviation 0.576
Average Change From Baseline in GSRS Overall Score at Day 0 to 72 Hours From the Initiation of Randomized Study Treatment Change from Day 0 to Day 3	-0.28 units on scale Standard Deviation 0.665	-0.18 units on scale Standard Deviation 0.528

SECONDARY outcome

Timeframe: Day 10 to Week 10

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Percentage of Participants Who Required GI Symptomatic Therapy During the Study	33 percentage of participants	33 percentage of participants

SECONDARY outcome

Timeframe: Day 0 to Week 10

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Percentage of Participants Who Discontinued DMF Therapy Due to GI-Related Adverse Events (AEs) From Day 0 to Week 10	7 percentage of participants	9 percentage of participants

SECONDARY outcome

Timeframe: Day of first DMF dose (up to 27 days before Day 0) to Week 10

Population: The MITT: All participants who were randomized, received at least 1 dose of DMF treatment, received at least 1 dose of study treatment (montelukast or placebo) on/after the first DMF dose date, and had at least 1 GSRS score measurement during the Day 1 - Day 10 period.

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.

Outcome measures

Measure	MITT-Placebo n=30 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received a montelukast-matching placebo tablet once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with placebo, then were followed for 2 additional weeks before a final phone interview. One participant randomized to placebo was excluded from the MITT.	MITT-Montelukast n=33 Participants Participants who reached the predefined threshold in scores on the GSRS during the Run-in Period entered the Study Treatment Period. Participants continued to receive 240 mg DMF twice daily and also received 10 mg of montelukast once daily by mouth for 8 weeks. Participants received only 240 mg DMF twice daily for 2 weeks after discontinuing treatment with montelukast, then were followed for 2 additional weeks before a final phone interview.
Percentage of Participants Who Experienced AEs Related to Flushing	23 percentage of participants	36 percentage of participants

Adverse Events

DMF Safety Population

Serious events: 3 serious events

Other events: 35 other events

Deaths: 0 deaths

Primary Safety Population-Placebo

Serious events: 2 serious events

Other events: 14 other events

Deaths: 0 deaths

Primary Safety Population-Montelukast

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Measure	DMF Safety Population n=98 participants at risk Participants who received at least 1 dose of DMF.	Primary Safety Population-Placebo n=31 participants at risk Participants who received at least 1 dose of placebo during the Study Treatment Period.	Primary Safety Population-Montelukast n=33 participants at risk Participants who received at least 1 dose of montelukast during the Study Treatment Period.
Blood and lymphatic system disorders Microcytic anaemia	1.0% 1/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.2% 1/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Investigations Alanine aminotransferase increased	1.0% 1/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.2% 1/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Investigations Aspartate aminotransferase increased	1.0% 1/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.2% 1/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Laryngeal squamous cell carcinoma	1.0% 1/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.0% 1/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Nervous system disorders Multiple sclerosis relapse	1.0% 1/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.2% 1/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.

Other adverse events

Measure	DMF Safety Population n=98 participants at risk Participants who received at least 1 dose of DMF.	Primary Safety Population-Placebo n=31 participants at risk Participants who received at least 1 dose of placebo during the Study Treatment Period.	Primary Safety Population-Montelukast n=33 participants at risk Participants who received at least 1 dose of montelukast during the Study Treatment Period.
Infections and infestations Viral upper respiratory tract infection	10.2% 10/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	16.1% 5/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	12.1% 4/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Nervous system disorders Paraesthesia	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.5% 2/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.0% 1/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Nervous system disorders Headache	5.1% 5/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.5% 2/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Nervous system disorders Migraine	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.1% 2/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Investigations Alanine aminotransferase increased	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.2% 1/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.1% 2/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Investigations Blood creatine phosphokinase increased	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.1% 2/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Investigations Liver function test increased	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.1% 2/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Vascular disorders Flushing	21.4% 21/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	12.9% 4/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	15.2% 5/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
General disorders Fatigue	5.1% 5/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	12.9% 4/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.0% 1/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.5% 2/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	3.0% 1/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Musculoskeletal and connective tissue disorders Musculoskeletal stiffness	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.5% 2/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.1% 2/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Skin and subcutaneous tissue disorders Pruritus generalised	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.5% 2/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.
Psychiatric disorders Insomnia	0.00% 0/98 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	6.5% 2/31 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.	0.00% 0/33 • AEs were assessed for up to 16 weeks for the DMF Safety Population and for 8 weeks for the Primary Safety Population.

Additional Information

Biogen Study Medical Director

Biogen

Phone: 866-633-4636

Email: clinicaltrials@biogen.com

Results disclosure agreements

• Principal investigator is a sponsor employee Our agreement is subject to confidentiality but generally the PI can publish, for noncommercial purposes only, results and methods of the trial, but no other Sponsor Confidential Information. PI must give Sponsor no less than 60 days to review any manuscript for a proposed publication and must delay publication for up to an additional 90 days thereafter if Sponsor needs to file any patent application to protect any of Sponsor's intellectual property contained in the proposed publication.
• Publication restrictions are in place

Restriction type: OTHER