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    Clinical Trial Results:
    A Phase 3, double-blind, randomized study of RVT-101 versus placebo when added to existing stable donepezil treatment in subjects with mild to moderate Alzheimer’s Disease

    Summary
    EudraCT number
    		 2015-002957-37
    Trial protocol
    		 DE   GB   CZ   SK   ES   BG   HR   IT  
    Global end of trial date
    31 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Dec 2018
    First version publication date
    29 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RVT-101-3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02585934
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Axovant Sciences Ltd.
    Sponsor organisation address
    2 Church Street, Hamilton, Bermuda,
    Public contact
    Project Management, Worldwide Clinical Trials, +44 207121 61 61,
    Scientific contact
    Project Management, Worldwide Clinical Trials, 646 8220512,
    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
    20 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of RVT-101 versus placebo as adjuncts to stable donepezil therapy: - on cognitive function as measured by the ADAS-Cog-11 after 24 weeks of treatment. - on activities of daily living as measured by ADCS-ADL scale after 24 weeks of treatment
    Protection of trial subjects
    Subjects were required to provide full written informed consent prior to the performance of any protocol-specified procedure; or if unable to provide informed consent due to cognitive status, subject has provided assent and a legally acceptable representative has provided full written informed consent on behalf of the subject. Collection of AEs and SAEs were collected at the time of informed consent and continued until the follow-up contact. SAEs that were spontaneously reported by the subject or subject representative or discovered by the investigator or designee after the follow-up visit and up to 30 days after the last dose of investigational product were collected and reported. Subjects were withdrawn from the study based on consultation between the principal investigator and Medical Monitor, with the ultimate decision by the principal investigator or subject. Study safety data was periodically reviewed by an independent data monitoring committee.
    Background therapy
    		 -
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    01 Dec 2015
    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
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 349
    Country: Number of subjects enrolled
    Canada: 48
    Country: Number of subjects enrolled
    Australia: 36
    Country: Number of subjects enrolled
    Argentina: 123
    Country: Number of subjects enrolled
    Chile: 52
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 10
    Country: Number of subjects enrolled
    Serbia: 29
    Country: Number of subjects enrolled
    Singapore: 16
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Slovakia: 48
    Country: Number of subjects enrolled
    Spain: 74
    Country: Number of subjects enrolled
    United Kingdom: 193
    Country: Number of subjects enrolled
    Croatia: 32
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Czech Republic: 58
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 75
    Country: Number of subjects enrolled
    Italy: 67
    Worldwide total number of subjects
    1315
    EEA total number of subjects
    635
    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)
    202
    From 65 to 84 years
    1088
    85 years and over
    25

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were screened for eligibility during the Screening Period. An ICF was signed by each subject or by the caregiver with subject assent. Consent forms were also signed by the caregiver before any study-specific procedures were performed. Subjects were screened according to study inclusion/exclusion criteria.

    Period 1
    Period 1 title
    Double-Blind (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    A 24-week Double-Blind Treatment Period when neither subjects nor their caregivers nor investigators knew which of the 2 treatments the subject was receiving. Subjects were not informed of transition from the Single-Blind Run-In Period to the Double-Blind Treatment Period. RVT-101 and placebo were provided as tablets that are indistinguishable in appearance, smell, and taste.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    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
    Placebo was administered as tablets. Subjects were instructed to take 1 tablet orally each morning without regard to food for 24 weeks.

    Arm title
    		 RVT-101 35 mg
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    RVT-101
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RVT-101 was administered as pink film-coated round 35-mg tablets. Subjects were instructed to take 1 tablet orally each morning without regard to food for 24 weeks.

