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    Clinical Trial Results:
    A Multicenter, Open-Label, Long-Term Safety Extension of Phase II Studies ABE4869g and ABE4955g in Patients with Mild to Moderate Alzheimer's Disease

    Summary
    EudraCT number
    		 2012-003242-33
    Trial protocol
    		 GB   DE   ES  
    Global end of trial date
    08 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Feb 2018
    First version publication date
    16 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GN28525
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01723826
    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
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, 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
    Final
    Date of interim/final analysis
    08 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess long-term safety and tolerability of crenezumab administered subcutaneously (SC) every 2 weeks (q2w) or intravenously (IV) every 4 weeks (q4w), in eligible subjects with Alzheimer’s disease who participated in Study ABE4869g or ABE4955g and had completed the Week 73 study visit, including brain magnetic resonance imaging (MRI).
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 26
    Country: Number of subjects enrolled
    Canada: 69
    Country: Number of subjects enrolled
    United States: 206
    Worldwide total number of subjects
    360
    EEA total number of subjects
    85
    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)
    53
    From 65 to 84 years
    306
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 360 subjects were enrolled at 83 sites across 6 countries.

    Pre-assignment
    Screening details
    		 Subjects who completed either Phase II Study NCT01343966 or NCT01397578 and had Mini-Mental State Examination (MMSE) score of 10 or more at the time of screening were included. A total of 360/396 subjects were enrolled and included in Safety-Evaluable Population (Assigned Treatment); 47 in Group A, 67 in Group B, 101 in Group C and 145 in Group D.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group A
    Arm description
    		 Subjects who received placebo subcutaneously (SC) on their parent study followed by Crenezumab (Cren) SC, then Cren intravenously (IV), on Study NCT01723826.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Matching placebo to crenezumab 300 milligrams (mg) subcutaneously (SC) every two weeks (q2w).

    Investigational medicinal product name
    Crenezumab IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were randomized to receive crenezumab 15 milligrams per kilogram (mg/kg) intravenously (IV) every four weeks (q4w).

    Investigational medicinal product name
    Crenezumab SC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were randomized to receive crenezumab 300 milligrams (mg) subcutaneously (SC) every two weeks (q2w). Following the implementation of Protocol amendment, all subjects were transferred into the intravenously (IV) dosing arm and received crenezumab 15 milligrams per kilogram (mg/kg) every four weeks (q4w), starting 2-4 weeks after the last SC dose.

    Arm title
    		 Group B
    Arm description
    		 Subjects who received placebo intravenously (IV) on their parent study followed by Crenezumab (Cren) IV on Study NCT01723826.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Matching placebo to crenezumab 15 milligrams per kilogram (mg/kg) intravenously (IV) every four weeks (q4w).

    Investigational medicinal product name
    Crenezumab IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were randomized to receive crenezumab 15 milligrams per kilogram (mg/kg) intravenously (IV) every four weeks (q4w).

    Arm title
    		 Group C
    Arm description
    		 Subjects who received Crenezumab (Cren) subcutaneously (SC) on their parent study followed by Cren SC, then Cren intravenously (IV), on Study NCT01723826.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crenezumab SC
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were randomized to receive crenezumab 300 milligrams (mg) subcutaneously (SC) every two weeks (q2w). Following the implementation of Protocol amendment, all subjects were transferred into the intravenously (IV) dosing arm and received crenezumab 15 milligrams per kilogram (mg/kg) every four weeks (q4w), starting 2-4 weeks after the last SC dose.

    Investigational medicinal product name
    Crenezumab IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were randomized to receive crenezumab 15 milligrams per kilogram (mg/kg) intravenously (IV) every four weeks (q4w).

    Arm title
    		 Group D
    Arm description
    		 Subjects who received Crenezumab (Cren) intravenously (IV) on their parent study followed by Cren IV on Study NCT01723826.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crenezumab IV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were randomized to receive crenezumab 15 milligrams per kilogram (mg/kg) intravenously (IV) every four weeks (q4w).

