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    Clinical Trial Results:
    A Phase 3 Study in Subjects with Relapsing-Remitting Multiple Sclerosis to Evaluate the Tolerability of ALKS 8700 and Dimethyl Fumarate

    Summary
    EudraCT number
    		 2017-001294-16
    Trial protocol
    		 PL   DE  
    Global end of trial date
    27 Jun 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Jul 2020
    First version publication date
    17 Jun 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALK8700-A302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03093324
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    250 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were to evaluate the utility of two gastrointestinal (GI) symptom scales (Individual GI Symptom and Impact Scale {IGISIS} and Global GI Symptom and Impact Scale {GGISIS}) in assessing GI tolerability in adult subjects with Relapsing Remitting Multiple Sclerosis (RRMS) after administration of ALKS 8700 or Dimethyl Fumarate (DMF) in Part A, to compare the GI tolerability of ALKS 8700 and DMF in adult subjects with RRMS using IGISIS and GGISIS in Part B, and to evaluate the safety and tolerability of ALKS 8700 in adult subjects with RRMS in Parts A and B.
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorized representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 280
    Country: Number of subjects enrolled
    Poland: 220
    Country: Number of subjects enrolled
    Germany: 6
    Worldwide total number of subjects
    506
    EEA total number of subjects
    226
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    505
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 70 investigative sites in the United States, Germany, and Poland from March 15, 2017 to June 27, 2019.

    Pre-assignment
    Screening details
    		 A total of 506 subjects with relapsing remitting multiple-sclerosis were enrolled in this study. Of which 504 subjects received study drug and randomised in Parts A and B of the study (253 subjects in ALKS 8700 group and 251 in Dimethyl Fumarate group). A total of 478 subjects completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALKS 8700
    Arm description
    		 Subjects received ALKS 8700 231 milligrams (mg) along with ALKS 8700-matching placebo, oral capsules, twice daily (BID), for Week 1, followed by administration of ALKS 8700 462 mg, oral capsules, BID, for Week 2 to 5.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALKS 8700
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules, administered orally, twice daily from Week 1 to 5.

    Arm title
    		 Dimethyl Fumarate (DMF)
    Arm description
    		 Subjects received DMF 120 mg along with DMF-matching placebo, oral capsules, BID for Week 1, followed by administration of DMF 240 mg and DMF-matching placebo, oral capsules, BID, for week 2 to 5.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Dimethyl Fumarate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules, administered orally, twice daily from Week 1 to 5.

    Number of subjects in period 1 [1]
    		ALKS 8700 Dimethyl Fumarate (DMF)
    Started
    253
    251
    Completed
    245
    233
    Not completed
    8
    18
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    4
    15
         Protocol Deviation
    1
    1
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in baseline period is the number of subjects who were treated with the study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALKS 8700
    Reporting group description
    		 Subjects received ALKS 8700 231 milligrams (mg) along with ALKS 8700-matching placebo, oral capsules, twice daily (BID), for Week 1, followed by administration of ALKS 8700 462 mg, oral capsules, BID, for Week 2 to 5.

    Reporting group title
    Dimethyl Fumarate (DMF)
    Reporting group description
    		 Subjects received DMF 120 mg along with DMF-matching placebo, oral capsules, BID for Week 1, followed by administration of DMF 240 mg and DMF-matching placebo, oral capsules, BID, for week 2 to 5.

    Reporting group values
    		 ALKS 8700 Dimethyl Fumarate (DMF) Total
    Number of subjects
    		 253 251 504
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.7 ± 10.96 43.7 ± 9.90 -
    Sex: Female, Male
    Units: participants
        Female
    		 177 190 367
        Male
    		 76 61 137
    Race/Ethnicity, Customized
    Units: Subjects
        Not Hispanic or Latino
    		 248 241 489
        Hispanic or Latino
    		 5 10 15
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 232 227 459
        Black or African American
    		 20 20 40
        Other
    		 0 2 2
        Asian
    		 0 1 1
        Multiple races
    		 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    ALKS 8700
    Reporting group description
    		 Subjects received ALKS 8700 231 milligrams (mg) along with ALKS 8700-matching placebo, oral capsules, twice daily (BID), for Week 1, followed by administration of ALKS 8700 462 mg, oral capsules, BID, for Week 2 to 5.

