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    Clinical Trial Results:
    A Phase 3b, 12-month, Open-label, Multicenter Study to Evaluate the Efficacy and Safety of BIIB019, Daclizumab, in Subjects with Relapsing-Remitting Multiple Sclerosis (RRMS) Switching from Natalizumab (SUSTAIN)

    Summary
    EudraCT number
    2016-002820-10
    Trial protocol
    GB   DE   IT  
    Global end of trial date
    12 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Sep 2019
    First version publication date
    22 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    205MS305
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02881567
    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
    12 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effects of treatment with daclizumab on the proportion of subjects relapse-free at 6 months in RRMS subjects, who switched from treatment with natalizumab to daclizumab due to safety concerns. The secondary objectives of this study in this study population were to evaluate the effects of daclizumab on the following: 1) Multiple Sclerosis (MS) relapse activity including the annualized relapse rate (ARR) and the proportion of subjects experiencing relapses requiring hospitalization and/or steroid treatment 2) MS-related outcomes measured using magnetic resonance imaging (MRI) 3) Safety and tolerability in subjects previously treated with natalizumab.
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorised representative (e.g., parent or legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’s legally authorised 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
    18 Apr 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    41
    EEA total number of subjects
    27
    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)
    41
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects enrolled in the study at 11 investigative sites in Canada, Germany, Italy, and the United States from 05 April 2017 to 12 September 2018.

    Pre-assignment
    Screening details
    Subjects who discontinued treatment with natalizumab due to safety concerns were enrolled to receive daclizumab 150 milligrams (mg) per 1.0 millilitre (mL).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Daclizumab
    Arm description
    Subjects previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Daclizumab
    Investigational medicinal product code
    Other name
    Zinbryta
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Daclizumab was administered as 150 mg per 1.0 mL subcutaneously, once a month for up to 11 months.

    Number of subjects in period 1
    Daclizumab
    Started
    41
    Completed
    23
    Not completed
    18
         Investigator decision
    1
         Consent withdrawn
    1
         Adverse event
    1
         Study terminated by sponsor
    9
         Reason not Specified
    3
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daclizumab
    Reporting group description
    Subjects previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.

    Reporting group values
    Daclizumab Total
    Number of subjects
    41 41
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    41 41
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    36.9 ± 9.71 -
    Gender Categorical
    Units: Subjects
        Female
    28 28
        Male
    13 13
    Race
    Units: Subjects
        White
    9 9
        Black or African American
    4 4
        Not Reported Due to Confidentiality Regulation
    27 27
        Other (Aboriginal)
    1 1

    End points

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    End points reporting groups
    Reporting group title
    Daclizumab
    Reporting group description
    Subjects previously treated with natalizumab for at least 12 months and who discontinued treatment, received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.

    Primary: Percentage of Subjects Relapse-free at Month 6

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    End point title
    Percentage of Subjects Relapse-free at Month 6 [1]
    End point description
    Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. The Kaplan-Meier estimate of the percentage of subjects relapse-free at Month 6 is reported. FAS included all subjects enrolled in the study.
    End point type
    Primary
    End point timeframe
    Month 6
    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: No statistical analyses are reported for this endpoint.
    End point values
    Daclizumab
    Number of subjects analysed
    41
    Units: percentage of subjects
        number (not applicable)
    66.615
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Experiencing Relapse Requiring Hospitalization and/or Steroid Treatment at Month 12

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    End point title
    Percentage of Subjects Experiencing Relapse Requiring Hospitalization and/or Steroid Treatment at Month 12
    End point description
    Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Daclizumab
    Number of subjects analysed
    0 [2]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [2] - The study was terminated. No subjects reached the 12-month time point.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Relapse-free at Month 12

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    End point title
    Percentage of Subjects Relapse-free at Month 12
    End point description
    Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Daclizumab
    Number of subjects analysed
    0 [3]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [3] - The study was terminated. No subjects reached the 12-month time point.
    No statistical analyses for this end point

    Secondary: Annualised Relapse Rate (ARR) at Month 12

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    End point title
    Annualised Relapse Rate (ARR) at Month 12
    End point description
    Relapses were defined as new or recurrent neurological symptoms not associated with fever or infection, lasting at least 24 hours, and accompanied by new objective neurological findings upon examination by the Examining Neurologist. The ARR was calculated by tabulating the total number of relapses experienced in the group divided by the number of days up to the end of Month 12, and the ratio then multiplied by 365.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Daclizumab
    Number of subjects analysed
    0 [4]
    Units: relapses per year
        arithmetic mean (confidence interval 95%)
    ( to )
    Notes
    [4] - The study was terminated. No subjects reached the 12-month time point.
    No statistical analyses for this end point

