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    Clinical Trial Results:
    A Multicenter, Single-Arm, Open-Label, Study to Evaluate the Immunogenicity and Pharmacokinetics of BIIB019, Daclizumab High Yield Process (DAC HYP), Prefilled Syringe Administered by Subcutaneous Injection in Subjects With Relapsing-Remitting Multiple Sclerosis

    Summary
    EudraCT number
    		 2010-023856-97
    Trial protocol
    		 HU   CZ   PL  
    Global end of trial date
    26 Jan 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2017
    First version publication date
    08 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    205MS302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01462318
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, 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
    26 Jan 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess the immunogenicity of Daclizumab High Yield Process (DAC HYP) 150 mg administered every 4 weeks by subcutaneous (SC) injection using the pre-filled syringe (PFS) in subjects with relapsing-remitting multiple sclerosis (RRMS). The secondary objectives of this study are to characterize the pharmacokinetics (PK) of DAC HYP following single and multiple doses of DAC HYP administered by the PFS in a subset of participants with RRMS and to evaluate the effect of DAC HYP on the PK of probe drugs for cytochrome P450 (CYP) isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A).
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    Poland: 40
    Country: Number of subjects enrolled
    United States: 27
    Country: Number of subjects enrolled
    Hungary: 24
    Worldwide total number of subjects
    133
    EEA total number of subjects
    106
    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)
    133
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subject eligibility for the study was determined within 28 days prior to study entry.

    Period 1
    Period 1 title
    Main Study or TP-DI Study
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Main Study
    Arm description
    		 All subjects received DAC HYP 150 mg SC injections every 4 weeks over an initial 24-week treatment period (for a total of 6 injections), followed by a 20-week washout period. Those subjects from the Main Study who enrolled in the Intensive PK sub-study underwent serial DAC HYP PK sampling over the first and the last dosing intervals (on Day 1 [Week 0] and again on Day 141 [Week 20], the last dosing visit).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclizumab HYP
    Investigational medicinal product code
    BIIB019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    DAC HYP was administered using a 1 mL pre-filled syringe

    Investigational medicinal product name
    Omeprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Oral omeprazole 40 mg (capsule). Part of the probe drug cocktail combination of drugs that was completely administered within 5 minutes. Subjects remained under fasting conditions for another 2 hours after receiving the oral drug combination.

    Investigational medicinal product name
    Vitamin K
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral vitamin K 10 mg (tablet). Part of the probe drug cocktail combination of drugs that was completely administered within 5 minutes. Subjects remained under fasting conditions for another 2 hours after receiving the oral drug combination. Vitamin K was used to counteract warfarin’s anticoagulant effect prophylactically. If vitamin K tablets were not commercially available, alternate formulations such as SC or IV were used.

    Investigational medicinal product name
    Dextromethorphan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Oral dextromethorphan 30 mg (syrup). Part of the probe drug cocktail combination of drugs that was completely administered within 5 minutes. Subjects remained under fasting conditions for another 2 hours after receiving the oral drug combination.

    Arm title
    		 Therapeutic Protein-Drug Interaction (TP-DI) Sub-study
    Arm description
    		 In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, where the oral vitamin K was used prophylactically to counteract warfarin’s anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase. In Period 2, pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclizumab HYP
    Investigational medicinal product code
    BIIB019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    DAC HYP was administered using a 1 mL pre-filled syringe

    Investigational medicinal product name
    Midazolam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    Oral midazolam 5 mg. The preferred formulation was midazolam syrup formulation containing midazolam hydrochloride equivalent to 2 mg of midazolam/mL. Part of the probe drug cocktail combination of drugs that was completely administered within 5 minutes. Subjects remained under fasting conditions for another 2 hours after receiving the oral drug combination.

    Investigational medicinal product name
    Caffeine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral caffeine 200 mg (tablet or caplet). Part of the probe drug cocktail combination of drugs that was completely administered within 5 minutes. Subjects remained under fasting conditions for another 2 hours after receiving the oral drug combination.

