Multiple Sclerosis
Conditions
Brief summary
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.
Interventions
DRUGdimethyl fumarate
Starting dose of 120 mg twice daily orally After 7 days, maintenance dose of 240 mg twice daily orally
DRUGmontelukast
As described in the treatment arm
DRUGPlacebo
Matched placebo
Sponsors
Biogen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the GSRS From Day 0 to Day 10 | Baseline (Day 0), Day 10 (10 days after Day 0) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Change From Baseline in GSRS Overall Score at Day 1 to Week 10 | Baseline (Day 0), Day 1 (1 day after Day 0), Week 10 (10 weeks after Day 0) | 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. |
| Time to First Worsening From Baseline in GSRS Overall Score at Day 1 to Day 10 | Baseline (Day 0), Day 1 (1 day after Day 0) to Day 10 (10 days after Day 0) | 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. |
| Time to Recovery to Baseline GSRS Score From Last Occurrence of Worst GSRS Score at Day 1 to Week 8 | Baseline (Day 0), Day 1 (1 Day after Day 0) to Week 8 (8 weeks after Day 0) | 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. |
| Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Baseline (Day 0), Day 1 (1 Day after Day 0), Weeks 1 to 8 (1-8 weeks after Day 0) | 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. |
| Average Change From Baseline in GSRS Overall Score at Day 1 to Day 10 | Baseline (Day 0), Day 1 (1 day after Day 0), Day 10 (10 days after Day 0) | 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. |
| Percentage of Participants Who Required GI Symptomatic Therapy During the Study | Day 10 to Week 10 | 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. |
| Percentage of Participants Who Discontinued DMF Therapy Due to GI-Related Adverse Events (AEs) From Day 0 to Week 10 | 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. |
| Percentage of Participants Who Experienced AEs Related to Flushing | Day of first DMF dose (up to 27 days before 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. 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. |
| Average Change From Baseline in GSRS Overall Score at Day 0 to 72 Hours From the Initiation of Randomized Study Treatment | Baseline (Day 0), Day 3 (72 hours after Day 0) | 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. |
Countries
United States
Participant flow
Recruitment details
Participants were recruited from 50 sites in the United States.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| MITT- Placebo 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. | 30 |
| MITT-Montelukast 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. | 33 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 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 | Pregnancy | 1 | 0 | 0 |
| Run-in Period | Withdrawal by Subject | 1 | 0 | 0 |
| Study Treatment Period | Adverse Event | 0 | 6 | 3 |
| Study Treatment Period | GSRS Threshold Not Met | 0 | 1 | 0 |
| Study Treatment Period | Other | 0 | 3 | 0 |
| Study Treatment Period | Physician Decision | 0 | 0 | 1 |
| Study Treatment Period | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | MITT- Placebo | MITT-Montelukast | Total |
|---|---|---|---|
| Age, Continuous | 43.63 years STANDARD_DEVIATION 13 | 44.88 years STANDARD_DEVIATION 10.39 | 44.29 years STANDARD_DEVIATION 11.63 |
| Race and Ethnicity Not Collected | — | — | 0 Participants |
| Sex: Female, Male Female | 23 Participants | 27 Participants | 50 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 98 | 0 / 31 | 0 / 33 |
| other Total, other adverse events | 35 / 98 | 14 / 31 | 14 / 33 |
| serious Total, serious adverse events | 3 / 98 | 2 / 31 | 1 / 33 |
Outcome results
Primary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MITT-Placebo | 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 |
| MITT-Montelukast | Percentage of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the GSRS From Day 0 to Day 10 | 33 percentage of participants |
Comparison: Odds ratio is the odds of an event in the Montelukast treatment group divided by the odds of an event in the placebo treatment group. P-value is from the likelihood ratio test that the odds ratio is 1. CI = profile likelihood confidence interval.p-value: 0.061795% CI: [0.938, 20.832]weighted logistic regression model
Secondary
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 0 to 72 Hours From the Initiation of Randomized Study Treatment | Day 0 | 0.84 units on scale | Standard Deviation 0.576 |
| MITT-Montelukast | 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 | -0.18 units on scale | Standard Deviation 0.528 |
Comparison: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight (kg) and baseline GSRS score, and has unstructured variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and Day 3.p-value: 0.246995% CI: [-0.092, 0.349]Repeated measures model
Secondary
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Day 10 | Day 0 | 0.84 units on a scale | Standard Deviation 0.576 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Day 10 | Change From Day 1 to Day 10 | -0.23 units on a scale | Standard Deviation 0.499 |
Comparison: Results are obtained from an ANCOVA model for comparing average change of the GSRS score in the two treatment groups, adjusted for age, weight and baseline GSRS score. Weights, defined as the proportions of days with GSRS score recorded during the Day 1 - Day 10 period are applied to adjust for missing data.p-value: 0.375395% CI: [-0.104, 0.273]ANCOVA