    Number of subjects in period 1
    		Group A Group B Group C Group D
    Started
    47
    67
    101
    145
    Completed
    20
    28
    44
    58
    Not completed
    27
    39
    57
    87
         Physician decision
    1
    3
    4
    11
         Death
    -
    3
    2
    2
         Adverse event
    5
    1
    5
    6
         Non-compliance with study drug
    -
    1
    -
    -
         Non-compliance
    -
    1
    3
    3
         Lost to follow-up
    1
    3
    1
    1
         Reason not specified
    8
    8
    12
    14
         Protocol deviation
    1
    1
    3
    2
         Withdrawal by subject
    11
    18
    27
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects who received placebo subcutaneously (SC) on their parent study followed by Crenezumab (Cren) SC, then Cren intravenously (IV), on Study NCT01723826.

    Reporting group title
    Group B
    Reporting group description
    		 Subjects who received placebo intravenously (IV) on their parent study followed by Crenezumab (Cren) IV on Study NCT01723826.

    Reporting group title
    Group C
    Reporting group description
    		 Subjects who received Crenezumab (Cren) subcutaneously (SC) on their parent study followed by Cren SC, then Cren intravenously (IV), on Study NCT01723826.

    Reporting group title
    Group D
    Reporting group description
    		 Subjects who received Crenezumab (Cren) intravenously (IV) on their parent study followed by Cren IV on Study NCT01723826.

    Reporting group values
    		 Group A Group B Group C Group D Total
    Number of subjects
    		 47 67 101 145 360
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.9 ( 7.4 ) 71.9 ( 7.5 ) 72.3 ( 7.2 ) 72.2 ( 6.6 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 26 38 58 77 199
        Male
    		 21 29 43 68 161

    End points

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    End points reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 Subjects who received placebo subcutaneously (SC) on their parent study followed by Crenezumab (Cren) SC, then Cren intravenously (IV), on Study NCT01723826.

    Reporting group title
    Group B
    Reporting group description
    		 Subjects who received placebo intravenously (IV) on their parent study followed by Crenezumab (Cren) IV on Study NCT01723826.

    Reporting group title
    Group C
    Reporting group description
    		 Subjects who received Crenezumab (Cren) subcutaneously (SC) on their parent study followed by Cren SC, then Cren intravenously (IV), on Study NCT01723826.

    Reporting group title
    Group D
    Reporting group description
    		 Subjects who received Crenezumab (Cren) intravenously (IV) on their parent study followed by Cren IV on Study NCT01723826.

    Subject analysis set title
    PCP PL SC OLE CREN SC to IV
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject Analysis Set represents the population who received the treatment and were used for safety analysis. Here, PCP= Placebo-controlled portion; PL= Placebo; SC= Subcutaneous; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Subject analysis set title
    PCP PL IV OLE CREN IV
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject Analysis Set represents the population who received the treatment and were used for safety analysis. Here, PCP= Placebo-controlled portion; PL= Placebo; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Subject analysis set title
    PCP CREN SC OLE CREN SC to IV
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject Analysis Set represents the population who received the treatment and were used for safety analysis. Here, PCP= Placebo-controlled portion; PL= Placebo; SC= Subcutaneous; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Subject analysis set title
    PCP CREN IV OLE CREN IV
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subject Analysis Set represents the population who received the treatment and were used for safety analysis. Here, PCP= Placebo-controlled portion; PL= Placebo; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Primary: Percentage of Subjects with Adverse Events (AE)

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    End point title
    		 Percentage of Subjects with Adverse Events (AE) [1]
    End point description
    An AE was defined as any untoward medical occurrence in a subject administered a pharmaceutical product which does not necessarily have a causal relationship with the treatment. Safety Analysis population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 50 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Number of subjects analysed
    47
    63
    101
    149
    Units: percentage of subjects
        number (not applicable)
    89.4
    90.5
    96.0
    87.9
    No statistical analyses for this end point

