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    Clinical Trial Results:
    Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Two Year Study to Evaluate the Effect of Subcutaneous RO4909832 on Cognition and Function in Prodromal Alzheimer's Disease and Up to Three Years of an Open-Label Extension with Active Study Treatment

    Summary
    EudraCT number
    2010-019895-66
    Trial protocol
    GB   SE   DE   IT   ES   FI   NL   DK   CZ   BE   PT  
    Global end of trial date

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Jul 2016
    First version publication date
    15 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    WN25203
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01224106
    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 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann La Roche AG, +41 61 6878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    22 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2015
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the effect of gantenerumab versus placebo on the change in the Clinical Dementia Rating scale Sum of Boxes (CDR-SOB), and the change in an integrated global measure of cognition and functional ability after 2 years of treatment.
    Protection of trial subjects
    The Investigator ensured that this study is conducted in full conformance with the principles of the “Declaration of Helsinki” or with the laws and regulations of the country in which the research was conducted, whichever affords the greater protection to the participant. The study fully adhered to the principles outlined in “Guideline for Good Clinical Practice” International Council on Harmonisation (ICH) Tripartite Guideline or with local law if it afforded greater protection to the participant. For studies conducted in the European Union (EU)/European Economic Area (EEA) countries, the Investigator ensured compliance with the EU Clinical Trial Directive [2001/20/EC]. For studies conducted in the United States of America (USA) or under United States Investigational New Drug (USIND), the Investigator additionally ensured adherence to the basic principles of “Good Clinical Practice” as outlined in the current version of 21 Code of Federal Regulations, subchapter D, part 312, “Responsibilities of Sponsors and Investigators”, part 50, “Protection of Human Subjects”, and part 56, “Institutional Review Boards”.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 Nov 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 33
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 101
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    United Kingdom: 57
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 51
    Country: Number of subjects enrolled
    Germany: 55
    Country: Number of subjects enrolled
    Italy: 55
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Canada: 58
    Country: Number of subjects enrolled
    United States: 112
    Country: Number of subjects enrolled
    Argentina: 36
    Country: Number of subjects enrolled
    Australia: 49
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Mexico: 47
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 17
    Country: Number of subjects enrolled
    Turkey: 20
    Worldwide total number of subjects
    797
    EEA total number of subjects
    418
    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)
    162
    From 65 to 84 years
    627
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The screening period was up to 8 weeks. The study consisted of 3 parts. Parts 1 and 2 were terminated. Part 3 is currently ongoing as an open-label extension (OLE) with progressive uptitration to higher doses of active study drug.

    Period 1
    Period 1 title
    Treatment Period (Part 1 and 2) (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
    Placebo (Parts 1 and 2)
    Arm description
    Participants with Alzheimer's disease received placebo by subcutaneous (SC) injection every 4 weeks (q4w) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab matching placebo SC injection q4w.

    Arm title
    Gantenerumab 105 mg (Parts 1 and 2)
    Arm description
    Participants with Alzheimer's disease received gantenerumab 105 milligrams (mg) by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    RO4909832
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab SC injection q4w.

    Arm title
    Gantenerumab 225 mg (Parts 1 and 2)
    Arm description
    Participants with Alzheimer's disease received gantenerumab 225 mg by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Gantenerumab
    Investigational medicinal product code
    RO4909832
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Participants received gantenerumab SC injection q4w.

    Number of subjects in period 1
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Started
    266
    271
    260
    Completed
    187
    185
    180
    Not completed
    79
    86
    80
         Death
    3
    -
    -
         Physician decision
    6
    5
    4
         Adverse event
    -
    5
    3
         Unspecified
    -
    -
    1
         Subject/legal guardian decision
    7
    8
    8
         Sponsor decision to terminate study
    62
    68
    63
         Lost to follow-up
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received placebo by subcutaneous (SC) injection every 4 weeks (q4w) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 105 mg (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received gantenerumab 105 milligrams (mg) by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 225 mg (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received gantenerumab 225 mg by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Total
    Number of subjects
    266 271 260 797
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.5 ± 7.5 70.3 ± 7 71.3 ± 7.1 -
    Gender categorical
    Units: Subjects
        Female
    149 152 152 453
        Male
    117 119 108 344

    End points

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    End points reporting groups
    Reporting group title
    Placebo (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received placebo by subcutaneous (SC) injection every 4 weeks (q4w) for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 105 mg (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received gantenerumab 105 milligrams (mg) by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 225 mg (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received gantenerumab 225 mg by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Subject analysis set title
    Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants receiving placebo matching gantenurumab 225 mg were included in this analysis set.

