Tecfidera Slow-Titration Study (TITRATION)

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

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.

Study Overview

• Status: Terminated
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: dimethyl fumarate

• Study Type: Interventional
• Enrollment (Actual): 62
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium
    • Research Site
  • Wilrijk, Belgium
    • Research Site
• Czech Republic
  • Prague, Czech Republic
    • Research Site
• Italy
  • Montichiari, Italy
    • Research Site
  • Bolzano
    • Merano, Bolzano, Italy
      • Research Site
• United States
  • Arizona
    • Gilbert, Arizona, United States
      • Research Site
    • Phoenix, Arizona, United States
      • Research Site
  • California
    • Long Beach, California, United States
      • Research Site
  • Florida
    • Miami, Florida, United States
      • Research Site
  • Indiana
    • Avon, Indiana, United States
      • Research Site
    • Franklin, Indiana, United States
      • Research Site
  • Kansas
    • Overland Park, Kansas, United States
      • Research Site
  • Maine
    • Lewiston, Maine, United States
      • Research Site
  • North Carolina
    • Asheville, North Carolina, United States
      • Research Site
    • Cary, North Carolina, United States
      • Research Site
    • Charlotte, North Carolina, United States
      • Research Site
    • Wilmington, North Carolina, United States
      • Research Site
  • Ohio
    • Cincinnati, Ohio, United States
      • Research Site
  • Texas
    • Dallas, Texas, United States
      • Research Site
  • Washington
    • Wenatchee, Washington, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard Treatment (One-Week Titration); 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; Participants will be dosed twice daily for 12 weeks.; Other Names: BG00012; DMF; Tecfidera
Experimental: Slow Up-Titration (Six-Week Titration); 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; Participants will be dosed twice daily for 12 weeks.; Other Names: BG00012; DMF; Tecfidera

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Biogen

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): January 1, 2016

Study Registration Dates

• First Submitted: April 23, 2015
• First Submitted That Met QC Criteria: April 23, 2015
• First Posted (Estimate): April 28, 2015

Study Record Updates

• Last Update Posted (Actual): May 5, 2017
• Last Update Submitted That Met QC Criteria: March 27, 2017
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Dimethyl Fumarate
• Other Study ID Numbers: 109MS416; 2014-004562-22 (EudraCT Number)