    Number of subjects in period 1
    		Placebo RVT-101 35 mg
    Started
    654
    661
    Safety Population
    651
    656
    Intent-to-Treat Population
    633
    643
    Per-Protocol Population
    582
    603
    Completed
    581
    592
    Not completed
    73
    69
         Adverse event, serious fatal
    2
    3
         Consent withdrawn by subject
    21
    7
         Physician decision
    2
    3
         Adverse event, non-fatal
    20
    18
         Other
    5
    10
         Death
    -
    2
         Sponsor Termination
    2
    1
         Caregiver withdrew consent
    7
    7
         Lost to follow-up
    2
    2
         Lack of efficacy
    1
    2
         Protocol deviation
    11
    14

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    RVT-101 35 mg
    Reporting group description
    		 -

    Reporting group values
    		 Placebo RVT-101 35 mg Total
    Number of subjects
    		 654 661 1315
    Age categorical
    Intent-To-Treat (ITT) Population baseline characteristics have been entered for the Placebo (number of subjects=633) and RVT-101 (number of subjects=643) arms.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 97 99 196
        From 65-84 years
    		 551 557 1108
        85 years and over
    		 6 5 11
    Age continuous
    Intent-To-Treat (ITT) Population baseline characteristics have been entered for the Placebo (number of subjects=633) and RVT-101 (number of subjects=643) arms.
    Units: years
        arithmetic mean (full range (min-max))
    		 72.5 (50 to 86) 72.7 (50 to 85) -
    Gender categorical
    Units: Subjects
        Female
    		 406 398 804
        Male
    		 248 263 511

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    RVT-101 35 mg
    Reporting group description
    		 -

    Subject analysis set title
    RVT-101 Concentration Summary Statistics at Week 6
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Analysis completed on subjects in the PK population. The PK population will include all subjects in the Safety Population who undergo plasma PK sampling and have at least one post-baseline evaluable PK concentration result.

    Subject analysis set title
    RVT-101 Concentration Summary Statistics at Week 12
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Analysis completed on subjects in the PK population. The PK population will include all subjects in the Safety Population who undergo plasma PK sampling and have at least one post-baseline evaluable PK concentration result.

    Subject analysis set title
    RVT-101 Concentration Summary Statistics at Week 18
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Analysis completed on subjects in the PK population. The PK population will include all subjects in the Safety Population who undergo plasma PK sampling and have at least one post-baseline evaluable PK concentration result.

    Subject analysis set title
    RVT-101 Concentration Summary Statistics at Week 24
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Analysis completed on subjects in the PK population. The PK population will include all subjects in the Safety Population who undergo plasma PK sampling and have at least one post-baseline evaluable PK concentration result.

    Primary: Alzheimer’s Disease Assessment Scale – Cognitive Subscale 11 Items (ADAS-Cog-11) Score Change From Baseline to Week 24

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    End point title
    		 Alzheimer’s Disease Assessment Scale – Cognitive Subscale 11 Items (ADAS-Cog-11) Score Change From Baseline to Week 24
    End point description
    The 11-item ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. The ADAS-Cog-11 total score range is from 0 to 70, with a higher score indicating more severe cognitive impairment.
    End point type
    Primary
    End point timeframe
    Baseline, 24 weeks
    End point values
    		 Placebo RVT-101 35 mg
    Number of subjects analysed
    584
    577
    Units: NA
    584
    577
    Statistical analysis title
    		 Repeated Measures Analysis
    Comparison groups
    Placebo v RVT-101 35 mg
    Number of subjects included in analysis
    1161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2249 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.95
         upper limit
    		 0.22
    Notes
    [1] - The threshold for statistical significance was p=0.05

    Primary: Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score Change From Baseline to Week 24

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    End point title
    		 Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score Change From Baseline to Week 24
    End point description
    The ADCS-ADL scale measures functional impairment in terms of activities of daily living. The score ranges from 0 to 78. The lower the score, the greater the impairment; higher scores indicate better (more desirable) function
    End point type
    Primary
    End point timeframe
    Baseline, 24 weeks
    End point values
    		 Placebo RVT-101 35 mg
    Number of subjects analysed
    575
    588
    Units: NA
    575
    588
    Statistical analysis title
    		 Repeated Measures Analysis
    Comparison groups
    Placebo v RVT-101 35 mg
    Number of subjects included in analysis
    1163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.826 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.72
    Notes
    [2] - Tthe threshold for statistical significance was p=0.05