    Primary: Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 104

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    End point title
    Mean Change From Baseline in Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) Total Score at Week 104
    End point description
    The CDR-SOB is a global clinical staging instrument that sums 6 clinical ratings: 1) memory, 2) orientation, 3) judgment and problem solving, 4) involvement in community affairs, 5) home and hobbies, and 6) personal care based on the CDR interview. CDR included discussions with the participant and caregiver using a structured format. This scale was administered by a trained and certified global rater who did not have access to any information regarding adverse events experienced by the participant. Total CDR-SOB score is calculated as the sum of the six clinical ratings. The CDR-SOB score range for each domain is 0 to 3. CDR-SOB total score range is 0 (least impairment) to 18 (most impairment); a negative change from baseline indicates an improvement. The intent-to-treat (ITT) population included all participants who had received any dose of study treatment and had at least one post-baseline assessment of CDR-SOB. Number of subjects analyzed included number of participants evaluable.
    End point type
    Primary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    104
    105
    100
    Units: units on a scale
        arithmetic mean (standard deviation)
    1.19 ± 1.68
    1.41 ± 2.02
    1.47 ± 1.89
    Statistical analysis title
    Statistical analysis I
    Statistical analysis description
    Distribution of effect size was calculated based on mixed model repeated measure analysis.
    Comparison groups
    Gantenerumab 105 mg (Parts 1 and 2) v Placebo (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6744
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    -0.044
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.248
         upper limit
    0.161
    Statistical analysis title
    Statistical analysis II
    Statistical analysis description
    Distribution of effect size was calculated based on mixed model repeated measure analysis.
    Comparison groups
    Gantenerumab 225 mg (Parts 1 and 2) v Placebo (Parts 1 and 2)
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4494
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    -0.085
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.304
         upper limit
    0.135

    Secondary: Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 104

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    End point title
    Mean Change From Baseline in Alzheimer Disease Assessment Scale-Cognitive Subscale 11 (ADAS-Cog-11) Scores at Week 104
    End point description
    ADAS-Cog scale evaluates memory, language, and praxis with items such as orientation, word recall, word recognition, object identification, comprehension, and the completion of simple tasks. Analysis of the ADAS-Cog for this study was based upon 11 items: 1) word recall task, 2) naming objects and fingers, 3) following commands, 4) constructional praxis, 5) ideational praxis, 6) orientation, 7) word recognition, 8) remembering test instructions, 9) spoken language ability, 10) word finding difficulty in spontaneous speech, and 11) comprehension. This scale had to be administered by a trained and certified psychometric rater who did not have access to any information regarding adverse events experienced. The ADAS-Cog/11 ranged from 0 to 70 points, with higher scores indicating a greater degree of impairment. A negative change from baseline indicates a decrease in cognitive impairment. ITT population participants evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    105
    104
    100
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.68 ± 6.64
    3.52 ± 6.28
    3.97 ± 6.89
    Statistical analysis title
    Statistical analysis I
    Statistical analysis description
    Distribution of effect size based on mixed model repeated measures analysis.
    Comparison groups
    Gantenerumab 105 mg (Parts 1 and 2) v Placebo (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7458
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    0.035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.179
         upper limit
    0.25
    Statistical analysis title
    Statistical analysis II
    Statistical analysis description
    Distribution of effect size based on mixed model repeated measures analysis.
    Comparison groups
    Gantenerumab 225 mg (Parts 1 and 2) v Placebo (Parts 1 and 2)
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.723
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    0.042
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.191
         upper limit
    0.275

