Phase 4 Study of Effect of Aspirin on Flushing in Dimethyl Fumarate-Treated Participants With Relapsing-Remitting Multiple Sclerosis (ASSURE)

November 1, 2016 updated by: Biogen

A Phase 4, Randomized, Double-Blind Study With a Safety Extension Period to Evaluate the Effect of Aspirin on Flushing Events in Subjects With Relapsing-Remitting Multiple Sclerosis Treated With Tecfidera® (Dimethyl Fumarate) Delayed-Release Capsules

The primary objective of the study is to evaluate whether 150 mg enteric-coated aspirin (acetylsalicylic acid [ASA]) taken twice a day (BID) with dimethyl fumarate (DMF) administration or 75 mg enteric-coated ASA taken once daily in the morning (QAM) with DMF administration reduces the incidence and/or severity of flushing events in subjects with relapsing-remitting multiple sclerosis (RRMS) compared with ASA-placebo administered with DMF in the clinical practice setting.

Secondary objectives of this study are: to evaluate the safety and tolerability of DMF administered with and without enteric-coated ASA in the clinical practice setting; to evaluate the impact of DMF administration on quality of life as measured by the Short Form 36 (SF-36®) and European Quality of Life - 5 Dimensions - 5 Levels (EQ-5D-5L) questionnaires.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

241

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Ireland
      • Cork, Ireland
        • Research Site
      • Dublin, Ireland, DUBLIN 4
        • Research Site
      • Dublin, Ireland, Dublin 7
        • Research Site
      • Dublin, Ireland, Dublin 9
        • Research Site
  • United Kingdom
      • Basingstoke, United Kingdom, RG24 9NA
        • Research Site
      • Birmingham, United Kingdom, B15 2TH
        • Research Site
      • Cardiff, United Kingdom, CF14 4XW
        • Research Site
      • Edinburgh, United Kingdom, EHA 2XU
        • Research Site
      • Exeter, United Kingdom, EX2 5DW
        • Research Site
      • Glasgow, United Kingdom, G51 4TH
        • Research Site
      • Leicester, United Kingdom, LE5 4PW
        • Research Site
      • Liverpool, United Kingdom, L9 7LJ
        • Research Site
      • London, United Kingdom, SE5 9RS
        • Research Site
      • London, United Kingdom, SW17 0QT
        • Research Site
      • London, United Kingdom, WC1N 3BG
        • Research Site
      • Newcastle upon Tyne, United Kingdom, NE1 4LP
        • Research Site
      • Norwich, United Kingdom, NR4 7UY
        • Research Site
      • Nottingham, United Kingdom, NG7 2UH
        • Research Site
      • Plymouth, United Kingdom, PL6 8BX
        • Research Site
      • Salford, United Kingdom, M6 8HD
        • Research Site
      • Swansea, United Kingdom, SA6 6NL
        • Research Site

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Key Inclusion Criteria:

  • Naïve to fumaric acid esters (e.g. DMF, Fumaderm, compounded fumarates)
  • Diagnosed with RRMS and satisfies the approved therapeutic indication for DMF
  • Participants of childbearing potential must practice effective contraception and be willing and able to continue contraception throughout the study
  • Ability to complete the tolerability scales accurately using the electronic diary (eDiary) and ability to complete the paper Flushing Diaries

Key Exclusion Criteria:

  • Inability or unwillingness to comply with study requirements or, at the discretion of the Investigator, is deemed unsuitable for study participation
  • One or more major comorbidities that, in the opinion of the Investigator, may affect the outcome of the study or otherwise makes the subject an unsuitable candidate for study participation. The prevailing product labels for both DMF and ASA should be used as guides
  • Known active malignancies (subjects with cutaneous basal cell carcinoma that has been completely excised prior to study entry remain eligible)
  • Chronic use (≥7 consecutive days) of ASA- or nonsteroidal anti-inflammatory drugs (NSAID)-containing products within the month prior to enrollment in the study
  • A known intolerance to ASA
  • Active peptic ulceration or a history of peptic ulceration, hemophilia or other clotting disorders, or gout
  • Known hypersensitivity reactions (e.g., bronchospasm, rhinitis, urticaria) in response to ASA or NSAID administration
  • Impaired hepatic or renal function, in the opinion of the investigator
  • Female subject is pregnant, lactating, or will be attempting to become pregnant during the Double-Blind Period (first 12 weeks) of the study
  • Currently participating in another interventional clinical trial

