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    Clinical Trial Results:
    A Phase II, Multicenter , Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Investigate the Efficacy and Safety of RO4602522 Added to Background Alzheimer’s Disease Therapy in Patients with Moderate Alzheimer’s Disease

    Summary
    EudraCT number
    		 2012-000943-29
    Trial protocol
    		 SE   DE   GB   CZ   IT   PL  
    Global end of trial date
    03 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jun 2016
    First version publication date
    19 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BP28248
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01677754
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333,
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 061 6878333,
    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
    03 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a 12-month treatment of RO4602522 versus placebo added to background therapy of donepezil or rivastigmine in patients with moderate severity Alzheimer’s Disease (AD) (Mini Mental State Examination [MMSE] 13-20 inclusive), based on the mean change in Alzheimer’s Disease Assessment Scale – Cognitive Behavior Subscale [ADAS-Cog-11) scores cognitive endpoint, from baseline over time.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice. All subjects signed an informed consent form.
    Background therapy
    		 Study participation required a background therapy of treatment with acetylcholinesterase inhibitors (AChEIs) alone or in combination with memantine for at least 4 months, with the dose (of mono or dual therapy) stabilized for at least 3 months before screening. All formulations and dosages of the AChEIs donepezil, rivastigmine, and galantamine, as well as the combination of any AChEI with memantine were allowed, except treatment including donepezil 23 mg due to poor tolerability. Patients were to remain on the same dosing regimen of background treatment throughout the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Oct 2012
    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
    Poland: 53
    Country: Number of subjects enrolled
    Spain: 81
    Country: Number of subjects enrolled
    Sweden: 16
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Czech Republic: 82
    Country: Number of subjects enrolled
    France: 34
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    Canada: 46
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    United States: 102
    Worldwide total number of subjects
    540
    EEA total number of subjects
    334
    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)
    98
    From 65 to 84 years
    404
    85 years and over
    38

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 45-day screening period. At least 495 participants with moderate severity AD (MMSE 13-20 inclusive at screening) were randomized, equal ratio (1:1:1) to one of following 3 treatments: placebo, RO4602522 1 mg, or RO4602522 5 mg, as add-on to background therapy of AChEI (donepezil, rivastigmine, or galantamine) alone or in combination with memantine.

    Period 1
    Period 1 title
    Treatment Period (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
    		 RO4602522 1 mg
    Arm description
    		 2 x 0.5 mg tablets taken daily orally for 12 months in addition to background therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO4602522 1 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 0.5 mg tablet orally from each of two 0.5 mg tablet bottles at the same time every day throughout the study.

    Arm title
    		 RO4602522 5mg
    Arm description
    		 2 x 2.5 mg tablets taken daily orally for 12 months in addition to background therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    RO4602522 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 2.5 mg tablet orally from each of two 2.5 mg tablet bottles at the same time every day throughout the study.

    Arm title
    		 Placebo
    Arm description
    		 Matching dose tablet (0.5 mg or 2.5 mg) taken from each of 2 bottles daily for 12 months, in addition to background therapy.
    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
    One matching dose tablet (0.5 mg or 2.5 mg) taken orally from each of two bottles at the same time every day throughout the study.

    Number of subjects in period 1
    		RO4602522 1 mg RO4602522 5mg Placebo
    Started
    179
    180
    181
    Completed
    134
    142
    143
    Not completed
    45
    38
    38
         Adverse event, non-fatal
    15
    16
    12
         Death
    2
    1
    2
         Investigator-specified reasons
    11
    2
    3
         Non-compliance with study medication
    -
    1
    2
         Lost to follow-up
    4
    2
    -
         Sponsor decision
    1
    -
    1
         Lack of efficacy
    1
    1
    3
         Withdrawal by subject
    11
    15
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    RO4602522 1 mg
    Reporting group description
    		 2 x 0.5 mg tablets taken daily orally for 12 months in addition to background therapy.

    Reporting group title
    RO4602522 5mg
    Reporting group description
    		 2 x 2.5 mg tablets taken daily orally for 12 months in addition to background therapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching dose tablet (0.5 mg or 2.5 mg) taken from each of 2 bottles daily for 12 months, in addition to background therapy.

    Reporting group values
    		 RO4602522 1 mg RO4602522 5mg Placebo Total
    Number of subjects
    		 179 180 181 540
    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)
    		 37 35 26 98
        From 65-84 years
    		 132 131 141 404
        85 years and over
    		 10 14 14 38
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.9 ± 9 72.5 ± 9.47 73.8 ± 8.26 -
    Gender categorical
    Units: Subjects
        Female
    		 111 123 104 338
        Male
    		 68 57 77 202

    End points

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    End points reporting groups
    Reporting group title
    RO4602522 1 mg
    Reporting group description
    		 2 x 0.5 mg tablets taken daily orally for 12 months in addition to background therapy.