    Reporting group title
    Dimethyl Fumarate (DMF)
    Reporting group description
    		 Subjects received DMF 120 mg along with DMF-matching placebo, oral capsules, BID for Week 1, followed by administration of DMF 240 mg and DMF-matching placebo, oral capsules, BID, for week 2 to 5.

    Primary: Number of Days With Any Individual Gastrointestinal Symptom and Impact Scale (IGISIS) Individual Symptom Intensity Score ≥2 Relative to Exposure Days in Parts A and B

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    End point title
    		 Number of Days With Any Individual Gastrointestinal Symptom and Impact Scale (IGISIS) Individual Symptom Intensity Score ≥2 Relative to Exposure Days in Parts A and B
    End point description
    IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Subjects rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the subjects using e-diaries. The full analysis set (FAS) population included all enrolled subjects in the Safety population who had at least one post-baseline GI tolerability assessment (such as IGISIS) on or before the last dose date.
    End point type
    Primary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    253
    249
    Units: days
        arithmetic mean (standard deviation)
    1.5 ± 2.85
    2.5 ± 4.68
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.542
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 0.754

    Secondary: Number of Days With Any IGISIS Individual Symptom Intensity Score ≥2 Relative to Exposure Days in Part B

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    End point title
    		 Number of Days With Any IGISIS Individual Symptom Intensity Score ≥2 Relative to Exposure Days in Part B
    End point description
    IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Subjects rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the subjects using e-diaries. The FAS population included all enrolled subjects in the Safety population who had at least one post-baseline GI tolerability assessment (such as IGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for Part B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    194 [1]
    191 [2]
    Units: days
        arithmetic mean (standard deviation)
    1.3 ± 2.70
    2.2 ± 4.22
    Notes
    [1] - Number analysed are the subjects who were evaluated for this outcome measure.
    [2] - Number analysed are the subjects who were evaluated for this outcome measure.
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0007
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.356
         upper limit
    		 0.76

    Secondary: Number of Days With Any IGISIS Individual Symptom Intensity Score ≥1 Relative to Exposure Days in Parts A and B

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    End point title
    		 Number of Days With Any IGISIS Individual Symptom Intensity Score ≥1 Relative to Exposure Days in Parts A and B
    End point description
    IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Subjects rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the subjects using e-diaries. The FAS population included all enrolled subjects in the Safety population who had at least one post-baseline GI tolerability assessment (such as IGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    253
    249
    Units: days
        arithmetic mean (standard deviation)
    2.9 ± 4.46
    3.9 ± 5.84
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.714
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.554
         upper limit
    		 0.921

    Secondary: Number of Days With Any IGISIS Individual Symptom Intensity Score ≥3 Relative to Exposure Days in Parts A and B

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    End point title
    		 Number of Days With Any IGISIS Individual Symptom Intensity Score ≥3 Relative to Exposure Days in Parts A and B
    End point description
    IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Subjects rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the subjects using e-diaries. The FAS population included all enrolled subjects in the Safety population who had at least one postbaseline GI tolerability assessment (such as IGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    253
    249
    Units: days
        arithmetic mean (standard deviation)
    0.9 ± 2.25
    1.5 ± 3.85
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.555
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.357
         upper limit
    		 0.862

    Secondary: Number of Days With a Global GI Symptom and Impact Scale (GGISIS) Symptom Intensity Score ≥1 Relative to Exposure Days in Parts A and B

