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    Clinical Trial Results:
    A Phase III Randomized, Placebo-Controlled Clinical Trial to Study the Safety and Efficacy of Suvorexant (MK-4305) for the Treatment of Insomnia in Subjects with Alzheimer’s Disease

    Summary
    EudraCT number
    		 2015-003154-40
    Trial protocol
    		 FI   GB   IT  
    Global end of trial date
    30 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Oct 2019
    First version publication date
    13 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-4305-061
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02750306
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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
    30 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study's main objective was to examine the safety and efficacy of suvorexant (MK-4305) to improve sleep in individuals with Alzheimer's disease (AD). The primary hypothesis for the study was that suvorexant is superior to placebo in improving insomnia as measured by change from baseline in polysomnography (PSG)-derived total sleep time (TST) at Week 4.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 May 2016
    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
    Canada: 1
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Peru: 68
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 187
    Worldwide total number of subjects
    285
    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)
    83
    From 65 to 84 years
    193
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 This study included participants who had a diagnosis of probable Alzheimer’s disease and had sleep complaints that met DSM-5 criteria for a diagnosis of insomnia.

    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
    		 Suvorexant
    Arm description
    		 Participants received 1 suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' suvorexant dose could be increased to 20 mg if their Clinical Global Impression of Insomnia Severity (CGI-S) was >3 and investigators felt they could tolerate the increased dose.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Suvorexant
    Investigational medicinal product code
    Other name
    MK-4305
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 1 suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' suvorexant dose could be increased to 20 mg if their CGI-S was >3 and investigators felt they could tolerate the increased dose.

    Arm title
    		 Placebo
    Arm description
    		 Participants received 1 placebo-matching suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' placebo-matching dose could be increased to 20 mg if their CGI-S was >3 and investigators felt they could tolerate the increased dose.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants receive 1 placebo-matching suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' placebo-matching dose can be increased to 20 mg if their CGI-S is >3 and investigators feel they can tolerate the increased dose.

    Number of subjects in period 1
    		Suvorexant Placebo
    Started
    142
    143
    Completed
    136
    141
    Not completed
    6
    2
         Consent withdrawn by subject
    5
    2
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Suvorexant
    Reporting group description
    		 Participants received 1 suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' suvorexant dose could be increased to 20 mg if their Clinical Global Impression of Insomnia Severity (CGI-S) was >3 and investigators felt they could tolerate the increased dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 1 placebo-matching suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' placebo-matching dose could be increased to 20 mg if their CGI-S was >3 and investigators felt they could tolerate the increased dose.

    Reporting group values
    		 Suvorexant Placebo Total
    Number of subjects
    		 142 143 285
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.6 ( 8.7 ) 69.1 ( 8.5 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 91 95 186
        Male
    		 51 48 99
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 5 12 17
        Asian
    		 2 3 5
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Black or African American
    		 24 22 46
        White
    		 86 80 166
        More than one race
    		 25 25 50
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 89 93 182
        Not Hispanic or Latino
    		 52 50 102
        Unknown or Not Reported
    		 1 0 1
    Polysomnography-derived Total Sleep Time
    Note: One participant who failed the screening was inadvertently randomized and treated with suvorexant; had no polysomnography-derived total sleep time data.
    Units: Minutes
        arithmetic mean (standard deviation)
    		 279.1 ( 76.6 ) 271.2 ( 86.7 ) -

    End points

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    End points reporting groups
    Reporting group title
    Suvorexant
    Reporting group description
    		 Participants received 1 suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' suvorexant dose could be increased to 20 mg if their Clinical Global Impression of Insomnia Severity (CGI-S) was >3 and investigators felt they could tolerate the increased dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 1 placebo-matching suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' placebo-matching dose could be increased to 20 mg if their CGI-S was >3 and investigators felt they could tolerate the increased dose.