    Reporting group title
    RO4602522 5mg
    Reporting group description
    		 2 x 2.5 mg tablets taken daily orally for 12 months in addition to background therapy.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching dose tablet (0.5 mg or 2.5 mg) taken from each of 2 bottles daily for 12 months, in addition to background therapy.

    Primary: Mean Change from Baseline in Alzheimer’s Disease Assessment Scale – Cognitive Behavior Subscale (ADAS-Cog-11)

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    End point title
    		 Mean Change from Baseline in Alzheimer’s Disease Assessment Scale – Cognitive Behavior Subscale (ADAS-Cog-11)
    End point description
    Analysis of Intent to Treat (ITT) population
    End point type
    Primary
    End point timeframe
    Baseline to 52 weeks
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    140
    142
    142
    Units: Number
        arithmetic mean (standard deviation)
    5.074 ± 7.7956
    5.979 ± 7.3505
    4.857 ± 7.6222
    Statistical analysis title
    		 RO4602522 1mg vs Placebo
    Comparison groups
    RO4602522 1 mg v Placebo
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.855
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.92
         upper limit
    		 1.59
    Statistical analysis title
    		 RO4602522 5mg vs Placebo
    Comparison groups
    RO4602522 5mg v Placebo
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.259
    Method
    		 Mixed models analysis
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 2.75

    Secondary: Mean Alzheimer’s Disease Cooperative Study Clinician Global Impression of Change (ADCS-CGIC) Score

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    End point title
    		 Mean Alzheimer’s Disease Cooperative Study Clinician Global Impression of Change (ADCS-CGIC) Score
    End point description
    Percentages are based on the number of patients in the intent to treat population with an assessment at each visit.
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    142
    147
    147
    Units: Percentage
    number (not applicable)
        Marked Improvement
    2.1
    0.7
    0
        Moderate Improvement
    0.7
    1.4
    2
        Minimal Improvement
    5.6
    4.8
    5.4
        No change
    24.6
    23.8
    21.8
        Minimal worsening
    32.4
    36.7
    34.7
        Moderate worsening
    29.6
    25.9
    30.6
        Marked worsening
    4.9
    6.8
    5.4
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline over Time in Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score

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    End point title
    		 Mean Change from Baseline over Time in Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score
    End point description
    Analysis of the Intent to Treat (ITT) population
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    142
    145
    145
    Units: Number
        arithmetic mean (standard deviation)
    -6 ± 12.14
    -6.8 ± 11.75
    -8.2 ± 10.95
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline over Time in Behavioral Pathology in Alzheimer’s Disease Frequency- Weighted Severity Scale (BEHAVE-AD-FW) Total Score

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    End point title
    		 Mean Change from Baseline over Time in Behavioral Pathology in Alzheimer’s Disease Frequency- Weighted Severity Scale (BEHAVE-AD-FW) Total Score
    End point description
    Analysis of the Intent to Treat (ITT) population
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    143
    148
    146
    Units: Number
        arithmetic mean (standard deviation)
    1.1 ± 8.09
    1.4 ± 10.1
    4.5 ± 11.65
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline over Time in Apathy Evaluation Scale (AES) Score

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    End point title
    		 Mean Change from Baseline over Time in Apathy Evaluation Scale (AES) Score
    End point description
    Analysis of the Intent to Treat (ITT) population
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    142
    148
    145
    Units: Number
        arithmetic mean (standard deviation)
    4.3 ± 8.92
    4.5 ± 9.77
    4.2 ± 9.6
    No statistical analyses for this end point

    Secondary: Percentage Change from Baseline over Time in Global Deterioration Scale (GDS) Score

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    End point title
    		 Percentage Change from Baseline over Time in Global Deterioration Scale (GDS) Score
    End point description
    Baseline is defined as the most recent value recorded prior to first dose of study medication. Percentages are based on the number of patients with a score at each visit and at Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to week 52
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    141
    145
    145
    Units: Percentage
    number (not applicable)
        Decrease of 3
    0
    0.7
    0
        Decrease of 2
    1.4
    0.7
    1.4
        Decrease of 1
    2.8
    2.8
    2.8
        No change
    61.7
    60
    63.4
        Increase of 1
    27
    31
    26.9
        Increase of 2
    7.1
    4.1
    5.5
        Increase of 3
    0
    0.7
    0
    No statistical analyses for this end point

    Secondary: Percentage of Patients Worsening over Time in Behavioral Pathology in Alzheimer’s Disease Frequency- Weighted Severity Scale (BEHAVE-AD-FW) Score