    Investigational medicinal product name
    warfarin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral warfarin 10 mg (tablet). Part of the probe drug cocktail combination of drugs that was completely administered within 5 minutes. Subjects remained under fasting conditions for another 2 hours after receiving the oral drug combination.

    Number of subjects in period 1
    		Main Study Therapeutic Protein-Drug Interaction (TP-DI) Sub-study
    Started
    113
    20
    Enrolled in Intensive PK Substudy
    26 [1]
    0 [2]
    Completed
    105
    20
    Not completed
    8
    0
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    4
    -
         NotSpecified
    2
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Twenty-six subjects from this arm were enrolled in the intensive PK stubstudy.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: No subjects from this arm were enrolled in the intensive PK stubstudy.
    Period 2
    Period 2 title
    Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Extension Phase
    Arm description
    		 After completion of the washout period from the Main Study or the TP-DI sub-study, eligible subjects had the option to resume monthly open-label treatment with DAC HYP 150 mg in the extension phase of the study for up to 3 additional years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclizumab HYP
    Investigational medicinal product code
    BIIB019
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    DAC HYP was administered using a 1 mL pre-filled syringe

    Number of subjects in period 2 [3]
    		Extension Phase
    Started
    115
    Completed
    70
    Not completed
    45
         Consent withdrawn by subject
    15
         Adverse event, non-fatal
    22
         NotSpecified
    1
         Investigator Decision
    5
         Lost to follow-up
    1
         Disease Progression
    1
    Notes
    [3] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who resumed monthly open-label treatment with DAC HYP 150 mg in the extension phase of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main Study
    Reporting group description
    		 All subjects received DAC HYP 150 mg SC injections every 4 weeks over an initial 24-week treatment period (for a total of 6 injections), followed by a 20-week washout period. Those subjects from the Main Study who enrolled in the Intensive PK sub-study underwent serial DAC HYP PK sampling over the first and the last dosing intervals (on Day 1 [Week 0] and again on Day 141 [Week 20], the last dosing visit).

    Reporting group title
    Therapeutic Protein-Drug Interaction (TP-DI) Sub-study
    Reporting group description
    		 In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, where the oral vitamin K was used prophylactically to counteract warfarin’s anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase. In Period 2, pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP.

    Reporting group values
    		 Main Study Therapeutic Protein-Drug Interaction (TP-DI) Sub-study Total
    Number of subjects
    		 113 20 133
    Age Categorical
    Units: Subjects
        < 18 years
    		 0 0 0
        18 - 19 years
    		 0 1 1
        20 - 29 years
    		 28 4 32
        30 - 39 years
    		 40 7 47
        40 - 49 years
    		 31 5 36
        50 - 55 years
    		 14 3 17
        > 55 years
    		 0 0 0
    Gender, Male/Female
    Units: Subjects
        Female
    		 72 13 85
        Male
    		 41 7 48

    End points

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    End points reporting groups
    Reporting group title
    Main Study
    Reporting group description
    		 All subjects received DAC HYP 150 mg SC injections every 4 weeks over an initial 24-week treatment period (for a total of 6 injections), followed by a 20-week washout period. Those subjects from the Main Study who enrolled in the Intensive PK sub-study underwent serial DAC HYP PK sampling over the first and the last dosing intervals (on Day 1 [Week 0] and again on Day 141 [Week 20], the last dosing visit).

    Reporting group title
    Therapeutic Protein-Drug Interaction (TP-DI) Sub-study
    Reporting group description
    		 In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, where the oral vitamin K was used prophylactically to counteract warfarin’s anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase. In Period 2, pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP.
    Reporting group title
    Extension Phase
    Reporting group description
    		 After completion of the washout period from the Main Study or the TP-DI sub-study, eligible subjects had the option to resume monthly open-label treatment with DAC HYP 150 mg in the extension phase of the study for up to 3 additional years.

    Subject analysis set title
    TP-DI Sub-study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, and oral vitamin K 10 mg used prophylactically to counteract warfarin’s anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase. In Period 2 (Weeks 0, 4, 8, and 9), pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP 150 mg.