    Secondary: Clinical Global Impression of Change - Plus Caregiver Interview (CIBIC+) Score at Week 24

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    End point title
    		 Clinical Global Impression of Change - Plus Caregiver Interview (CIBIC+) Score at Week 24
    End point description
    The CIBIC+ assessment measures the global functioning of the subject. The CIBIC+ is scored as a seven-point categorical rating, ranging from a score of 1 (indicating "very much improved"), to a score of 4 (indicating "no change"), or to a score of 7 (indicating "very much worse.") Lower CIBIC+ scores indicate better (more desirable) function
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Placebo RVT-101 35 mg
    Number of subjects analysed
    568
    577
    Units: NA
    568
    577
    Statistical analysis title
    		 Repeated Measures Analysis
    Comparison groups
    Placebo v RVT-101 35 mg
    Number of subjects included in analysis
    1145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0234 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 -0.02
    Notes
    [3] - The threshold for statistical significance was p=0.05

    Secondary: The Dependence Scale (DS) Score Change From Baseline to Week 24

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    End point title
    		 The Dependence Scale (DS) Score Change From Baseline to Week 24
    End point description
    The DS measures the amount of assistance patients with dementia require in performing daily activities. The scale consists of 13 items, representing a range of severity from mild to severe levels of dependency. The score range is from 0 to 15 with higher scores indicating greater dependency.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 weeks
    End point values
    		 Placebo RVT-101 35 mg
    Number of subjects analysed
    568
    580
    Units: NA
    568
    580
    Statistical analysis title
    		 Repeated Measures Analysis
    Comparison groups
    Placebo v RVT-101 35 mg
    Number of subjects included in analysis
    1148
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2096 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.32
    Notes
    [4] - The threshold for statistical significance was p=0.05

    Secondary: Neuropsychiatric Inventory (NPI) Score Change From Baseline to Week 24

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    End point title
    		 Neuropsychiatric Inventory (NPI) Score Change From Baseline to Week 24
    End point description
    End point type
    Secondary
    End point timeframe
    The NPI is a behavior rating scale composed of a 12-item structured interview of the caregiver that is scored from 0 to 144 (the higher the score, the greater the psychiatric disturbance). It assesses 12 behavioral disturbances occurring in dementia patie
    End point values
    		 Placebo RVT-101 35 mg
    Number of subjects analysed
    570
    583
    Units: NA
    570
    583
    Statistical analysis title
    		 Repeated Measures Analysis
    Comparison groups
    Placebo v RVT-101 35 mg
    Number of subjects included in analysis
    1153
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.765 [5]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.09
         upper limit
    		 0.8
    Notes
    [5] - The threshold for statistical significance was p=0.05

    Secondary: ADAS-Cog-13 Score Change From Baseline to Week 24

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    End point title
    		 ADAS-Cog-13 Score Change From Baseline to Week 24
    End point description
    13-item ADAS-Cog assesses a range of cognitive abilities including memory, comprehension, orientation in time and place, and spontaneous speech. Most items are evaluated by tests, but some are dependent on clinician ratings on a 5-point scale. The ADAS-Cog-13 is the ADAS-Cog-11 with 2 additional items: delayed word recall and total digit cancellation. Scores for the ADAS-Cog-13 range from 0 to 85 with higher scores indicating greater dysfunction.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 weeks
    End point values
    		 Placebo RVT-101 35 mg
    Number of subjects analysed
    576
    583
    Units: NA
    576
    583
    Statistical analysis title
    		 Repeated Measures Analysis
    Comparison groups
    Placebo v RVT-101 35 mg
    Number of subjects included in analysis
    1159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2472 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.03
         upper limit
    		 0.27
    Notes
    [6] - The threshold for statistical significance was p=0.05