    Primary: Change from Baseline in Polysomnography-derived Total Sleep Time (TST) at Week 4

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    End point title
    		 Change from Baseline in Polysomnography-derived Total Sleep Time (TST) at Week 4
    End point description
    TST was measured at Baseline and at Week 4 in a sleep laboratory by polysomnography, during an 8-hour recording period beginning at participants' habitual bedtime. The analysis population for this end point included all randomized participants who received at least 1 dose of study medication, had a baseline value for change from baseline analyses, and at least 1 post-randomization observation for the analysis endpoint subsequent to at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Suvorexant Placebo
    Number of subjects analysed
    135
    139
    Units: Minutes
        least squares mean (confidence interval 95%)
    73.4 (61.3 to 85.5)
    45.2 (33.3 to 57.2)
    Statistical analysis title
    		 Change from Baseline in TST at Week 4
    Comparison groups
    Suvorexant v Placebo
    Number of subjects included in analysis
    274
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.00128 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    28.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.1
         upper limit
    		 45.2
    Notes
    [1] - P-Value for the Difference in Least Squares Means

    Primary: Percentage of Participants Who Experienced One or More Adverse Events

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    End point title
    		 Percentage of Participants Who Experienced One or More Adverse Events [2]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this end point included all randomized participants who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 6 weeks
    Notes
    [2] - 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 between-group statistical analysis was performed for this end point.
    End point values
    		 Suvorexant Placebo
    Number of subjects analysed
    142
    143
    Units: Percentage of participants
        number (not applicable)
    22.5
    16.1
    No statistical analyses for this end point

    Primary: Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event

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    End point title
    		 Percentage of Participants Who Discontinued Study Drug Due to an Adverse Event [3]
    End point description
    An adverse event (AE) is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. The analysis population for this end point included all randomized participants who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Up to 4 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: No between-group statistical analysis was performed for this end point.
    End point values
    		 Suvorexant Placebo
    Number of subjects analysed
    142
    143
    Units: Percentage of participants
        number (not applicable)
    0.7
    0.7
    No statistical analyses for this end point

    Secondary: Change from Baseline in Polysomnography-derived Wakefulness After Persistent Sleep Onset (WASO) at Week 4

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    End point title
    		 Change from Baseline in Polysomnography-derived Wakefulness After Persistent Sleep Onset (WASO) at Week 4
    End point description
    WASO was measured at Baseline and at Week 4 in a sleep laboratory by polysomnography during an 8-hour recording period beginning at participants' habitual bedtime. The analysis population for this end point included all randomized participants who received at least 1 dose of study medication, had a baseline value for change from baseline analyses, and at least 1 post-randomization observation for the analysis endpoint subsequent to at least 1 dose of study medication.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 4
    End point values
    		 Suvorexant Placebo
    Number of subjects analysed
    134
    137
    Units: Minutes
        least squares mean (confidence interval 95%)
    -45.0 (-53.8 to -36.3)
    -29.4 (-38.1 to -20.7)
    Statistical analysis title
    		 Change from Baseline in WASO at Week 4
    Comparison groups
    Suvorexant v Placebo
    Number of subjects included in analysis
    271
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01354 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Difference in Least Squares Means
    Point estimate
    -15.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.1
         upper limit
    		 -3.3
    Notes
    [4] - P-Value for the Difference in Least Squares Means

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Up to 6 weeks
    Adverse event reporting additional description
    All randomized participants who received at least 1 dose of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Suvorexant
    Reporting group description
    		 Participants received 1 suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' suvorexant dose could be increased to 20 mg if their CGI-S was >3 and investigators felt they could tolerate the increased dose.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received 1 placebo-matching suvorexant tablet every night for up to 4 weeks. After 2 weeks of double-blind treatment at 10 mg, participants' placebo-matching dose could be increased to 20 mg if their CGI-S was >3 and investigators felt they could tolerate the increased dose.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no non-serious adverse events that met the incidence greater than 5% threshold.
    Serious adverse events
    		 Suvorexant Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 143 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 143 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Suvorexant Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 142 (0.00%)
    0 / 143 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2017
    Amendment 1: The primary reason for this amendment was to incorporate changes to various sections of the protocol, including Trial Summary, Subject Inclusion Criteria, Subject Exclusion Criteria, Stratification, Concomitant Medications Allowed, and others.

    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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    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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