    Subject analysis set title
    TP-DI Substudy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, and oral vitamin K 10 mg used prophylactically to counteract warfarin’s anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase. In Period 2 (Weeks 0, 4, 8, and 9), pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP 150 mg.

    Subject analysis set title
    TP-DI Substudy
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In Period 1 (Week -1), the probe-drug cocktail (consisting of oral midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg, and oral vitamin K 10 mg used prophylactically to counteract warfarin’s anticoagulant effect) was administered 7 days before the first dose of DAC HYP 150 mg in the 3-year extension phase. In Period 2 (Weeks 0, 4, 8, and 9), pretreatment with DAC HYP 150 mg was administered at Weeks 0, 4, and 8. The probe-drug cocktail was administered 7 days after the third dose of DAC HYP 150 mg.

    Primary: Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay

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    End point title
    		 Number of Participants With Anti-DAC HYP Binding Antibodies (ADAbs): Electrochemiluminescent (ECL) Anti-Drug Antibody (ADA) Assay [1] [2]
    End point description
    Participants with post-baseline (PB) ADAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose).
    End point type
    Primary
    End point timeframe
    Up to 44 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented, per protocol.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Main Study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    113
    Units: participants
        PB ADAbs through Week 44=negative; n=113
    78
        PB ADAbs through Week 44=positive; n=113
    35
        PB ADAbs in treatment period=negative; n=113
    92
        PB ADAbs in treatment period=positive; n=113
    21
        PB ADAbs in post-treatment period=negative; n=110
    89
        PB ADAbs in post-treatment period=positive; n=110
    21
    No statistical analyses for this end point

    Primary: Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay

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    End point title
    		 Number of Participants With Anti-DAC HYP Neutralizing Antibodies (NAbs): ECL ADA Assay [3] [4]
    End point description
    Participants with PB NAbs through Week 44, in the treatment period (extends up to 42 days after the last dose during the main study), and in the post-treatment period (43 days after the last dose until the end of the post-treatment period dose).
    End point type
    Primary
    End point timeframe
    Up to 44 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented, per protocol.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Main Study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    113
    Units: participants
        PB NAbs through Week 44=negative; n=113
    105
        PB NAbs through Week 44=positive; n=113
    8
        PB NAbs in treatment period=negative; n=113
    109
        PB NAbs in treatment period=positive; n=113
    4
        PB NAbs in post-treatment period=negative; n=110
    104
        PB NAbs in post-treatment period=positive; n=110
    6
    No statistical analyses for this end point

    Primary: TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug

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    End point title
    		 TP-DI Sub-study: Area-Under-the-Curve From Zero to Infinity (AUCinf) of Each Probe Drug [5]
    End point description
    AUCinf of each of the following cytochrome P450 (CYP) isoenzyme substrates: midazolam (CYP3A), S-warfarin + vitamin K (CYP2C9), and omeprazole (CYP2C19). The AUC from zero to 12 hours (AUC0-12) was calculated for caffeine (CYP1A2).
    End point type
    Primary
    End point timeframe
    Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses are attached as pdfs.
    End point values
    		 TP-DI Sub-study
    Number of subjects analysed
    20
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Midazolam (Period 1) AUCinf; n=20
    786.75 ± 328.794
        Midazolam+DAC HYP (Period 2) AUCinf; n=19
    816.87 ± 403.958
        S-warfarin (Period 1) AUCinf; n=17
    19292.9 ± 5524.6
        S-warfarin+DAC HYP (Period 2) AUCinf; n=18
    19609.3 ± 4620.64
        Omeprazole (Period 1) AUCinf; n=18
    2214.5 ± 2622.15
        Omeprazole+DAC HYP (Period 2) AUCinf; n=19
    1770 ± 1673.8
        Caffeine (Period 1) AUC0-12; n=20
    35742.4 ± 13942.71
        Caffeine+DAC HYP (Period 2) AUC0-12; n=20
    37449.2 ± 14367.04
    Attachments
    		 Untitled (Filename: Stat Analysis OM3 p2.pdf)
    Untitled (Filename: Stat Analysis OM3 p1.pdf)
    No statistical analyses for this end point