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    End point title
    		 Number of Days With a Global GI Symptom and Impact Scale (GGISIS) Symptom Intensity Score ≥1 Relative to Exposure Days in Parts A and B
    End point description
    GGISIS is a global scale to assess the overall intensity of GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea). Subjects rated the intensity of GI symptoms via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). GGISIS was completed by the subjects using e-diaries. The FAS population included all enrolled subjects in the Safety population who had at least one postbaseline GI tolerability assessment (such as GGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    252 [3]
    247 [4]
    Units: days
        arithmetic mean (standard deviation)
    2.1 ± 4.43
    2.8 ± 5.19
    Notes
    [3] - Number analysed are the subjects who were evaluated for this outcome measure.
    [4] - Number analysed are the subjects who were evaluated for this outcome measure.
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.033
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.696
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.499
         upper limit
    		 0.972

    Secondary: Number of Days With a GGISIS Symptom Intensity Score ≥2 Relative to Exposure Days in Parts A and B

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    End point title
    		 Number of Days With a GGISIS Symptom Intensity Score ≥2 Relative to Exposure Days in Parts A and B
    End point description
    GGISIS is a global scale to assess the overall intensity of GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea). Subjects rated the intensity of GI symptoms via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). GGISIS was completed by the subjects using e-diaries. The FAS population included all enrolled subjects in the Safety population who had at least one post-baseline GI tolerability assessment (such as GGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    252 [5]
    247 [6]
    Units: days
        arithmetic mean (standard deviation)
    1.1 ± 3.25
    1.5 ± 3.53
    Notes
    [5] - Number analysed are the subjects who were evaluated for this outcome measure.
    [6] - Number analysed are the subjects who were evaluated for this outcome measure.
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.068
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.662
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.425
         upper limit
    		 1.031

    Secondary: Number of Days With a GGISIS Symptom Intensity Score ≥3 Relative to Exposure Days in Parts A and B

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    End point title
    		 Number of Days With a GGISIS Symptom Intensity Score ≥3 Relative to Exposure Days in Parts A and B
    End point description
    GGISIS is a global scale to assess the overall intensity of GI symptoms (nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea). Subjects rated the intensity of GI symptoms via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). GGISIS was completed by the subjects using e-diaries. The FAS population included all enrolled subjects in the Safety population who had at least one postbaseline GI tolerability assessment (such as GGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    252 [7]
    247 [8]
    Units: days
        arithmetic mean (standard deviation)
    0.7 ± 2.26
    0.9 ± 2.57
    Notes
    [7] - Number analysed are the subjects who were evaluated for this outcome measure.
    [8] - Number analysed are the subjects who were evaluated for this outcome measure.
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Number of event days was analysed by a negative binomial regression model, with the logarithmic transformation of the number of exposure days as the ‘’offset’’ parameter and treatment group as a factor and adjusting for study part, region (US and non-US), age, and body mass index (BMI).
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    499
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.215
    Method
    		 Negative Binomial Regression Model
    Parameter type
    		 Rate ratio
    Point estimate
    0.713
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.417
         upper limit
    		 1.217

    Secondary: Worst IGISIS Individual Symptom Intensity Score During the 5-Week Treatment Period in Parts A and B