    Secondary: Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 104

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    End point title
    Mean Change From Baseline in Mini Mental State Exam (MMSE) Score at Week 104
    End point description
    The MMSE is a brief, practical screening test for cognitive dysfunction. The test consists of five sections (orientation, registration, attention-calculation, recall, and language); the total score can range from 0 to 30, with a higher score indicating better function. A positive change score indicates improvement. ITT population, number of subjects analyzed is equal to number of participants evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    104
    105
    99
    Units: units on a scale
        arithmetic mean (standard deviation)
    -2.31 ± 3.23
    -2.46 ± 3.68
    -2.25 ± 3.31
    Statistical analysis title
    Statistical analysis I
    Statistical analysis description
    Distribution of effect size based on mixed model repeated measures analysis
    Comparison groups
    Gantenerumab 105 mg (Parts 1 and 2) v Placebo (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7973
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    -0.028
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.242
         upper limit
    0.186
    Statistical analysis title
    Statistical analysis II
    Statistical analysis description
    Distribution of effect size based on mixed model repeated measures analysis
    Comparison groups
    Gantenerumab 225 mg (Parts 1 and 2) v Placebo (Parts 1 and 2)
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4793
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    0.084
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.15
         upper limit
    0.319

    Secondary: Mean Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Composite Score at Week 104

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    End point title
    Mean Change From Baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) Composite Score at Week 104
    End point description
    A composite memory score was created based on a summation of Z-scores (using the baseline population as the standardization distribution) for each of: 'z' Delayed Match to Sample (DMS) percent correct, 'z' Paired Associates Learning (PAL), 'z' First Trial Memory Score (FTMS), 'z' Pattern Recognition Memory (PRM) immediate percent correct, 'z' PRM delayed percent correct and 'z' Spatial Working Memory (SWM) between errors (where SWM between Errors is reverse scored). At subsequent time points, Z scores were calculated as [(time point score - baseline mean)/ baseline SD] (positive). ITT population, number of subjects analyzed is equal to number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    90
    87
    80
    73
    Units: units on a scale
        arithmetic mean (standard deviation)
    -1.72 ± 2.99
    -1.37 ± 2.74
    -1.4 ± 3.11
    -1.93 ± 3.08
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 104

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    End point title
    Mean Change from Baseline in Free and Cued Selective Reminding Test (FCSRT) Score at Week 104
    End point description
    FCSRT assesses verbal episodic memory. Performances in free recalls, cued recalls and in a recognition task were analyzed, as the process of encoding is controlled. Participants were asked to remember a list of 16 words. Three tasks of free and cued recalls, as well as 1 recognition task and one delayed recall give the scores. Total recall was obtained by the addition of cued recalls to free recalls. Maximum score is 48 for immediate: 16 words multiplied by (*) 3 corresponding to immediate free recall + immediate cued recall + immediate recognition test. Maximum score is 64 (better score) when delayed recall: 16 words*4. The minimum score is 0 (worse). ITT population, number of subjects analyzed is equal to number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    100
    102
    97
    79
    Units: units on a scale
        arithmetic mean (standard deviation)
    -4.05 ± 8.73
    -4.11 ± 8.57
    -6.42 ± 8.45
    -4.05 ± 8.68
    No statistical analyses for this end point

    Secondary: Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 104

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    End point title
    Mean Change From Baseline in Functional Activities Questionnaire (FAQ) Score at Week 104
    End point description
    Participants completed the FAQ for physical function. Overall scores ranged from 0 (independent) to 30 (dependent) where lower scores represented an improvement in physical function. ITT population, number of subjects analyzed is equal to number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    105
    104
    99
    84
    Units: units on a scale
        arithmetic mean (standard deviation)
    3.59 ± 4.93
    4.89 ± 6.2
    4.03 ± 5.75
    3.6 ± 4.93
    Statistical analysis title
    Statistical analysis I
    Statistical analysis description
    Distribution of effect size based on mixed model repeated measures analysis.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0825
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    -0.191
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.407
         upper limit
    0.025
    Statistical analysis title
    Statistical analysis II
    Statistical analysis description
    Distribution of effect size based on mixed model repeated measures analysis.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7171
    Method
    Mixed models analysis
    Parameter type
    effect size
    Point estimate
    0.043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.276