    Primary: TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio

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    End point title
    		 TP-DI Sub-study: Dextromethorphan to Dextrorphan Urine Concentration Ratio [6]
    End point description
    End point type
    Primary
    End point timeframe
    Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and for 12 hours after probe-drug cocktail administration
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analyses are attached as pdfs.
    End point values
    		 TP-DI Sub-study
    Number of subjects analysed
    20
    Units: ratio
    arithmetic mean (standard deviation)
        Dextromethorphan (Period 1)
    0.42468 ± 1.258565
        Dextromethorphan+DAC HYP (Period 2)
    0.48939 ± 1.813077
    Attachments
    		 Untitled (Filename: Stat Analysis OM4.pdf)
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Maximum Observed Concentration (Cmax) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Maximum Observed Concentration (Cmax) of DAC HYP [7]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    25
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Day 1 (Week 0); n=25
    12.63 ± 4.639
        Day 141 (Week 20); n=24
    29.07 ± 10.812
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Time to Reach Maximum Concentration (Tmax) of DAC HYP [8]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    25
    Units: day
    arithmetic mean (standard deviation)
        Day 1 (Week 0); n=25
    9.31 ± 6.368
        Day 141 (Week 20); n=24
    6.41 ± 3.273
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Area-Under-the-Curve From Start to End of the Dosing Interval (AUCtau) of DAC HYP [9]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 and Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    25
    Units: day*mcg/mL
    arithmetic mean (standard deviation)
        Week 0 (Day 1); n=25
    255.25 ± 88.569
        Week 20; n=24
    638.1 ± 256.076
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Minimum Concentrations (Cmin) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Minimum Concentrations (Cmin) of DAC HYP [10]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    24
    Units: mcg/mL
        arithmetic mean (standard deviation)
    14.93 ± 6.327
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Apparent Volume of Distribution (V/F) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Apparent Volume of Distribution (V/F) of DAC HYP [11]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    24
    Units: Liters
        arithmetic mean (standard deviation)
    8.21 ± 2.81
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Elimination Half-Life (t½) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Elimination Half-Life (t½) of DAC HYP [12]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    24
    Units: day
        arithmetic mean (standard deviation)
    21.92 ± 5.473
    No statistical analyses for this end point

    Secondary: Intensive PK sub-study: Apparent Clearance (CL/F) of DAC HYP

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    End point title
    		 Intensive PK sub-study: Apparent Clearance (CL/F) of DAC HYP [13]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 141 (Week 20) at pre-dose and 8, 24, 72 and 120 hours post-dose and 7, 10, 14 and 21 days post-dose
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was collected for the Intensive PK sub-study only, per protocol.
    End point values
    		 Main Study
    Number of subjects analysed
    24
    Units: L/day
        arithmetic mean (standard deviation)
    0.27 ± 0.108
    No statistical analyses for this end point

    Secondary: TP-DI sub-study: Cmax of Each Probe Drug

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    End point title
    		 TP-DI sub-study: Cmax of Each Probe Drug
    End point description
    Cmax of each of the following cytochrome P450 (CYP) isoenzyme substrates: midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), omeprazole (CYP2C19), and dextromethorphan (CYP2D6)
    End point type
    Secondary
    End point timeframe
    Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration
    End point values
    		 TP-DI Substudy
    Number of subjects analysed
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        Midazolam (Period 1); n=20
    271.05 ± 106.925
        MIdazolam+DACHYP (Period 2); n=19
    311.21 ± 147.912
        Caffeine (Period 1); n=20
    4965 ± 1312.69
        Caffeine+DAC HYP (Period 2); n=19
    5399.5 ± 1364.05
        S-Warfarin (Period 1); n=20
    635.65 ± 140.291
        S-Warfarin+DAC HYP (Period 2); n=19
    649.74 ± 155.977
        Omeprazole (Period 1); n=19
    776.95 ± 513.344
        Omeprazole+DAC HYP (Period 2); n=19
    771.16 ± 540.331
    Attachments
    		 Untitled (Filename: Stat Analysis OM12 p1.pdf)
    Untitled (Filename: Stat Analysis OM12 p2.pdf)
    Untitled (Filename: Stat Analysis OM12 p3.pdf)
    No statistical analyses for this end point

