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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Multicenter Study of Rapastinel in the Prevention of Relapse in Patients with Major Depressive Disorder

    Summary
    EudraCT number
    2018-000064-28
    Trial protocol
    HU   SE   SK   PL   BG  
    Global end of trial date
    11 Jul 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Jul 2020
    First version publication date
    27 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RAP-MD-33
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03614156
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow, Marlow Buckinghamshire SL7 1YL, United Kingdom, SL7 1YL
    Public contact
    Clinical Trials Registry Team, Allergan plc, 001 877‐277‐8566, IR-CTRegistration@Allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan, 001 862-261-7000, IR-CTRegistration@allergan.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
    11 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Jul 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial is to evaluate the efficacy, safety, and tolerability of 450 milligrams (mg) or 225 mg of Rapastinel compared to placebo in the prevention of relapse in participants with major depressive disorder (MDD).
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Aug 2018
    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
    Hungary: 11
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    United States: 335
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Slovakia: 5
    Worldwide total number of subjects
    363
    EEA total number of subjects
    17
    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)
    330
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients from RAP-MD-33 completed one of the rapastinel lead-in studies - RAP-MD-30, RAP-MD-31, or RAP-MD-32.

    Pre-assignment
    Screening details
    A total of 363 patients enrolled in the Open Label Treatment Period (OLTP). Of these, 209 completed the OLTP and 137 entered the Double Blind Treatment Period (DBTP) and were randomized.

    Pre-assignment period milestones
    Number of subjects started
    363
    Intermediate milestone: Number of subjects
    Completed Open Label Treatment Period: 209
    Number of subjects completed
    137

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 7
    Reason: Number of subjects
    Lack of efficacy: 18
    Reason: Number of subjects
    Consent withdrawn by subject: 36
    Reason: Number of subjects
    Lost to follow-up: 10
    Reason: Number of subjects
    Protocol deviation: 2
    Reason: Number of subjects
    Protocol-specified withdrawal met: 6
    Reason: Number of subjects
    Non-compliance with study drug: 1
    Reason: Number of subjects
    Study terminated by sponsor: 74
    Reason: Number of subjects
    Did not meet stability criteria: 72
    Period 1
    Period 1 title
    Double-Blind Treatment Period (DBTP) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo weekly
    Arm description
    Placebo (prefilled syringe, weekly IV administration)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Intravenous IV administration once per week.

    Arm title
    Rapastinel clinically driven schedule
    Arm description
    Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)
    Arm type
    Experimental

    Investigational medicinal product name
    Rapastinel
    Investigational medicinal product code
    AGN-241659 (previously GLYX-13)
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rapastinel intravenous IV administration

    Arm title
    Rapastinel weekly
    Arm description
    Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)
    Arm type
    Experimental

    Investigational medicinal product name
    Rapastinel
    Investigational medicinal product code
    AGN-241659 (previously GLYX-13)
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rapastinel intravenous IV administration

    Number of subjects in period 1 [1]
    Placebo weekly Rapastinel clinically driven schedule Rapastinel weekly
    Started
    40
    42
    55
    Entered Safety Follow Up Period
    26
    30
    35
    Completed
    10
    11
    10
    Not completed
    30
    31
    45
         Consent withdrawn by subject
    4
    1
    1
         Adverse event, non-fatal
    2
    -
    1
         Miscellaneous Reasons
    1
    -
    -
         Study terminated by sponsor
    22
    26
    38
         Lost to follow-up
    -
    3
    4
         Protocol deviation
    1
    1
    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 baseline period consists only of those 137 participants who were randomized out of the overall 363 enrolled participants.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo weekly
    Reporting group description
    Placebo (prefilled syringe, weekly IV administration)

    Reporting group title
    Rapastinel clinically driven schedule
    Reporting group description
    Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

    Reporting group title
    Rapastinel weekly
    Reporting group description
    Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

    Reporting group values
    Placebo weekly Rapastinel clinically driven schedule Rapastinel weekly Total
    Number of subjects
    40 42 55 137
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    33 40 53 126
        From 65-84 years
    7 2 2 11
        85 years and over
    0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    47.0 ± 13.95 43.6 ± 12.57 43.9 ± 11.66 -
    Sex: Female, Male
    Units: Participants
        Female
    30 29 44 103
        Male
    10 13 11 34
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    1 0 0 1
        Asian
    3 2 2 7
        Native Hawaiian or Other Pacific Islander
    1 2 0 3
        Black or African American
    8 5 11 24
        White
    27 33 42 102
        More than one race
    0 0 0 0
        Unknown or Not Reported
    0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    3 8 9 20
        Not Hispanic or Latino
    37 34 46 117
        Unknown or Not Reported
    0 0 0 0
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    84.84 ± 17.856 85.88 ± 19.207 88.53 ± 19.240 -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    168.31 ± 8.996 166.92 ± 9.858 168.47 ± 9.196 -
    BMI
    Units: kg/m^2
        arithmetic mean (standard deviation)
    29.89 ± 5.686 30.95 ± 7.289 31.15 ± 6.279 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo weekly
    Reporting group description
    Placebo (prefilled syringe, weekly IV administration)