    Secondary: Number of Subjects with New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions at Months 6 and 12

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    End point title
    Number of Subjects with New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions at Months 6 and 12
    End point description
    New Gadolinium-Enhanced (Gd+) and T1 Hypointense Lesions were assessed using magnetic resonance imaging (MRI). FAS included all subjects enrolled in the study. Number of Subjects Analyzed is the number of subjects with available assessment. 'n' signifies the number of subjects analysed at specified time point. '99999' for Month 6, T1 Hypointense Lesions indicates that no data was collected. '99999' for Month 12, Gd+ and Month 12, T1 Hypointense Lesions indicates that the study was terminated and no subjects reached the 12-month time point.
    End point type
    Secondary
    End point timeframe
    Months 6 and 12
    End point values
    Daclizumab
    Number of subjects analysed
    11
    Units: subjects
        Month 6, Gd+ Lesions (n= 11)
    3
        Month 6, T1 Hypointense Lesions (n=0)
    99999
        Month 12, Gd+ Lesions (n= 0)
    99999
        Month 12, T1 Hypointense Lesions (n= 0)
    99999
    No statistical analyses for this end point

    Secondary: Number of Subjects with New and Newly Enlarged T2 Hypointense Lesions at Months 6 and 12

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    End point title
    Number of Subjects with New and Newly Enlarged T2 Hypointense Lesions at Months 6 and 12
    End point description
    New and newly enlarged T2 Hypointense Lesions were measured by MRI. FAS included all subjects enrolled in the study. Number of Subjects Analyzed is the number of subjects with available assessment. 'n' signifies the number of subjects analysed at specified time point. '99999' indicates that the study was terminated and no subjects reached the 12-month time point.
    End point type
    Secondary
    End point timeframe
    Months 6 and 12
    End point values
    Daclizumab
    Number of subjects analysed
    11
    Units: subjects
        Month 6 (n=11)
    3
        Month 12 (n= 0)
    99999
    No statistical analyses for this end point

    Secondary: Permanent Discontinuation Rate of Daclizumab at Month 12

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    End point title
    Permanent Discontinuation Rate of Daclizumab at Month 12
    End point description
    Permanent Discontinuation Rate was calculated as the ratio of number of subjects who had permanently discontinued daclizumab prior to Month 12 over the total number of subjects who received at least 1 dose of daclizumab in the study.
    End point type
    Secondary
    End point timeframe
    Month 12
    End point values
    Daclizumab
    Number of subjects analysed
    0 [5]
    Units: ratio
        arithmetic mean (confidence interval 95%)
    ( to )
    Notes
    [5] - The study was terminated. No subjects reached the 12-month time point
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE can 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. An SAE is any untoward medical occurrence that at any dose results in death or in the view of the Investigator, places the subject at immediate risk of death or requires inpatient hospitalisation or prolongation of existing hospitalisation or results in persistent or significant disability or results in a birth defect. Safety Population included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    The first dose of study drug to within 30 days of last dose (up to 11 months)
    End point values
    Daclizumab
    Number of subjects analysed
    41
    Units: subjects
        Subjects with AEs
    27
        Subjects with SAEs
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects with Clinically Relevant Shifts in Laboratory Assessments

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    End point title
    Number of Subjects with Clinically Relevant Shifts in Laboratory Assessments
    End point description
    Clinical Laboratory assessments were tests of Chemistry and Hematology. The investigator determined if any of the laboratory results were clinically relevant shifts from Baseline. Safety Population included all enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    First dose of study drug to within 30 days of last dose (up to 11 months)
    End point values
    Daclizumab
    Number of subjects analysed
    41
    Units: subjects
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to within 30 days of last dose (up to 11 months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Daclizumab
    Reporting group description
    Subjects previously treated with natalizumab for at least 12 months and who discontinued treatment received daclizumab 150 mg per 1.0 mL administered subcutaneously once a month for up to 11 months.

    Serious adverse events
    Daclizumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 41 (21.95%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Multiple sclerosis relapse
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Encephalitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 41 (2.44%)
         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
    Daclizumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 41 (56.10%)
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Nervous system disorders
    Migraine
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Multiple sclerosis relapse
         subjects affected / exposed
    7 / 41 (17.07%)
         occurrences all number
    7
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    7 / 41 (17.07%)
         occurrences all number
    11
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Infections and infestations
    Influenza
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    11
    Nasopharyngitis
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Mar 2018
    The study was terminated and enrollment closed due to the Sponsor’s decision to discontinue the daclizumab clinical development program. This was concurrent with the announcement of the voluntary worldwide withdrawal of Zinbryta (daclizumab) for relapsing MS.
    -

    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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