    Secondary: TP-DI Sub-study: CL/F of Each Probe Drug

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    End point title
    		 TP-DI Sub-study: CL/F of Each Probe Drug
    End point description
    CL/F of each of the following cytochrome P450 (CYP) isoenzyme substrates: midazolam (CYP3A), caffeine (CYP1A2), warfarin + vitamin K (CYP2C9), omeprazole (CYP2C19), and dextromethorphan (CYP2D6)
    End point type
    Secondary
    End point timeframe
    Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration), pre-cocktail dose and at 0.5 and 1, 2, 3, 4, 6, 8, 10 , 24, 48, 72 and 96 hours post-probe drug cocktail administration
    End point values
    		 TP-DI Substudy
    Number of subjects analysed
    20
    Units: mL/hr
    arithmetic mean (standard deviation)
        Midazolam (Period 1); n=20
    7625.7 ± 3849.92
        Midazolam+DAC HYP (Period 2); n=19
    7298.6 ± 2844.22
        S-Warfarin (Period 1); n=17
    565.86 ± 184.129
        S-Warfarin+DAC HYP (Period 2); n=18
    541.46 ± 150.298
        Omeprazole (Period 1); n=18
    41612.4 ± 30003.48
        Omeprazole+DAC HYP (Period 2); n=19
    41772.4 ± 29810.3
    No statistical analyses for this end point

    Secondary: TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 hours Post-Omeprazole Dosing

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    End point title
    		 TP-DI Sub-study: Omeprazole/Hydroxyomeprazole Concentration Ratio at 2 hours Post-Omeprazole Dosing
    End point description
    End point type
    Secondary
    End point timeframe
    Week 43 (7 days prior to DAC HYP administration) and Week 53 (7 days after DAC HYP administration) at 2 hours after probe drug cocktail administration
    End point values
    		 TP-DI Substudy
    Number of subjects analysed
    17
    Units: ratio
    arithmetic mean (standard deviation)
        Omeprazole (Period 1)
    2.673 ± 4.7878
        Omeprazole+ DAC HYP (Period 2)
    1.028 ± 0.9297
    Attachments
    		 Untitled (Filename: Stat Analysis OM14.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Screening (for serious adverse events) or first dose of study treatment on Day 1 (for adverse events) through the end of treatment (Week 188 +/- 4 days) plus 24 weeks +/- 10 days after last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    DAC HYP 150 mg
    Reporting group description
    		 DAC HYP 150 mg by SC injection using the PFS every 4 weeks for24 weeks followed by a 20-week washout period. After completion of the washout period, participants could resume monthly DAC HYP 150 mg using the PFS for up to 3 additional years. Participants in the TP-DI sub-study received s probe-drug cocktail administration at Weeks 43 and 53. The probe-drug cocktail consisted of midazolam 5 mg, caffeine 200 mg, S-warfarin 10 mg, vitamin K 10 mg, omeprazole 40 mg, and dextromethorphan 30 mg. The oral vitamin K was used to counteract warfarin’s anticoagulant effect prophylactically.