    Secondary: Mean Change From Baseline in CDR-Global Score at Week 104

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    End point title
    Mean Change From Baseline in CDR-Global Score at Week 104
    End point description
    Global CDR is derived from the scores in each of the 6 categories ("box scores") as follows. Memory (M) is considered the primary category and all others are secondary. CDR=M if at least 3 secondary categories are given the same score as M. Whenever 3 or more secondary categories are given a score greater or less than the memory score, CDR = score of majority of secondary categories on whichever side of M has the greater number of secondary categories. When 3 secondary categories are scored on one side of M and two secondary categories are scored on the other side of M, CDR=M. When M = 0.5, CDR = 1 if at least 3 of the other categories are scored one or greater. If M=0.5, CDR cannot be 0; it can only be 0.5 or 1. If M=0, CDR=0 unless there is impairment (0.5 or greater) in 2 or more secondary categories, in which case CDR=0.5. ITT population, number of subjects analyzed is equal to number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    104
    105
    100
    83
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.1 ± 0.29
    0.18 ± 0.36
    0.14 ± 0.33
    0.1 ± 0.31
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline in Neuropsychiatric Inventory (NPI) Questionnaire Score at Week 104

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    End point title
    Mean Change from Baseline in Neuropsychiatric Inventory (NPI) Questionnaire Score at Week 104
    End point description
    The NPI is a retrospective (to 1 month) caregiver-informant interview assessing frequency and severity of 12 neuropsychiatric symptom domains. The NPI score is based on the sum of the severity ratings (0=absent, 1=mild, 3=severe). The 12 symptom domains include delusions, hallucinations, agitation/aggression, dysphoria/depression, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behavioral disturbances, and appetite/eating abnormalities. The NPI severity score is based on severity ratings (0=absent, 1=mild to 3=severe). ITT population, number of subjects analyzed is equal to number of participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    103
    105
    99
    82
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.6 ± 3.22
    0.39 ± 2.57
    0.34 ± 2.84
    0.72 ± 3.35
    No statistical analyses for this end point

    Secondary: Percent Change from Baseline in Cerebrospinal Fluid Biomarkers (Phosphorylated-tau [p-tau], Amyloid Beta 1-42 [Abeta 1-42], Total tau [t-tau]) at Week 104

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    End point title
    Percent Change from Baseline in Cerebrospinal Fluid Biomarkers (Phosphorylated-tau [p-tau], Amyloid Beta 1-42 [Abeta 1-42], Total tau [t-tau]) at Week 104
    End point description
    CSF biomarker phospho-tau (p-tau) is an indicator of neuronal injury and neurodegeneration. An elevation in levels of tau, as well as specific p-tau species, is thought to be a marker for progressive cellular degeneration in AD. ITT population, number of subjects analyzed is equal to number of participants evaluable for this end point. "n" represents number of participants evaluable for the specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    263
    264
    254
    211
    Units: percent change
    arithmetic mean (standard deviation)
        p-tau (n=72,71,66,56)
    2.77 ± 20.69
    -4.78 ± 11.9
    -7.34 ± 10.09
    2.84 ± 23.19
        t-tau (n=72,71,66,56)
    3.43 ± 19.95
    -1.36 ± 12.89
    -2.12 ± 11.01
    3.46 ± 22.32
        Abeta (n=69,64,65,56)
    4.87 ± 36.14
    2.45 ± 24.57
    15.2 ± 45.24
    4.3 ± 39.31
    Statistical analysis title
    Statistical analysis I
    Statistical analysis description
    Statistical analysis of the Abeta 1-42 CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 105 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9734
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis II
    Statistical analysis description
    Statistical analysis of the Abeta 1-42 CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 225 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0629
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis III
    Statistical analysis description
    Statistical analysis of the p-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 105 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0084
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis IV
    Statistical analysis description
    Statistical analysis of the p-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 225 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis V
    Statistical analysis description
    Statistical analysis of the t-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 105 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 105 mg (Parts 1 and 2)
    Number of subjects included in analysis
    527
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0903
    Method
    Mixed models analysis
    Confidence interval
    Statistical analysis title
    Statistical analysis VI
    Statistical analysis description
    Statistical analysis of the t-tau CSF biomarker between "Placebo (Parts 1 and 2)" and "Gantenerumab 225 mg (Parts 1 and 2)" treatment arms at Week 104.
    Comparison groups
    Placebo (Parts 1 and 2) v Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects included in analysis
    517
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0434
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Percent Change from Baseline in Hippocampal Volume at Week 104