    Primary: Percentage of Subjects by Nature of Adverse Events

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    End point title
    		 Percentage of Subjects by Nature of Adverse Events [2]
    End point description
    A serious adverse event is any AE that meets any of the following criteria: fatal, life threatening, requires or prolongs inpatient hospitalization, results in persistent or significant disability/incapacity, congenital anomaly/birth defect in a neonate/infant. Non-Serious Adverse events of special interest for this study include the following: cerebral vascular edema, Superficial siderosis of central nervous system, cerebral micro-hemorrhages or macro-hemorrhages, pneumonia, liver injury. Safety Analysis population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 50 months
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Number of subjects analysed
    47
    63
    101
    149
    Units: percentage of subjects
    number (not applicable)
        Serious Adverse Events (SAE)
    19.1
    22.2
    21.8
    23.5
        Non-Serious Adverse Events (Non-SAE)
    87.2
    88.9
    94.1
    87.2
    No statistical analyses for this end point

    Primary: Percentage of Subjects by Severity of Adverse Events

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    End point title
    		 Percentage of Subjects by Severity of Adverse Events [3]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 50 months
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Number of subjects analysed
    47
    63
    101
    149
    Units: percentage of subjects
    number (not applicable)
        Grade 1
    19.1
    34.9
    29.7
    22.1
        Grade 2
    44.7
    31.7
    43.6
    40.3
        Grade 3
    12.8
    17.5
    16.8
    19.5
        Grade 4
    8.5
    1.6
    3.0
    1.3
        Grade 5
    4.3
    4.8
    3.0
    4.7
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Human Anti-Therapeutic Antibody (ATA) Formation

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    End point title
    		 Percentage of Subjects with Human Anti-Therapeutic Antibody (ATA) Formation [4]
    End point description
    Anti-therapeutic antibodies (ATA), a measurement to explore the potential relationship of immunogenicity response with pharmacokinetics, safety and efficacy. Percentage of participants at post-baseline with positive results for ATA against crenezumab are reported. Safety Analysis population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Pre-dose (Day-14), predose at Week 25, 49, 97, Follow-up Week 8 (Week 153) and 12 (Week 157)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Number of subjects analysed
    47
    63
    101
    149
    Units: percentage of subjects
        number (not applicable)
    9.1
    3.4
    9.1
    0.7
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Amyloid-Related Imaging Abnormalities-Edema/Effusions (ARIA-E)

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    End point title
    		 Percentage of Subjects with Amyloid-Related Imaging Abnormalities-Edema/Effusions (ARIA-E) [5]
    End point description
    Alzheimer's disease (AD) is associated with amyloid-related imaging abnormalities (ARIA). The occurrence of imaging abnormalities believed to represent cerebral vasogenic edema, has been reported in association with the investigational use of compounds that are intended to treat Alzheimer’s disease by reducing Abeta in the brain. Here, the percentage of subjects with symptomatic and asymptomatic ARIA-E were reported. Safety Analysis population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 23, 47, 71, 97, 121 and 153
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Number of subjects analysed
    47
    63
    101
    149
    Units: percentage of subjects
    number (not applicable)
        Symptomatic
    0
    0
    0
    0
        Asymptomatic
    0
    0
    0
    0.7
    No statistical analyses for this end point

    Primary: Percentage of Subjects with Amyloid-Related Imaging Abnormalities-Hemorrhage (ARIA-H)

