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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02090413
Recruitment Status : Completed
First Posted : March 18, 2014
Results First Posted : December 28, 2016
Last Update Posted : December 28, 2016
Sponsor:
Information provided by (Responsible Party):
Biogen

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Relapsing-Remitting Multiple Sclerosis Drug: dimethyl fumarate Drug: acetylsalicylic acid Drug: ASA-Placebo Phase 4

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 241 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : May 2014
Actual Primary Completion Date : February 2015
Actual Study Completion Date : November 2015

Resource links provided by the National Library of Medicine


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
  • Tecfidera
  • DMF

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
  • Tecfidera
  • DMF

Drug: acetylsalicylic acid
enteric-coated capsule
Other Names:
  • ASA
  • aspirin

Drug: ASA-Placebo
matched placebo
Other Name: 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
  • Tecfidera
  • DMF

Drug: ASA-Placebo
matched placebo
Other Name: placebo




Primary Outcome Measures :
  1. 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.

  2. 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).

  3. 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.

  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).


Secondary Outcome Measures :
  1. 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).

  2. 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).

  3. 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).

  4. 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).

  5. 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).

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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).

  13. 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).

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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."



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02090413


Locations
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Ireland
Research Site
Cork, Ireland
Research Site
Dublin, Ireland, Dublin 4
Research Site
Dublin, Ireland, Dublin 7
Research Site
Dublin, Ireland, Dublin 9
United Kingdom
Research Site
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
Sponsors and Collaborators
Biogen
Investigators
Layout table for investigator information
Study Director: Medical Director Biogen
Layout table for additonal information
Responsible Party: Biogen
ClinicalTrials.gov Identifier: NCT02090413    
Other Study ID Numbers: 109MS406
2013-001895-40 ( EudraCT Number )
First Posted: March 18, 2014    Key Record Dates
Results First Posted: December 28, 2016
Last Update Posted: December 28, 2016
Last Verified: November 2016
Keywords provided by Biogen:
multiple sclerosis
flushing
aspirin
Additional relevant MeSH terms:
Layout table for MeSH terms
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Sclerosis
Flushing
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Skin Manifestations
Aspirin
Dimethyl Fumarate
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Inflammatory Agents
Antirheumatic Agents
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action
Platelet Aggregation Inhibitors
Cyclooxygenase Inhibitors
Enzyme Inhibitors
Antipyretics
Dermatologic Agents