NOTE: Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: DMF + ASA 150 mg BID

DMF 120 mg taken BID for the first 7 days and 240 mg BID from Week 2 through Week 48.

ASA 150 mg is taken BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA is prohibited; between Weeks 9 and 48, ASA is allowed as needed.)
Drug: dimethyl fumarate
Other Names:
  • BG00012
  • DMF
  • Tecfidera
Drug: acetylsalicylic acid
enteric-coated capsule
Other Names:
  • ASA
  • aspirin
Experimental: DMF + ASA 75 mg QAM

DMF 120 mg taken BID for the first 7 days and 240 mg BID from Week 2 through Week 48.

ASA 75 mg is taken in the morning (QAM) and ASA-Placebo is taken in the evening (QPM) from Day 1 through Week 4. (Between Weeks 5 and 8, ASA is prohibited; between Weeks 9 and 48, ASA is allowed as needed.)
Drug: dimethyl fumarate
Other Names:
  • BG00012
  • DMF
  • Tecfidera
Drug: acetylsalicylic acid
enteric-coated capsule
Other Names:
  • ASA
  • aspirin
Drug: ASA-Placebo
matched placebo
Other Names:
  • placebo
Experimental: DMF + ASA-Placebo BID

DMF 120 mg taken BID for the first 7 days and 240 mg BID from Week 2 through Week 48.

ASA-Placebo is taken BID from Day 1 through Week 4. (Between Weeks 5 and 8, ASA is prohibited; between Weeks 9 and 48, ASA is allowed as needed.)
Drug: dimethyl fumarate
Other Names:
  • BG00012
  • DMF
  • Tecfidera
Drug: ASA-Placebo
matched placebo
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Reporting Overall Flushing Events During the First 4 Weeks of Treatment, as Assessed by the Modified Global Flushing Severity Scale (MGFSS)
Time Frame: Day 2 to Week 4
Participant-reported flushing events during the first 4 weeks treatment, recorded on the hand-held participant reporting device (eDiary) as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects). Day 1 data are not included in the analysis because MGFSS question refers to last 24 hours flushing score.
Day 2 to Week 4
Percentage of Participants Reporting Overall Flushing Events During the First 4 Weeks of Treatment, as Assessed by the Modified Flushing Severity Scale (MFSS)
Time Frame: Day 1 to Week 4
Participant-reported flushing events during the first 4 weeks of treatment recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Day 1 to Week 4
Worst Severity Scores of Overall Flushing During the First 4 Weeks of Treatment, as Assessed by MGFSS
Time Frame: Day 2 to Week 4
Worst severity of participant-reported flushing events during the first 4 weeks of treatment recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects). Day 1 data are not included in the analysis because MGFSS question refers to last 24 hours flushing score.
Day 2 to Week 4
Worst Severity Scores of Overall Flushing During the First 4 Weeks of Treatment, as Assessed by MFSS
Time Frame: Day 1 to Week 4
Worst severity of participant-reported flushing events during the first 4 weeks of treatment recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin.This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Day 1 to Week 4

