Tecfidera Slow-Titration Study

Study Overview
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Brief Summary
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The primary objective of the study is to assess whether a 6-week titration (compared with a 1-week titration) is effective in reducing the incidence of dimethyl fumarate (DMF [Tecfidera])-related gastrointestinal (GI) adverse events (AEs) in participants with multiple sclerosis (MS). The secondary objective of this study is to assess whether a 6-week titration (compared with a 1-week titration) is effective in reducing the average severity and duration of GI symptoms over 12 weeks of DMF treatment in this study population.

Official Title
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A Multicenter, Treatment-Blind Phase 3b Study to Evaluate Whether 6-Week Up-Titration in Tecfidera® Dose is Effective in Reducing the Incidence of Gastrointestinal Adverse Events in Patients With Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: dimethyl fumarate


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Diagnosis of MS consistent with locally labeled indication for DMF No prior treatment with DMF Female subjects of childbearing potential who are not surgically sterile and male subjects must practice effective contraception during their participation in the study Have had a recent complete blood count (CBC), including lymphocyte count, that does not preclude participation in the study, in the judgement of the investigator Key Exclusion Criteria: Have a recent history or ongoing GI illness (e.g., peptic ulcer, irritable bowel syndrome) or any other current condition with GI signs and symptoms (e.g., nausea, vomiting, abdominal pain, or diarrhea) that may interfere with assessment of study endpoints Have other major comorbid conditions that preclude participation in the study, as determined by the investigator Participant is pregnant, breastfeeding, or planning a pregnancy during the study period Are receiving concomitant disease-modifying therapies for MS including, but not limited to, natalizumab, interferon beta, glatiramer acetate, fingolimod, alemtuzumab, teriflunomide, or laquinimod at screening History of severe allergic or anaphylactic reactions or known drug hypersensitivity NOTE: Other protocol defined Inclusion/Exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Treatment (One-Week Titration)<br>120 mg DMF twice daily for 1 week, then 240 mg (as 2 120-mg capsules) DMF twice daily for 11 weeks | Drug: dimethyl fumarate<br>* Participants will be dosed twice daily for 12 weeks.<br>* Other names: BG00012;|
| Experimental: Slow Up-Titration (Six-Week Titration)<br>120 mg DMF once daily (morning dose) and placebo once daily (evening dose) for 2 weeks, then 120 mg DMF twice daily for 2 weeks, then 240 mg (as 2 120-mg capsules) DMF in the morning and 120 mg in the evening for 2 weeks, then 240 mg (as 2 120-mg capsules) DMF twice daily for 6 weeks | Drug: dimethyl fumarate<br>* Participants will be dosed twice daily for 12 weeks.<br>* Other names: BG00012;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants With a Worsening in Severity of Gastrointestinal (GI) Adverse Events (AEs) on the Gastrointestinal Symptom Rating Scale (GSRS) | The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It was modified for daily recall in this study. GSRS is a rating scale consisting of 15 items for assessment of GI symptoms (see Appendix 1). Items are scored for intensity on a 7-grade Likert scale, defined by descriptive anchors such that 0 = none, 1 = minor, 2 = mild, 3 =moderate, 4 = moderately severe, 5 = severe, and 6 = very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 0 to 6; a score of 0 indicates that no symptoms are present, and a score of 6 indicates the worst possible degree of all symptoms. A higher score relative to Baseline indicates worsening of severity. | from Week 2 (Baseline) to Week 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average Change From Baseline in GSRS Scores During DMF Treatment | Average change from baseline in GSRS scores over the 12 weeks of DMF treatment as measured by the total change in GSRS scores from baseline divided by the total number of days with GSRS scores recorded. The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It was modified for daily recall in this study. GSRS is a rating scale consisting of 15 items for assessment of GI symptoms (see Appendix 1). Items are scored for intensity on a 7-grade Likert scale, defined by descriptive anchors such that 0 = none, 1 = minor, 2 = mild, 3 =moderate, 4 = moderately severe, 5 = severe, and 6 = very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 0 to 6; a score of 0 indicates that no symptoms are present, and a score of 6 indicates the worst possible degree of all symptoms. | Week 2 (Baseline), Week 14 | 
| Time to First Worsening From Baseline in GSRS Score | The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It was modified for daily recall in this study. GSRS is a rating scale consisting of 15 items for assessment of GI symptoms (see Appendix 1). Items are scored for intensity on a 7-grade Likert scale, defined by descriptive anchors such that 0 = none, 1 = minor, 2 = mild, 3 =moderate, 4 = moderately severe, 5 = severe, and 6 = very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 0 to 6; a score of 0 indicates that no symptoms are present, and a score of 6 indicates the worst possible degree of all symptoms. A higher score relative to Baseline indicates worsening of severity. | Week 2 (Baseline), Week 14 | 
| Time to Recovery to Baseline From Last Occurrence of Worst GSRS Score | The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It was modified for daily recall in this study. GSRS is a rating scale consisting of 15 items for assessment of GI symptoms (see Appendix 1). Items are scored for intensity on a 7-grade Likert scale, defined by descriptive anchors such that 0 = none, 1 = minor, 2 = mild, 3 =moderate, 4 = moderately severe, 5 = severe, and 6 = very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 0 to 6; a score of 0 indicates that no symptoms are present, and a score of 6 indicates the worst possible degree of all symptoms. A higher score relative to Baseline indicates worsening of severity. | Week 2 (Baseline), Week 14 | 
| Average Change From Baseline in GSRS Scores to the End of Weeks 4, 6, 8, 10, 12, and 14 | Average change from baseline to end of DMF treatment in the GSRS. The GSRS is a weekly recall scale to rate the severity of GI symptoms in participants. It was modified for daily recall in this study. GSRS is a rating scale consisting of 15 items for assessment of GI symptoms (see Appendix 1). Items are scored for intensity on a 7-grade Likert scale, defined by descriptive anchors such that 0 = none, 1 = minor, 2 = mild, 3 =moderate, 4 = moderately severe, 5 = severe, and 6 = very severe discomfort. The overall GSRS score is the mean of these 15 items, varying from 0 to 6; a score of 0 indicates that no symptoms are present, and a score of 6 indicates the worst possible degree of all symptoms. | Week 2 (Baseline), Weeks 4, 6, 8, 10, 12, 14 |