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    End point title
    Percent Change from Baseline in Hippocampal Volume at Week 104
    End point description
    Change from baseline in hippocampal right volume (HRV) and hippocampal left volume (HLV) were analyzed at Week 104 using magnetic resonance imaging. ITT population. Number of subjects analyzed is equal to number of participants evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 104
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    131
    124
    119
    107
    Units: percent change
    arithmetic mean (standard deviation)
        HRV
    -7.61 ± 4.03
    -7.52 ± 3.96
    -7.34 ± 3.84
    -7.7 ± 4.01
        HLV
    -7.8 ± 4.28
    -7.76 ± 3.74
    -7.27 ± 3.78
    -8.12 ± 4.19
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156

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    End point title
    Percent Change From Baseline in Cortical Composite Sustained Uptake Volume Ratio (SUVr) in Different Brain Regions at Week 156
    End point description
    The different regions of the brain that were analyzed included cerebellum gray, whole cerebellum, composite white matter, subcortical white matter, pons and composite reference. ITT population. Number of subjects analyzed is equal to number of participants evaluable for this end point.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 156
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2) Placebo Match Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    6
    4
    10
    4
    Units: percent change
    arithmetic mean (standard deviation)
        cerebellum gray
    6.26 ± 9.1
    2.7 ± 10.59
    -8.36 ± 9.11
    5.95 ± 11.13
        whole cerebellum
    5.41 ± 7.13
    2.07 ± 8.65
    -8.44 ± 8.06
    5.17 ± 8.66
        composite white matter
    2.75 ± 3.18
    -0.87 ± 2.95
    -4.86 ± 6.35
    3.07 ± 2.07
        subcortical white matter
    4.83 ± 4.95
    1.69 ± 4.45
    -0.42 ± 8.26
    4.59 ± 0.55
        pons
    1.72 ± 2.51
    -2.83 ± 3.39
    -6.99 ± 5.65
    2.1 ± 2.73
        composite reference
    4.5 ± 3.48
    1.19 ± 5.63
    -6.75 ± 6.1
    4.46 ± 4.49
    No statistical analyses for this end point

    Secondary: Gantenerumab Plasma Concentration at Different Time Points

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    End point title
    Gantenerumab Plasma Concentration at Different Time Points [1]
    End point description
    ITT population. Number of subjects analysed is equal to number of participants evaluable for this end point. "n" represents number of participants evaluable for the specified category.
    End point type
    Secondary
    End point timeframe
    Prior to injections at Weeks 1, 8, 20, 44, 53, 68, 100, 101
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is related to gantenerumab plasma concentration thus, placebo arm is not included.
    End point values
    Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    239
    227
    Units: micrograms per milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Week 1 (n=239,227)
    3.56 ± 2.36
    7.4 ± 4.28
        Week 8 (n=237,225)
    2.87 ± 1.84
    5.92 ± 3.16
        Week 20 (n=228,220)
    3.7 ± 2.15
    7.66 ± 4.14
        Week 44 (n=212,199)
    4.08 ± 2.44
    8.22 ± 4.51
        Week 53 (n=195,185)
    6.77 ± 3.94
    15 ± 9.34
        Week 68 (n=165,155)
    3.95 ± 2.35
    8.91 ± 4.86
        Week 100 (n=98,86)
    4.35 ± 2.34
    9.4 ± 4.69
        Week 101 (n=95,77)
    7.32 ± 3.53
    16.63 ± 7.96
    No statistical analyses for this end point