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    End point title
    		 Percentage of Subjects with Amyloid-Related Imaging Abnormalities-Hemorrhage (ARIA-H) [6]
    End point description
    Alzheimer's disease (AD) is associated with amyloid-related imaging abnormalities (ARIA). Cerebral micro-hemorrhages (microbleeds [MBs]) are radiologically defined as small dot-like foci of signal loss observed on MRI sequences sensitive for paramagnetic tissue properties. The occurrence of MBs has also been identified as an adverse event in anti-amyloid vaccination trials, and together with superficial siderosis, they have been termed “amyloid-related imaging abnormalities-hemorrhage (ARIA-H). Safety Analysis population included all subjects who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Weeks 23, 47, 71, 97, 121 and 153
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported.
    End point values
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Number of subjects analysed
    47
    63
    101
    149
    Units: percentage of subjects
    number (not applicable)
        Superficial Siderosis
    2.1
    0
    3.0
    0.7
        New Micro-hemorrhage
    6.4
    9.5
    4.0
    6.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 50 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    PCP PL SC OLE CREN SC to IV
    Reporting group description
    		 Subject Analysis Set represents the population who received the treatment and were used for all safety analyses. Here, PCP= Placebo-controlled portion; PL= Placebo; SC= Subcutaneous; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Reporting group title
    PCP PL IV OLE CREN IV
    Reporting group description
    		 Subject Analysis Set represents the population who received the treatment and were used for all safety analyses. Here, PCP= Placebo-controlled portion; PL= Placebo; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Reporting group title
    PCP CREN SC OLE CREN SC to IV
    Reporting group description
    		 Subject Analysis Set represents the population who received the treatment and were used for all safety analyses. Here, PCP= Placebo-controlled portion; PL= Placebo; SC= Subcutaneous; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Reporting group title
    PCP CREN IV OLE CREN IV
    Reporting group description
    		 Subject Analysis Set represents the population who received the treatment and were used for all safety analyses. Here, PCP= Placebo-controlled portion; PL= Placebo; OLE= Open-label extension; CREN= Crenezumab; IV= Intravenous.