    Secondary: Measurement of Concentrations of RVT-101 in Plasma

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    End point title
    		 Measurement of Concentrations of RVT-101 in Plasma
    End point description
    Measurement collected at timepoints Week 6, Week 12, Week 18, and Week 24
    End point type
    Secondary
    End point timeframe
    Week 6, Week 12, Week 18, Week 24
    End point values
    		 RVT-101 Concentration Summary Statistics at Week 6 RVT-101 Concentration Summary Statistics at Week 12 RVT-101 Concentration Summary Statistics at Week 18 RVT-101 Concentration Summary Statistics at Week 24
    Number of subjects analysed
    563
    579
    454
    562
    Units: ng/mL
        geometric mean (confidence interval 95%)
    201.11 (191.88 to 210.78)
    170.95 (164.40 to 177.76)
    198.69 (189.36 to 208.48)
    193.36 (184.60 to 202.53)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Collection of AEs and SAEs will begin at the time a subject signs informed consent and continues until the follow-up contact.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    RVT-101
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo RVT-101
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 651 (6.76%)
    40 / 656 (6.10%)
         number of deaths (all causes)
    2
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acoustic neuroma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    3 / 651 (0.46%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cancer
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor peripheral circulation
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 651 (0.00%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mood altered
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somatic symptom disorder
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    3 / 651 (0.46%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    3 / 651 (0.46%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stoma obstruction
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 651 (0.15%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Mitral valve prolapse
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 651 (0.31%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    3 / 651 (0.46%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 651 (0.00%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 651 (0.31%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 651 (0.15%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 651 (0.15%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Inner ear disorder
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertigo positional
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal vascular ectasia
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    1 / 651 (0.15%)
    0 / 656 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 651 (0.31%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 651 (0.15%)
    2 / 656 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 651 (0.15%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 651 (0.00%)
    1 / 656 (0.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo RVT-101
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 651 (25.50%)
    191 / 656 (29.12%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    29 / 651 (4.45%)
    37 / 656 (5.64%)
         occurrences all number
    29
    37
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 651 (1.84%)
    19 / 656 (2.90%)
         occurrences all number
    12
    19
    Headache
         subjects affected / exposed
    18 / 651 (2.76%)
    17 / 656 (2.59%)
         occurrences all number
    18
    17
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 651 (2.61%)
    13 / 656 (1.98%)
         occurrences all number
    17
    13
    Nausea
         subjects affected / exposed
    13 / 651 (2.00%)
    17 / 656 (2.59%)
         occurrences all number
    13
    17
    Respiratory, thoracic and mediastinal disorders
    Bronchitis
         subjects affected / exposed
    10 / 651 (1.54%)
    14 / 656 (2.13%)
         occurrences all number
    10
    14
    Cough
         subjects affected / exposed
    7 / 651 (1.08%)
    15 / 656 (2.29%)
         occurrences all number
    7
    15
    Nasopharyngitis
         subjects affected / exposed
    19 / 651 (2.92%)
    23 / 656 (3.51%)
         occurrences all number
    19
    23
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    15 / 651 (2.30%)
    11 / 656 (1.68%)
         occurrences all number
    15
    11
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    26 / 651 (3.99%)
    25 / 656 (3.81%)
         occurrences all number
    26
    25

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Nov 2015
    Amendment #1 includes the changes to the original protocol RVT-101-3001, version 1.0 dated 24 August 2015: modifying the creatinine clearance exclusion criterion, clarifying the contact information for serious adverse events (SAEs), and removing the requirement for including subject initials in SAE reports.
    13 Apr 2016
    Protocol RVT-101-3001 version 3.0 includes the following changes to protocol version 2.0 dated 19 November 2015: subjects will now have the option to enter a 12-month Open-Label Extension study (study RVT-101-3002) after completion of the current lead-in study (RVT-101-3001); subjects will not be required to undergo the follow-up visit/Visit 9 of this study if they enter the open-label extension study; and administrative changes were made for clarification.

    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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