    Secondary: Time to Onset of Dementia

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    End point title
    Time to Onset of Dementia
    End point description
    Data for this endpoint is available only in figures and the same is uploaded as an attachment.
    End point type
    Secondary
    End point timeframe
    Every 6 months to up to 3 years (1096 days)
    End point values
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    Units: days
        number (not applicable)
    Attachments
    Time to onset of dementia
    Notes
    [2] - Data for this endpoint is available only in figure and the same is uploaded as an attachment.
    [3] - Data for this endpoint is available only in figure and the same is uploaded as an attachment.
    [4] - Data for this endpoint is available only in figure and the same is uploaded as an attachment.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 5 years (Until data cut-off date of 22 June 2015)
    Adverse event reporting additional description
    Safety evaluable population
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received placebo by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 105 mg (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received gantenerumab 105 mg by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Reporting group title
    Gantenerumab 225 mg (Parts 1 and 2)
    Reporting group description
    Participants with Alzheimer's disease received gantenerumab 225 mg by SC injection q4w for 104 weeks or approximately 2 years during Part 1 of the study. Participants who completed the Week 104 visit were given an option to continue the treatment received during Part 1 for 2 additional years in Part 2.

    Serious adverse events
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    55 / 266 (20.68%)
    48 / 271 (17.71%)
    46 / 260 (17.69%)
         number of deaths (all causes)
    6
    0
    2
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Malignant hypertension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Peripheral artery aneurysm
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Surgical and medical procedures
    Hip arthroplasty
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Spinal decompression
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Urethral dilation procedure
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Benign ovarian tumour
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Biliary cancer metastatic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Bladder cancer
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Bladder transitional cell carcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone sarcoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Breast cancer stage II
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal tract adenoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glioma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Intraductal proliferative breast lesion
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Lung cancer metastatic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal neoplasm benign
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Plasmacytoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    2 / 266 (0.75%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Renal oncocytoma
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Small cell carcinoma
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Tongue neoplasm malignant stage unspecified
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Type I hypersensitivity
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Malaise
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Agitation
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Behavioral and psychological symptoms of dementia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Confusional state
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Major depression
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Suicide attempt
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Cystocele
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Ovarian cyst
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Prostatomegaly
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Fall
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Head injury
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Hip fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Lower limb fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Meniscus injury
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematuria
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Radiation mucositis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Radius fracture
         subjects affected / exposed
    2 / 266 (0.75%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Spinal fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Acute myocardial infarction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Angina pectoris
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Angina unstable
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Atrial fibrillation
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Atrial thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac ventricular thrombosis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 266 (0.00%)
    2 / 271 (0.74%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 266 (0.75%)
    0 / 271 (0.00%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial rupture
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Sinus arrest
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    0 / 260 (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
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Delirium
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Pulmonary embolism
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Balance disorder
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Dementia with Lewy bodies
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Dizziness
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Partial seizures
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Radial nerve palsy
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retrograde amnesia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Seizure