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percentage of Participants Reporting Overall Flushing Events During Weeks 5-8 and Weeks 9-12 of Treatment, as Assessed by MGFSS
Time Frame: Week 5 to Week 12
Participant-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Week 5 to Week 12
Percentage of Participants Reporting Overall Flushing Events During Weeks 5-8 and Weeks 9-12 of Treatment, as Assessed by MFSS
Time Frame: Week 5 to Week 12
Participant-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Week 5 to Week 12
Worst Severity Scores of Overall Flushing During Weeks 5-8 and Weeks 9-12 of the Study, as Assessed by MGFSS
Time Frame: Week 5 to Week 12
Worst severity of participant-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Week 5 to Week 12
Worst Severity Scores of Overall Flushing During Weeks 5-8 and Weeks 9-12 of the Study, as Assessed by MFSS
Time Frame: Week 5 to Week 12
Worst severity of participant-reported flushing events during Weeks 5-8 and Weeks 9-12 of the study recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Week 5 to Week 12
Duration of Flushing Episodes During Weeks 1-4, 5-8 and 9-12 of the Study, as Assessed by MGFSS
Time Frame: Day 1 to Week 12
Duration of participant-reported flushing events during weeks 1-4, 5-8 and 9-12 of the study recorded on the eDiary as assessed by MGFSS. The MGFSS measures the side effects related to flushing during the past 24 hours. Flushing means redness, warmth, tingling or itching of the skin. Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects).
Day 1 to Week 12
Duration of Flushing Episodes During Weeks 1-4, 5-8 and 9-12 of the Study, as Assessed by MFSS
Time Frame: Day 1 to Week 12
Duration of participant-reported flushing events during weeks 1-4, 5-8 and 9-12 of the study recorded on the eDiary as assessed by MFSS. MFSS questionnaire measures the side effects related to flushing following drug administration. Flushing means redness, warmth, tingling or itching of the skin. This questionnaire relates only to the period of time since the investigational drug was administered and was to be completed within 10 hours of taking the study drug (2 times/day). Each question is rated on a scale from 0 (no flushing side effects) to 10 (extreme flushing side effects). For participants with more than 1 flushing event during a visit interval, the average duration for the visit interval was used.
Day 1 to Week 12
Number of Participants With Self-Reported Flushing Events During Weeks 13 to 48
Time Frame: Week 13 to Week 48
Participant-reported flushing events (which include redness, warmth, tingling, and/or itching of the skin) during Weeks 13 to 48 of treatment were recorded in the CRF.
Week 13 to Week 48
Number of Participants Experiencing Treatment-Emergent Adverse Events (AEs), Serious AEs (SAEs), and Discontinuations Due to AEs in the First 12 Weeks
Time Frame: Day 1 to Week 12
AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity, or; results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed above. A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug.
Day 1 to Week 12
Number of Participants Experiencing Treatment-Emergent AEs, SAEs, and Discontinuations Due to AEs in Weeks 13 to 48
Time Frame: Week 13 to Week 48
AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: any untoward medical occurrence that at any dose: results in death; in the view of the Investigator, places the participant at immediate risk of death (a life-threatening event); requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity, or; results in a congenital anomaly/birth defect. An SAE may also be any other medically important event that, in the opinion of the Investigator, may jeopardize the participant or may require intervention to prevent one of the other outcomes listed above. A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug.
Week 13 to Week 48
Number of Participants Discontinuing Treatment and Discontinuing the Study Due to Treatment-emergent Flushing AEs in the First 12 Weeks
Time Frame: Day 1 to Week 12
A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug. Flushing AEs include redness, warmth, tingling, and/or itching of the skin.
Day 1 to Week 12
Number of Participants Discontinuing Treatment and Discontinuing the Study Due to Treatment-Emergent Flushing AEs in Weeks 13 to 48
Time Frame: Week 13 to Week 48
A treatment-emergent AE is defined as any AE that occurs after the first administration of DMF or ASA/Placebo drug. Flushing AEs include redness, warmth, tingling, and/or itching of the skin.
Week 13 to Week 48
Change From Baseline at Weeks 24 and 48 in Quality of Life Measurements as Assessed by Short Form-36 (SF-36) Questionnaire: Physical Component Summary (PCS)