    Serious adverse events
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 47 (19.15%)
    14 / 63 (22.22%)
    22 / 101 (21.78%)
    35 / 149 (23.49%)
         number of deaths (all causes)
    2
    3
    3
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal adenocarcinoma
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Metastatic neoplasm
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exsanguination
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hypertension
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    2 / 101 (1.98%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Gait disturbance
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 63 (1.59%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Disorientation
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    2 / 101 (1.98%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fracture displacement
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 63 (1.59%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Sinus tachycardia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Basilar artery stenosis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 63 (3.17%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Dementia alzheimer's type
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 63 (3.17%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 1
    Dementia with lewy bodies
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    2 / 101 (1.98%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    2 / 149 (1.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 63 (3.17%)
    3 / 101 (2.97%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    alternative dictionary used: MedDRA 20.0
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    2 / 101 (1.98%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    1 / 101 (0.99%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    2 / 101 (1.98%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 63 (1.59%)
    0 / 101 (0.00%)
    0 / 149 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Adult failure to thrive
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    1 / 149 (0.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dehydration
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 63 (0.00%)
    0 / 101 (0.00%)
    3 / 149 (2.01%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PCP PL SC OLE CREN SC to IV PCP PL IV OLE CREN IV PCP CREN SC OLE CREN SC to IV PCP CREN IV OLE CREN IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 47 (78.72%)
    51 / 63 (80.95%)
    80 / 101 (79.21%)
    97 / 149 (65.10%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 63 (1.59%)
    2 / 101 (1.98%)
    0 / 149 (0.00%)
         occurrences all number
    8
    1
    2
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 63 (3.17%)
    2 / 101 (1.98%)
    3 / 149 (2.01%)
         occurrences all number
    3
    2
    2
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 47 (4.26%)
    0 / 63 (0.00%)
    8 / 101 (7.92%)
    4 / 149 (2.68%)
         occurrences all number
    2
    0
    8
    4
    Injection site erythema
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 63 (1.59%)
    8 / 101 (7.92%)
    2 / 149 (1.34%)
         occurrences all number
    13
    1
    10
    2
    Injection site extravasation
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 63 (1.59%)
    3 / 101 (2.97%)
    4 / 149 (2.68%)
         occurrences all number
    5
    1
    7
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 47 (10.64%)
    3 / 63 (4.76%)
    8 / 101 (7.92%)
    11 / 149 (7.38%)
         occurrences all number
    11
    3
    9
    13
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    9 / 47 (19.15%)
    4 / 63 (6.35%)
    13 / 101 (12.87%)
    13 / 149 (8.72%)
         occurrences all number
    9
    4
    20
    14
    Anxiety
         subjects affected / exposed
    1 / 47 (2.13%)
    4 / 63 (6.35%)
    8 / 101 (7.92%)
    15 / 149 (10.07%)
         occurrences all number
    1
    4
    9
    16
    Depression
         subjects affected / exposed
    3 / 47 (6.38%)
    8 / 63 (12.70%)
    5 / 101 (4.95%)
    7 / 149 (4.70%)
         occurrences all number
    3
    9
    5
    7
    Insomnia
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 63 (1.59%)
    8 / 101 (7.92%)
    8 / 149 (5.37%)
         occurrences all number
    6
    1
    10
    9
    Delusion
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 63 (1.59%)
    7 / 101 (6.93%)
    4 / 149 (2.68%)
         occurrences all number
    3
    1
    7
    6
    Confusional state
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 63 (1.59%)
    3 / 101 (2.97%)
    3 / 149 (2.01%)
         occurrences all number
    3
    1
    4
    4
    Investigations
    Weight decreased
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 63 (3.17%)
    8 / 101 (7.92%)
    7 / 149 (4.70%)
         occurrences all number
    4
    2
    11
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    7 / 47 (14.89%)
    8 / 63 (12.70%)
    26 / 101 (25.74%)
    18 / 149 (12.08%)
         occurrences all number
    10
    11
    42
    28
    Laceration
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 63 (3.17%)
    10 / 101 (9.90%)
    7 / 149 (4.70%)
         occurrences all number
    3
    3
    11
    7
    Contusion
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 63 (3.17%)
    6 / 101 (5.94%)
    8 / 149 (5.37%)
         occurrences all number
    6
    2
    8
    10
    Skin abrasion
         subjects affected / exposed
    0 / 47 (0.00%)
    4 / 63 (6.35%)
    5 / 101 (4.95%)
    3 / 149 (2.01%)
         occurrences all number
    0
    4
    5
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 47 (4.26%)
    5 / 63 (7.94%)
    11 / 101 (10.89%)
    10 / 149 (6.71%)
         occurrences all number
    2
    5
    14
    11
    Cerebral microhaemorrhage
         subjects affected / exposed
    3 / 47 (6.38%)
    4 / 63 (6.35%)
    3 / 101 (2.97%)
    6 / 149 (4.03%)
         occurrences all number
    3
    5
    3
    7
    Headache
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 63 (3.17%)
    8 / 101 (7.92%)
    3 / 149 (2.01%)
         occurrences all number
    1
    2
    10
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 47 (12.77%)
    3 / 63 (4.76%)
    11 / 101 (10.89%)
    14 / 149 (9.40%)
         occurrences all number
    7
    3
    12
    23
    Vomiting
         subjects affected / exposed
    0 / 47 (0.00%)
    3 / 63 (4.76%)
    5 / 101 (4.95%)
    8 / 149 (5.37%)
         occurrences all number
    0
    5
    6
    11
    Constipation
         subjects affected / exposed
    0 / 47 (0.00%)
    4 / 63 (6.35%)
    3 / 101 (2.97%)
    5 / 149 (3.36%)
         occurrences all number
    0
    4
    3
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 47 (4.26%)
    5 / 63 (7.94%)
    2 / 101 (1.98%)
    6 / 149 (4.03%)
         occurrences all number
    7
    5
    2
    7
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 63 (0.00%)
    5 / 101 (4.95%)
    8 / 149 (5.37%)
         occurrences all number
    4
    0
    6
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 47 (4.26%)
    5 / 63 (7.94%)
    8 / 101 (7.92%)
    8 / 149 (5.37%)
         occurrences all number
    4
    6
    10
    10
    Back pain
         subjects affected / exposed
    3 / 47 (6.38%)
    4 / 63 (6.35%)
    7 / 101 (6.93%)
    8 / 149 (5.37%)
         occurrences all number
    3
    5
    7
    8
    Muscle spasms
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 63 (0.00%)
    4 / 101 (3.96%)
    1 / 149 (0.67%)
         occurrences all number
    3
    0
    6
    2
    Tendonitis
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 63 (3.17%)
    1 / 101 (0.99%)
    0 / 149 (0.00%)
         occurrences all number
    3
    2
    1
    0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 47 (14.89%)
    9 / 63 (14.29%)
    16 / 101 (15.84%)
    18 / 149 (12.08%)
         occurrences all number
    8
    13
    23
    34
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 47 (10.64%)
    11 / 63 (17.46%)
    10 / 101 (9.90%)
    13 / 149 (8.72%)
         occurrences all number
    7
    14
    11
    13
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 47 (12.77%)
    5 / 63 (7.94%)
    15 / 101 (14.85%)
    13 / 149 (8.72%)
         occurrences all number
    7
    5
    20
    15
    Bronchitis
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 63 (3.17%)
    4 / 101 (3.96%)
    9 / 149 (6.04%)
         occurrences all number
    2
    2
    5
    9