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    End point title
    		 Worst IGISIS Individual Symptom Intensity Score During the 5-Week Treatment Period in Parts A and B
    End point description
    IGISIS assessed the intensity of five individual GI symptoms: nausea, vomiting, upper abdominal pain, lower abdominal pain, and diarrhea. Subjects rated the intensity of each individual symptom via an 11-point numeric rating scale ranging from 0 (did not have) to 10 (extreme). IGISIS was completed by the subjects using e-diaries. Scores were averaged for 5-week treatment period. The FAS population included all enrolled subjects in the Safety population who had at least one postbaseline GI tolerability assessment (such as IGISIS) on or before the last dose date.
    End point type
    Secondary
    End point timeframe
    End of treatment (up to Week 6) for both Parts A and B
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    253
    249
    Units: days
    arithmetic mean (standard deviation)
        Nausea
    0.9 ± 1.55
    1.2 ± 1.98
        Vomiting
    0.2 ± 0.74
    0.6 ± 1.84
        Upper Abdominal Pain
    0.8 ± 1.58
    1.3 ± 2.06
        Lower Abdominal Pain
    0.8 ± 1.60
    1.0 ± 1.84
        Diarrhea
    1.1 ± 2.09
    1.3 ± 2.19
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Nausea: DMF is used as a referenced group in the model, adjusting for study parts, region (US and non-US), age and BMI.
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.043
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Vomiting: DMF is used as a referenced group in the model, adjusting for study parts, region (US and non-US), age and BMI.
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.7
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Upper Abdominal Pain: DMF is used as a referenced group in the model, adjusting for study parts, region (US and non-US), age and BMI.
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Lower Abdominal Pain: DMF is used as a referenced group in the model, adjusting for study parts, region (US and non-US), age and BMI.
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.403
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15
    Statistical analysis title
    		 ALKS 8700 Vs DMF
    Statistical analysis description
    Diarrhea: DMF is used as a referenced group in the model, adjusting for study parts, region (US and non-US), age and BMI.
    Comparison groups
    ALKS 8700 v Dimethyl Fumarate (DMF)
    Number of subjects included in analysis
    502
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.261
    Method
    		 ANCOVA
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.19

    Secondary: Number of Subjects with Adverse Events (AEs)

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    End point title
    		 Number of Subjects with Adverse Events (AEs)
    End point description
    An AE is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. The Safety population included all enrolled subjects who had received at least one dose of study drug during the double-blind Treatment Period.
    End point type
    Secondary
    End point timeframe
    End of study (up to Week 10)
    End point values
    		 ALKS 8700 Dimethyl Fumarate (DMF)
    Number of subjects analysed
    253
    251
    Units: subjects
    198
    210
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    End of study (up to Week 10)
    Adverse event reporting additional description
    The Safety population included all enrolled subjects who had received at least one dose of study drug during the double-blind Treatment Period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Dimethyl Fumarate (DMF)
    Reporting group description
    		 Subjects received DMF 120 mg along with DMF-matching placebo, oral capsules, BID for Week 1, followed by administration of DMF 240 mg and DMF-matching placebo, oral capsules, BID, for week 2 to 5.

    Reporting group title
    ALKS 8700
    Reporting group description
    		 Subjects received ALKS 8700 231 milligrams (mg) along with ALKS 8700-matching placebo, oral capsules, twice daily (BID), for Week 1, followed by administration of ALKS 8700 462 mg, oral capsules, BID, for Week 2 to 5.