    Serious adverse events
    		 DAC HYP 150 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 133 (24.81%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Sarcoidosis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Endometrial hypertrophy
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endometriosis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    10 / 133 (7.52%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Haemolytic anaemia
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous sarcoidosis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Erythema nodosum
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Hydronephrosis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Furuncle
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatitis e
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 133 (1.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Streptococcal urinary tract infection
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    1 / 133 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DAC HYP 150 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 133 (79.70%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 133 (6.77%)
         occurrences all number
    13
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 133 (15.79%)
         occurrences all number
    35
    Hypoaesthesia
         subjects affected / exposed
    9 / 133 (6.77%)
         occurrences all number
    11
    Migraine
         subjects affected / exposed
    7 / 133 (5.26%)
         occurrences all number
    10
    Multiple sclerosis relapse
         subjects affected / exposed
    58 / 133 (43.61%)
         occurrences all number
    147
    Muscle spasticity
         subjects affected / exposed
    7 / 133 (5.26%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    8 / 133 (6.02%)
         occurrences all number
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 133 (9.02%)
         occurrences all number
    21
    Influenza like illness
         subjects affected / exposed
    13 / 133 (9.77%)
         occurrences all number
    90
    Pyrexia
         subjects affected / exposed
    12 / 133 (9.02%)
         occurrences all number
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 133 (6.77%)
         occurrences all number
    11
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    11 / 133 (8.27%)
         occurrences all number
    13
    Depression
         subjects affected / exposed
    9 / 133 (6.77%)
         occurrences all number
    10
    Insomnia
         subjects affected / exposed
    9 / 133 (6.77%)
         occurrences all number
    9
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    7 / 133 (5.26%)
         occurrences all number
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 133 (7.52%)
         occurrences all number
    10
    Back pain
         subjects affected / exposed
    14 / 133 (10.53%)
         occurrences all number
    16
    Muscle spasms
         subjects affected / exposed
    7 / 133 (5.26%)
         occurrences all number
    8
    Muscular weakness
         subjects affected / exposed
    10 / 133 (7.52%)
         occurrences all number
    12
    Pain in extremity
         subjects affected / exposed
    9 / 133 (6.77%)
         occurrences all number
    13
    Spinal pain
         subjects affected / exposed
    7 / 133 (5.26%)
         occurrences all number
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 133 (14.29%)
         occurrences all number
    30
    Influenza
         subjects affected / exposed
    8 / 133 (6.02%)
         occurrences all number
    10
    Oral herpes
         subjects affected / exposed
    7 / 133 (5.26%)
         occurrences all number
    16
    Pharyngitis
         subjects affected / exposed
    15 / 133 (11.28%)
         occurrences all number
    23
    Sinusitis
         subjects affected / exposed
    11 / 133 (8.27%)
         occurrences all number
    24
    Upper respiratory tract infection
         subjects affected / exposed
    33 / 133 (24.81%)
         occurrences all number
    63
    Urinary tract infection
         subjects affected / exposed
    30 / 133 (22.56%)
         occurrences all number
    56

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2011
    - The primary reason for this amendment was to increase subject monitoring for laboratory signals related to hepatic function (LFTs to be assessed monthly throughout the treatment period), and to update criteria for temporary suspension and discontinuation of study treatment for subjects who develop elevations in ALT, AST, or total bilirubin. Subjects who permanently discontinued study treatment due to elevated LFTs were to be evaluated for possible toxicological, infectious, immunological, and metabolic causes of liver injury. - Audit C Questionnaire was added to Medical History at Screening Visit. - Wording of “Interim analyses” section was revised to clarify that ongoing data review/analyses of both the main study data and Intensive PK substudy data may be performed.
    16 Apr 2012
    - Changes were made to prohibit concomitant treatment with medications that have an established association with hepatotoxicity or cutaneous hypersensitivity reactions. - Changes were made to provide monthly LFT results to the Neurologist prior to administration of study treatment. - Changes were made to provide subjects with the option of an additional 3 years of open-label treatment with DAC HYP. - The sample size was reduced from 150 to 100 subjects. - The upper limit for the age of eligibility was increased from 55 years to 65 years. - The parameters for concomitant IFN-β treatment were revised. - The criteria for subject withdrawal from the study were revised to include subjects who developed a chronic viral infection.
    28 Sep 2012
    - A TP-DI substudy as added as part of the 3-year treatment extension. - PD testing was removed at timepoints that were no longer considered informative for characterizing response to DAC HYP. - The timepoints for the tests and assessments listed in Table 1 were revised. In addition, hematology and blood chemistry testing were removed from the Unscheduled Relapse Assessment. These changes were made to minimize subject burden in the study. - The timing for the confirmatory hematology tests for discontinuation of DAC HYP was revised.

    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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