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Aug 2012
    1. Language was added to ensure subjects were followed for at least 90 days from their last dose of study drug, if they discontinue prematurely. 2. The Week 2 visit was removed in order to decrease visit burden for subjects and caregivers. 3. A baseline Columbia Suicide Severity Rating Scale (C-SSRS) measurement was added at Day 1.
    23 Aug 2013
    1. Included and excluded concomitant medications at screening and throughout the duration of the study were clarified. 2. Mini-Mental State Examination (MMSE) score required at enrollment was modified from greater than equal to 12 to greater than equal to 10. 3. Additional details regarding calculation and administration of the IV dose were provided.
    19 Aug 2014
    1. Clinical study information on the closed studies NCT01397578 and NCT01343966 was provided. 2. Human clinical pharmacology and immunogenicity information was updated. 3. The SC dosing regimen was eliminated. Subjects previously receiving crenezumab 300 mg SC q2w now received crenezumab 15 mg/kg IV q4w, starting 2-4 weeks after the last SC dose. 4. An additional protocol-defined adverse event of special interest (AESI) was added to comply with internal Roche/Genentech pharmacovigilance policy, in line with Module VI of Guideline on good pharmacovigilance practices: suspected transmission of an infectious agent by the study drug, suggestive of a quality defect, with contamination of the concerned medicinal product. 5. An additional protocol-defined AESI was added to comply with internal Roche/Genentech pharmacovigilance policy to monitor for Hy’s Law deviations of liver function. 6. An additional protocol-defined AESI for pneumonia was added. 7. Subjects were allowed to switch from a marketed treatment for Alzheimer’s disease to a treatment at an equivalent dose if the marketed treatment for Alzheimer’s disease is no longer available, either commercially or through the subject’s insurance formulary. 8. Clarification was added for reporting persistent or recurrent adverse events.
    28 Aug 2014
    1. Visit at Weeks 23, 47, 71, and 93 that were inadvertently omitted from the Protocol’s Study Flowcharts were included.
    22 Nov 2014
    1. Clinical pharmacokinetics (PK) assessments were updated to include an elimination half-life estimate based on a population PK analysis of pooled PK data. 2. Based on the updated crenezumab half-life of 24.6 days, and updated Roche safety reporting policy, adverse events and pregnancy reporting periods were changed from 90 days to 8 weeks. It was also clarified that male subjects with partners with reproductive potential should use contraception for at least 8 weeks after the last dose of study drug. 3. The two safety follow-up visits have been consolidated into one safety follow-up visit occurring 8 weeks after the last administration of study drug. This change was made based on the safety profile to date of crenezumab and the above-mentioned updated Roche safety reporting policy. 4. The Open-Label Extension (OLE) treatment period was expanded by 52 weeks. Subjects could receive 13 additional doses (at Weeks 97, 101, 105, 109, 113, 117, 121, 125, 129, 133, 137, 141, and 145). For subjects who entered this additional OLE treatment period, safety follow-up visits occurred at Week 153. Subjects who had already discontinued treatment (either because of early treatment discontinuation or because they have already had their Week 93 dosing visit) could enter the additional OLE treatment period if they had not discontinued treatment for safety reasons. Subjects who have completed Study GN28525 or discontinued from Study GN28525 were not eligible to receive additional treatment. 5. Because the feeder studies NCT01343966 and NCT01397578 were completed and unblinded, it was specified that the Internal Safety Monitoring Committee would be disbanded, and periodic review of safety data would be conducted by the Sponsor project team.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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