    Serious adverse events
    		 Dimethyl Fumarate (DMF) ALKS 8700
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 251 (1.20%)
    4 / 253 (1.58%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 251 (0.80%)
    3 / 253 (1.19%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 253 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 253 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Dimethyl Fumarate (DMF) ALKS 8700
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    191 / 251 (76.10%)
    175 / 253 (69.17%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 251 (3.59%)
    14 / 253 (5.53%)
         occurrences all number
    9
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 251 (1.99%)
    9 / 253 (3.56%)
         occurrences all number
    5
    9
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    2 / 251 (0.80%)
    6 / 253 (2.37%)
         occurrences all number
    2
    6
    Vascular disorders
    Flushing
         subjects affected / exposed
    102 / 251 (40.64%)
    83 / 253 (32.81%)
         occurrences all number
    120
    113
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 251 (5.58%)
    10 / 253 (3.95%)
         occurrences all number
    14
    11
    Multiple sclerosis relapse
         subjects affected / exposed
    5 / 251 (1.99%)
    8 / 253 (3.16%)
         occurrences all number
    5
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 251 (5.18%)
    6 / 253 (2.37%)
         occurrences all number
    14
    6
    Feeling hot
         subjects affected / exposed
    6 / 251 (2.39%)
    4 / 253 (1.58%)
         occurrences all number
    9
    6
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    24 / 251 (9.56%)
    16 / 253 (6.32%)
         occurrences all number
    25
    17
    Abdominal pain lower
         subjects affected / exposed
    17 / 251 (6.77%)
    15 / 253 (5.93%)
         occurrences all number
    22
    17
    Abdominal pain upper
         subjects affected / exposed
    39 / 251 (15.54%)
    17 / 253 (6.72%)
         occurrences all number
    51
    18
    Diarrhoea
         subjects affected / exposed
    56 / 251 (22.31%)
    39 / 253 (15.42%)
         occurrences all number
    67
    47
    Nausea
         subjects affected / exposed
    52 / 251 (20.72%)
    37 / 253 (14.62%)
         occurrences all number
    61
    41
    Vomiting
         subjects affected / exposed
    22 / 251 (8.76%)
    9 / 253 (3.56%)
         occurrences all number
    22
    9
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    21 / 251 (8.37%)
    20 / 253 (7.91%)
         occurrences all number
    35
    26
    Generalised erythema
         subjects affected / exposed
    9 / 251 (3.59%)
    4 / 253 (1.58%)
         occurrences all number
    12
    5
    Pruritus
         subjects affected / exposed
    18 / 251 (7.17%)
    18 / 253 (7.11%)
         occurrences all number
    24
    25
    Pruritus generalised
         subjects affected / exposed
    6 / 251 (2.39%)
    2 / 253 (0.79%)
         occurrences all number
    6
    2
    Rash
         subjects affected / exposed
    6 / 251 (2.39%)
    4 / 253 (1.58%)
         occurrences all number
    7
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 251 (4.38%)
    15 / 253 (5.93%)
         occurrences all number
    11
    15
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 251 (3.59%)
    9 / 253 (3.56%)
         occurrences all number
    9
    9
    Urinary tract infection
         subjects affected / exposed
    9 / 251 (3.59%)
    8 / 253 (3.16%)
         occurrences all number
    9
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2016
    The protocol was amended to update the following- 1. Supplementary instructions on intake of study drug were provided. 2. Exclusion criterion (EC) was modified to include a statement regarding overall clinical assessment of the subject as one of the EC. 3. Exclusion criteria were updated were modified to clarify GI-related and other medical history and to reflect prior treatments that may exclude participation in the study. 4. The Screening period was extended from 3 to 4 weeks based on feedback from study sites. 5. Language related to sample size consideration for the study was updated. These modifications were made to clarify how the sample size was calculated for this study. In addition, the number of subjects for pharmacokinetic (PK) analysis was also reduced to n=20 from the previously projected n=50. 6. The pregnancy testing and contraception requirements were modified. The contraception section of the original protocol was updated to specify that all male and female subjects must agree to the use of two methods of contraception for the duration of the study and 30 days after the final dose of study drug.
    20 Sep 2018
    The protocol was amended to update the following- 1. Changes were made to the primary, secondary, and exploratory endpoints for the study. Study endpoints were to be potentially revised based on an exploratory analysis of Part A primary and secondary endpoint data. Based on an analysis of results from Part A, appropriate changes to the primary and secondary endpoints were identified, and new exploratory endpoints were added. 2. The number of subjects was increased from 300 to 380 in Part B and from 420 to 500 for the entire study. Power considerations for the revised primary endpoint of the mean number of days with any IGISIS individual symptom intensity score ≥2 accounted for the increase in sample size. 3. Pooled GI tolerability data from Parts A and B were analysed for the primary and secondary endpoints. Analysis of the pooled data from Parts A and B provided adequate power to compare the GI tolerability of ALKS 8700 and DMF. 4. The descriptions of multiple sclerosis and treatments were updated. Revisions included updated information about multiple sclerosis and results of Phase 3 studies for DMF.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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