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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: dimethyl fumarate
* Drug: acetylsalicylic acid
* Drug: ASA-Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Experimental: DMF + ASA 150 mg BID<br>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<br> <br> * Other names: DMF;Drug: acetylsalicylic acid<br>* enteric-coated capsule<br>* Other names: aspirin;|
| Experimental: DMF + ASA 75 mg QAM<br>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<br> <br> * Other names: DMF;Drug: acetylsalicylic acid<br>* enteric-coated capsule<br>* Other names: aspirin;Drug: ASA-Placebo<br>* matched placebo<br>* Other names: placebo;|
| Experimental: DMF + ASA-Placebo BID<br>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<br> <br> * Other names: DMF;Drug: ASA-Placebo<br>* matched placebo<br>* Other names: placebo;|

What is the study measuring?
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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) | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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) | 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) | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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multiple sclerosis, flushing, aspirin