Secondary
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Week 10 | Day 0 | 0.84 units on scale | Standard Deviation 0.576 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Week 10 | Change From Day 1 to Week 10 | -0.31 units on scale | Standard Deviation 0.55 |
Comparison: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and Week 10.p-value: 0.037695% CI: [0.005, 0.158]Repeated measures model
Secondary
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Placebo | 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 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 8 | -0.31 unit on scale | Standard Deviation 0.548 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 5 | -0.28 unit on scale | Standard Deviation 0.533 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Day 0 | 0.84 unit on scale | Standard Deviation 0.576 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 1 | -0.21 unit on scale | Standard Deviation 0.498 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 2 | -0.25 unit on scale | Standard Deviation 0.495 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 3 | -0.26 unit on scale | Standard Deviation 0.522 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 4 | -0.26 unit on scale | Standard Deviation 0.537 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 6 | -0.29 unit on scale | Standard Deviation 0.537 |
| MITT-Montelukast | Average Change From Baseline in GSRS Overall Score at Day 1 to Weeks 1 to 8 | Change from Day 1 to Week 7 | -0.30 unit on scale | Standard Deviation 0.544 |
Comparison: Change from Day 1 to Week 1: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.174395% CI: [-0.052, 0.283]Repeated measures model
Comparison: Change from Day 1 to Week 2: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.267795% CI: [-0.063, 0.221]Repeated measures model
Comparison: Change from Day 1 to Week 3: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.178895% CI: [-0.04, 0.211]Repeated measures model
Comparison: Change from Day 1 to Week 4: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.086695% CI: [-0.015, 0.216]Repeated measures model
Comparison: Change from Day 1 to Week 5: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.050995% CI: [0, 0.201]Repeated measures model
Comparison: Change from Day 1 to Week 6: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.064995% CI: [-0.006, 0.182]Repeated measures model
Comparison: Change from Day 1 to Week 7: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.047995% CI: [0.001, 0.176]Repeated measures model
Comparison: Change from Day 1 to Week 8: Results are obtained from a repeated measures model for change from baseline (Day 0) in the GSRS score. The model includes treatment, day and treatment by day interaction, adjusted for age, weight(kg) and baseline GSRS score, and has spatial-exponential variance-covariance structure. The P-value is for testing the null hypothesis of no difference between the two treatment groups in the average change from baseline (Day 0) between Day 1 and the specified time point.p-value: 0.05495% CI: [-0.001, 0.166]Repeated measures model
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MITT-Placebo | Percentage of Participants Who Discontinued DMF Therapy Due to GI-Related Adverse Events (AEs) From Day 0 to Week 10 | 7 percentage of participants |
| MITT-Montelukast | Percentage of Participants Who Discontinued DMF Therapy Due to GI-Related Adverse Events (AEs) From Day 0 to Week 10 | 9 percentage of participants |
p-value: 1Fisher's Exact
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MITT-Placebo | Percentage of Participants Who Experienced AEs Related to Flushing | 23 percentage of participants |
| MITT-Montelukast | Percentage of Participants Who Experienced AEs Related to Flushing | 36 percentage of participants |
p-value: 0.2604Chi-squared
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MITT-Placebo | Percentage of Participants Who Required GI Symptomatic Therapy During the Study | 33 percentage of participants |
| MITT-Montelukast | Percentage of Participants Who Required GI Symptomatic Therapy During the Study | 33 percentage of participants |
p-value: 1Chi-squared
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MITT-Placebo | Time to First Worsening From Baseline in GSRS Overall Score at Day 1 to Day 10 | 10 days |
| MITT-Montelukast | Time to First Worsening From Baseline in GSRS Overall Score at Day 1 to Day 10 | 7 days |
Comparison: Hazard ratio and the P-value are based on the Cox's proportional hazard regression model, adjusted for age, weight and baseline GSRS score. Hazard ratio (HR) is the ratio of hazard rates of Montelukast and placebo treatment groups. P-value is from the Wald test that HR is 1. CI = Wald confidence interval.p-value: 0.795295% CI: [0.554, 2.164]Regression, Cox
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MITT-Placebo | Time to Recovery to Baseline GSRS Score From Last Occurrence of Worst GSRS Score at Day 1 to Week 8 | 1 days |
| MITT-Montelukast | Time to Recovery to Baseline GSRS Score From Last Occurrence of Worst GSRS Score at Day 1 to Week 8 | 1 days |
Comparison: Hazard ratio and the P-value are based on the Cox's proportional hazard regression model, adjusted for age, weight and baseline GSRS score. Hazard ratio (HR) is the ratio of hazard rates of Montelukast and placebo treatment groups. P-value is from the Wald test that HR is 1. CI = Wald confidence interval.p-value: 0.832895% CI: [0.563, 1.589]Regression, Cox