    Reporting group title
    Rapastinel clinically driven schedule
    Reporting group description
    Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

    Reporting group title
    Rapastinel weekly
    Reporting group description
    Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

    Primary: Time to First Relapse During the 52 Weeks of the Double-Blind Treatment Period (DBTP)

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    End point title
    Time to First Relapse During the 52 Weeks of the Double-Blind Treatment Period (DBTP) [1]
    End point description
    Time in days from randomization to relapse. The primary efficacy analysis will compare the time to relapse between placebo and rapastinel treatment groups using the log-rank test. Due to study termination, there are not enough events to allow for any statistically meaningful estimation of the Time to First Relapse. As a result, only the time to relapse at the 25th percentile is presented for each study arm, without confidence intervals.
    End point type
    Primary
    End point timeframe
    52 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: Due to study termination, there are not enough events to allow for any meaningful statistical analysis.
    End point values
    Placebo weekly Rapastinel clinically driven schedule Rapastinel weekly
    Number of subjects analysed
    40
    42
    55
    Units: Days(Time of Relapse at 25th percentile)
        number (not applicable)
    94
    177
    157
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The study consisted of an 8 to 16 week OLTP; followed by a randomized DBTP of up to 52 weeks; followed by a 2 week safety period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.2
    Reporting groups
    Reporting group title
    Open-Label Treatment Period
    Reporting group description
    Rapastinel 225 milligrams (mg) or 450 mg intravenous (IV) once a week during OLTP.

    Reporting group title
    Placebo weekly
    Reporting group description
    Placebo (prefilled syringe, weekly IV administration)

    Reporting group title
    Rapastinel clinically driven schedule
    Reporting group description
    Rapastinel 450 mg or 225 mg (prefilled syringe, clinically driven schedule IV administration, variable interval, placebo on intervening weeks)

    Reporting group title
    Rapastinel weekly
    Reporting group description
    Rapastinel 450 mg or 225 mg (prefilled syringe, weekly intravenous IV administration)

    Serious adverse events
    Open-Label Treatment Period Placebo weekly Rapastinel clinically driven schedule Rapastinel weekly
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 363 (1.10%)
    1 / 40 (2.50%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Nervous system disorders
    Partial seizures
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 363 (0.00%)
    1 / 40 (2.50%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 363 (0.28%)
    0 / 40 (0.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcoholism
         subjects affected / exposed
    0 / 363 (0.00%)
    0 / 40 (0.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Open-Label Treatment Period Placebo weekly Rapastinel clinically driven schedule Rapastinel weekly
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 363 (12.12%)
    17 / 40 (42.50%)
    9 / 42 (21.43%)
    13 / 55 (23.64%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 363 (5.51%)
    3 / 40 (7.50%)
    1 / 42 (2.38%)
    3 / 55 (5.45%)
         occurrences all number
    23
    5
    1
    4
    Dizziness
         subjects affected / exposed
    1 / 363 (0.28%)
    2 / 40 (5.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    2
    2
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 363 (0.55%)
    2 / 40 (5.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 363 (0.28%)
    4 / 40 (10.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    1
    4
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 363 (1.10%)
    2 / 40 (5.00%)
    1 / 42 (2.38%)
    2 / 55 (3.64%)
         occurrences all number
    4
    2
    1
    2
    Vomiting
         subjects affected / exposed
    2 / 363 (0.55%)
    3 / 40 (7.50%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    2
    3
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    2 / 363 (0.55%)
    2 / 40 (5.00%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
         occurrences all number
    3
    2
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 363 (0.00%)
    2 / 40 (5.00%)
    0 / 42 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 363 (4.96%)
    1 / 40 (2.50%)
    4 / 42 (9.52%)
    3 / 55 (5.45%)
         occurrences all number
    19
    1
    4
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 363 (4.13%)
    3 / 40 (7.50%)
    1 / 42 (2.38%)
    0 / 55 (0.00%)
         occurrences all number
    16
    3
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 363 (7.16%)
    0 / 40 (0.00%)
    4 / 42 (9.52%)
    5 / 55 (9.09%)
         occurrences all number
    31
    0
    4
    5
    Bronchitis
         subjects affected / exposed
    2 / 363 (0.55%)
    2 / 40 (5.00%)
    0 / 42 (0.00%)
    1 / 55 (1.82%)
         occurrences all number
    2
    2
    0
    1

    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? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to study termination, the target number of participants needed to achieve target power and statistically reliable results was not met.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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