Time Frame: Baseline, Week 24, Week 48 or early termination (ET)
SF-36 is a self-administered, generic health status questionnaire consisting of 36 questions that measure 8 health concepts: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems and mental health. The score for a domain is an average of the individual question scores, which are scaled 0 (worst health-related quality of life) to 100 (best health-related quality of life). Score from physical function, role physical, bodily pain, and general health domains were averaged to calculate PCS. Total score range for PCS was 0 (lowest level of physical functioning) to 100 (highest level of physical functioning).
Baseline, Week 24, Week 48 or early termination (ET)
Change From Baseline at Weeks 24 and 48 in Quality of Life Measurements as Assessed by Short Form-36 (SF-36) Questionnaire: Mental Component Summary (MCS)
Time Frame: Baseline, Week 24, Week 48 or ET
SF-36 is a self-administered, generic health status questionnaire consisting of 36 questions that measure 8 health concepts: physical functioning, role limitations due to physical problems, bodily pain, general health perception, vitality, social functioning, role limitations due to emotional problems and mental health. The score for a domain is an average of the individual question scores, which are scaled 0 (worst health-related quality of life) to 100 (best health-related quality of life). Score from mental health, role emotional, social functioning, and vitality domains were averaged to calculate MCS. Total score range for MCS was 0 (lowest level of physical functioning) to 100 (highest level of physical functioning).
Baseline, Week 24, Week 48 or ET
Change From Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the European Quality of Life 5-Dimensions Questionnaire (EQ-5D-5L) Questionnaire: Mobility
Time Frame: Baseline, Week 24, Week 48 or ET
EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-Visual Analog Scale (EQ-VAS). The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3). A negative change from Baseline indicates improvement.
Baseline, Week 24, Week 48 or ET
Change From Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Self-Care
Time Frame: Baseline, Week 24, Week 48 or ET
EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3). A negative change from Baseline indicates improvement.
Baseline, Week 24, Week 48 or ET
Change From Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Usual Activities
Time Frame: Baseline, Week 24, Week 48 or ET
EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3). A negative change from Baseline indicates improvement.
Baseline, Week 24, Week 48 or ET
Change From Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Pain/Discomfort
Time Frame: Baseline, Week 24, Week 48 or ET
EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3). A negative change from Baseline indicates improvement.
Baseline, Week 24, Week 48 or ET
Change From Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-5D-5L Questionnaire: Anxiety/Depression
Time Frame: Baseline, Week 24, Week 48 or ET
EQ-5D-5L is a standardized, subject-rated instrument for use as a measure of health outcomes. The EQ 5D-5L includes 2 components: the EQ-5D-5L descriptive system and the EQ-VAS. The EQ-5D-5L descriptive system provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has "no problems" (1), "some problems" (2), or "severe problems" (3). A negative change from Baseline indicates improvement.
Baseline, Week 24, Week 48 or ET
Change From Baseline to Week 24 and Week 48 in Quality of Life Measurements as Assessed by the EQ-VAS
Time Frame: Baseline, Week 24, Week 48 or ET
For the EQ-VAS, the participant was instructed to draw a line on a 20-cm vertical scale at the point that best describes his or her own health, where 0 represents the "worst imaginable health state" and 100 represents the "best imaginable health state."
Baseline, Week 24, Week 48 or ET

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Biogen

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2014

Primary Completion (Actual)

February 1, 2015

Study Completion (Actual)

November 1, 2015

Study Registration Dates

First Submitted

March 14, 2014

First Submitted That Met QC Criteria

March 14, 2014

First Posted (Estimate)

March 18, 2014

Study Record Updates

Last Update Posted (Estimate)

December 28, 2016

Last Update Submitted That Met QC Criteria

November 1, 2016

Last Verified

November 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 109MS406
  • 2013-001895-40 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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