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Syncope
         subjects affected / exposed
    2 / 266 (0.75%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thalamic infarction
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Transient global amnesia
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    2 / 260 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 266 (0.00%)
    2 / 271 (0.74%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Abdominal pain
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Diarrhoea
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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 haemorrhage
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Gastritis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Hiatus hernia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 266 (0.75%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatic mass
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Umbilical hernia
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Renal and urinary disorders
    Bladder obstruction
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Haematuria
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Cholelithiasis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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 reactive
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Osteoarthritis
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Spinal column stenosis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Endocrine disorders
    Diabetes insipidus
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Diabetes mellitus
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Abdominal abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Atypical pneumonia
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Bacterial sepsis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Cellulitis
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Cholecystitis infective
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 266 (0.00%)
    1 / 271 (0.37%)
    0 / 260 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         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 abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural infection bacterial
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Pneumonia
         subjects affected / exposed
    1 / 266 (0.38%)
    1 / 271 (0.37%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Sepsis
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Subcutaneous abscess
         subjects affected / exposed
    0 / 266 (0.00%)
    0 / 271 (0.00%)
    1 / 260 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 266 (0.38%)
    0 / 271 (0.00%)
    0 / 260 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (Parts 1 and 2) Gantenerumab 105 mg (Parts 1 and 2) Gantenerumab 225 mg (Parts 1 and 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    163 / 266 (61.28%)
    188 / 271 (69.37%)
    189 / 260 (72.69%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 266 (6.77%)
    11 / 271 (4.06%)
    20 / 260 (7.69%)
         occurrences all number
    20
    11
    23
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    28 / 266 (10.53%)
    23 / 271 (8.49%)
    27 / 260 (10.38%)
         occurrences all number
    42
    32
    38
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 266 (4.89%)
    11 / 271 (4.06%)
    13 / 260 (5.00%)
         occurrences all number
    14
    13
    13
    Nervous system disorders
    ARIA-E
         subjects affected / exposed
    2 / 266 (0.75%)
    18 / 271 (6.64%)
    34 / 260 (13.08%)
         occurrences all number
    2
    20
    36
    ARIA-H
         subjects affected / exposed
    31 / 266 (11.65%)
    58 / 271 (21.40%)
    36 / 260 (13.85%)
         occurrences all number
    51
    92
    64
    Dizziness
         subjects affected / exposed
    21 / 266 (7.89%)
    21 / 271 (7.75%)
    26 / 260 (10.00%)
         occurrences all number
    21
    27
    35
    Headache
         subjects affected / exposed
    36 / 266 (13.53%)
    34 / 271 (12.55%)
    25 / 260 (9.62%)
         occurrences all number
    50
    47
    36
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 266 (3.01%)
    7 / 271 (2.58%)
    15 / 260 (5.77%)
         occurrences all number
    8
    7
    20
    Injection site erythema
         subjects affected / exposed
    3 / 266 (1.13%)
    29 / 271 (10.70%)
    35 / 260 (13.46%)
         occurrences all number
    3
    133
    114
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    18 / 266 (6.77%)
    20 / 271 (7.38%)
    16 / 260 (6.15%)
         occurrences all number
    23
    20
    16
    Depression
         subjects affected / exposed
    13 / 266 (4.89%)
    23 / 271 (8.49%)
    25 / 260 (9.62%)
         occurrences all number
    14
    23
    25
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 266 (4.89%)
    15 / 271 (5.54%)
    15 / 260 (5.77%)
         occurrences all number
    18
    22
    18
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 266 (7.89%)
    12 / 271 (4.43%)
    16 / 260 (6.15%)
         occurrences all number
    29
    14
    17
    Back pain
         subjects affected / exposed
    26 / 266 (9.77%)
    16 / 271 (5.90%)
    26 / 260 (10.00%)
         occurrences all number
    33
    18
    31
    Musculoskeletal pain
         subjects affected / exposed
    16 / 266 (6.02%)
    6 / 271 (2.21%)
    5 / 260 (1.92%)
         occurrences all number
    18
    7
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    10 / 266 (3.76%)
    10 / 271 (3.69%)
    14 / 260 (5.38%)
         occurrences all number
    10
    12
    18
    Influenza
         subjects affected / exposed
    13 / 266 (4.89%)
    13 / 271 (4.80%)
    15 / 260 (5.77%)
         occurrences all number
    14
    18
    17
    Nasopharyngitis
         subjects affected / exposed
    17 / 266 (6.39%)
    30 / 271 (11.07%)
    20 / 260 (7.69%)
         occurrences all number
    34
    40
    35
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 266 (4.14%)
    13 / 271 (4.80%)
    18 / 260 (6.92%)
         occurrences all number
    14
    15
    21
    Urinary tract infection
         subjects affected / exposed
    25 / 266 (9.40%)
    16 / 271 (5.90%)
    22 / 260 (8.46%)
         occurrences all number
    37
    25
    38