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    End point title
    		 Percentage of Patients Worsening over Time in Behavioral Pathology in Alzheimer’s Disease Frequency- Weighted Severity Scale (BEHAVE-AD-FW) Score
    End point description
    Analysis of Intent to Treat (ITT) population; BEHAVE-AD-FW worsening, defined as an increase of more than 20% in any domain, where the baseline score for the same domain was > 0 (across the 3 treatment groups, 2 patients did not have total score at baseline and 138 had a score of 0).
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    111
    111
    101
    Units: Percentage
        number (not applicable)
    44.1
    44.1
    54.5
    No statistical analyses for this end point

    Secondary: Percentage of Patients Worsening over Time in Alzheimer’s Disease Cooperative Study Clinician Global Impression of Change (ADCS-CGIC) Scores

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    End point title
    		 Percentage of Patients Worsening over Time in Alzheimer’s Disease Cooperative Study Clinician Global Impression of Change (ADCS-CGIC) Scores
    End point description
    Analysis of the Intent to Treat (ITT) population;Percentages were based on the number of patients in the intent-to-treat population with a rating at each visit. Worsened for ADCS-CGIC is defined as a rating of “Minimal Worsening,” “Moderate Worsening,” or “Marked Worsening.”
    End point type
    Secondary
    End point timeframe
    Baseline to 52 weeks
    End point values
    		 RO4602522 1 mg RO4602522 5mg Placebo
    Number of subjects analysed
    142
    147
    147
    Units: Percentage
        number (not applicable)
    66.9
    69.4
    70.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe was 52 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo Group
    Reporting group description
    		 -

    Reporting group title
    R04602522 1 mg Group
    Reporting group description
    		 -

    Reporting group title
    R04602522 5 mg
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo Group R04602522 1 mg Group R04602522 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 181 (12.71%)
    18 / 179 (10.06%)
    19 / 180 (10.56%)
         number of deaths (all causes)
    3
    3
    2
         number of deaths resulting from adverse events
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Metastatic squamous cell carcinoma
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Uterine cancer
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression Suicidal
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Suicide attempt
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 179 (0.00%)
    2 / 180 (1.11%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    2 / 180 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Brain contusion
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial Bones Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral Neck Fracture
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic Fracture
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Vitritis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Toxic nodular goitre
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Urinary Tract Infection
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 179 (1.68%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 181 (1.10%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 181 (0.55%)
    0 / 179 (0.00%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    0 / 180 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 181 (0.00%)
    1 / 179 (0.56%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 181 (0.00%)
    0 / 179 (0.00%)
    1 / 180 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Group R04602522 1 mg Group R04602522 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 181 (40.88%)
    77 / 179 (43.02%)
    75 / 180 (41.67%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 181 (6.08%)
    11 / 179 (6.15%)
    9 / 180 (5.00%)
         occurrences all number
    15
    13
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 181 (7.73%)
    14 / 179 (7.82%)
    12 / 180 (6.67%)
         occurrences all number
    24
    15
    16
    Eye disorders
    Cataract
         subjects affected / exposed
    17 / 181 (9.39%)
    11 / 179 (6.15%)
    13 / 180 (7.22%)
         occurrences all number
    19
    12
    16
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 181 (7.18%)
    11 / 179 (6.15%)
    16 / 180 (8.89%)
         occurrences all number
    19
    13
    21
    Vomiting
         subjects affected / exposed
    10 / 181 (5.52%)
    8 / 179 (4.47%)
    9 / 180 (5.00%)
         occurrences all number
    10
    10
    24
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 181 (4.42%)
    10 / 179 (5.59%)
    7 / 180 (3.89%)
         occurrences all number
    8
    11
    7
    Insomnia
         subjects affected / exposed
    4 / 181 (2.21%)
    7 / 179 (3.91%)
    9 / 180 (5.00%)
         occurrences all number
    4
    7
    9
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    13 / 181 (7.18%)
    13 / 179 (7.26%)
    12 / 180 (6.67%)
         occurrences all number
    16
    17
    13
    Nasopharyngitis
         subjects affected / exposed
    10 / 181 (5.52%)
    14 / 179 (7.82%)
    12 / 180 (6.67%)
         occurrences all number
    12
    15
    14
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 181 (3.31%)
    10 / 179 (5.59%)
    4 / 180 (2.22%)
         occurrences all number
    8
    11
    5
    Influenza
         subjects affected / exposed
    1 / 181 (0.55%)
    3 / 179 (1.68%)
    11 / 180 (6.11%)
         occurrences all number
    1
    3
    11

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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.
    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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