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2011
    - An overall benefit-risk assessment subsection was added; information about the ribonucleic acid (RNA) sampling was added to the optional responsible conduct of research (RCR) sampling; age range for inclusion was changed from 50-85 to 50-80; text were added for contraception requirements for women of childbearing potential; and inclusion criteria were amended to allow for screening of participants with abnormal memory function based on the FCSRT-Immediate Recall (IR) up to one month prior to the first screening visit. - Experience at sites indicated that several participants fail screening solely for right bundle branch block (RBBB). As electrocardiogram (ECG) monitoring study was also used to collect data for this biological investigational drug in order to obtain regulatory waiver for a thorough QT study, the possibility to allow RBBB participants who may not be included in QTc analysis was reviewed again with the conclusion that RBBB participants can be enrolled. - One of the exclusion criteria was reformatted to more clearly quantify the amount of use permitted for some agents; information regarding the Columbia-Suicide Severity Rating Scale (C-SSRS) test was added; instructions were added to be followed in the event of a second occurrence of 2 new microbleeds on a single magnetic resonance imaging (MRI), and explanation of the procedures to be followed if a new microbleed is seen on an MRI. - Analysis plan was clarified to mention that analysis may include measurement of beta amyloid pyroglutamate and cerebrospinal fluid (CSF) biomarkers; and information regarding missed dose, and information regarding analysis and sample collection of anti-drug antibody (ADA) was added.
    14 Mar 2012
    - The sample size was updated; requirements for post-screening CDR global score and FCSRT-IR evaluations were added; requirements for separate interim data review committee or a separate group performing unblinded analysis were removed. - A negative pregnancy test requirement prior to start of treatment was extended for throughout the duration of treatment for women of child bearing potential. It was added that women of child-bearing potential must have a pregnancy test done at the site prior to each dose. - A paragraph requesting investigators to report increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) in combination with an increase in total bilirubin or jaundice as an serious adverse event (SAE) to the Sponsor due to regulatory reasons.
    15 Feb 2013
    - Information regarding two interim analysis, an administrative interim analysis and a subsequent futility analysis, was added; text regarding sensitivity analysis and subgroup analysis were added - The primary efficacy comparison of the high dose gantenerumab arm to the placebo arm was changed so that only placebo participants with APOE 0e4 or APOE 1e4 were to be included in the analysis, and not the ones with APOE 2e4. - Part 2 (extension) of the study was added; procedures to follow in the event of amyloid related imaging abnormalities-hemosiderin deposits (ARIA-H) findings and abnormal manetic resonance imaging (MRI) findings were updated to reflect extension of the study. - Information regarding the use of symptomatic treatment for Alzheimer's disease during the study was updated; frequency for testing of the primary endpoint (CDR) as well as the ADAS-cog and MMSE was updated to every 3 months through Year 4 from every 3 months through Year 2; details regarding availability of blinded interim safety data in the Investigator Brochure (IB) was added; and the information on possible analysis of concentration effect relationship using PK data was added.
    17 Jul 2014
    - Relevant protocol sections were updated to better align with the independent MRI Review Committee (MRI-C) Charter that was revised. Guidance was added with regard to the reset of MRI schedules after withheld and then restarted dosing due to MRI findings. - Requirements for a final follow-up visit for safety and limited efficacy evaluations at 52 weeks after the final dose. The reporting period for adverse events (AEs) was updated accordingly. - CSF biomarkers, Abeta1−42, t-tau, and p-tau, were changed to secondary objective from exploratory objectives. Clarification about MRI volumetric measures was also added. - Guidance was added for the shelf life of reconstituted investigational medicinal product (IMP) prepared under aseptic and non-aseptic conditions. - Reporting period for pregnancies was adjusted to take into account 5 half-lives of study medication, in agreement with the standard operating procedure (SOP) for safety report process of the Sponsor. Information regarding precautionary measures were added in the case of abnormally low neutrophils (moderate to severe neutropenia) to align WN25203 with other gantenerumab protocols.
    16 Sep 2015
    Based on the futility analysis findings, Part 1 and 2 of the study was terminated in December 2014. The OLE, Part 3 was added to test gantenerumab at higher doses expected to have a clinically relevant effect. Revised dosing titration schemes were imposed for the OLE to manage risks of ARIA. This amendment also provides updated safety assessments and updated formulation information.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    19 Dec 2014
    Based on the futility analysis findings, dosing in Part 1 and 2 of the study was terminated on 19 December 2014. However, due to the observed effect of gantenerumab on amyloid plaques, further higher doses than previously studied in Part 1 and 2 of are being explored in Part 3 to evaluate the potential benefit for gantenerumab to slow the progression of AD.
    16 Sep 2015

    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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