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    Clinical Trial Results:
    A Phase I/II Double-Blind, Randomized, Placebo-Controlled, Adaptive Design Study of the Safety, Tolerability, Immunogenicity, and Efficacy of ACI-24 in Patients with Mild to Moderate Alzheimer's Disease

    Summary
    EudraCT number
    2008-006257-40
    Trial protocol
    FI   SE   DK  
    Global end of trial date
    16 Oct 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ACI-24-0701
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    AC Immune SA
    Sponsor organisation address
    EPFL Innovation Park - Building B, Lausanne, Switzerland, 1015
    Public contact
    Clinical Project Manager, AC Immune SA, +41 213459121, clinicaltrials@acimmune.com
    Scientific contact
    Clinical Project Manager, AC Immune SA, +41 213459121, clinicaltrials@acimmune.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
    21 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall study objective was to assess the safety, immunogenicity, and efficacy of repeated doses of ACI-24 at 4 different dose levels administered to patients with mild to moderate Alzheimer’s disease (AD). The study was a 2-step seamless adaptive design study. Four doses were tested for safety and biological efficacy (Step 1). The most effective dose, assuming adequate safety, was intended to be expanded in Step 2 to obtain proof of concept in terms of cognitive efficacy. Step 2 was not performed.
    Protection of trial subjects
    Only patients able to give informed consent were enrolled and patients had to be cared by a reliable spouse or other live-in caregiver who gave written consent to assist with clinical assessments and reports safety issues. An interval of at least 1 week between first dose administration in the first 4 patients in each cohort enhanced safety. Furthermore, the dose-cohorts were studied in a sequential manner, each cohort had to complete 4 immunizations and safety data including data 2 weeks after the fourth injection (ie, at visit 8 [Week 14]) were reviewed by the Data Safety Monitoring Board (DSMB) before enrolment into the next cohort commenced. Note regarding long term Follow-up duration: The safety Follow-up period was reduced from 2 to 1 year for patients of Cohort 4 who received an additional boosting dose (dose 8) since no safety concerns were observed in Cohorts 1-3.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Jan 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
    Sweden: 21
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    Finland: 15
    Worldwide total number of subjects
    48
    EEA total number of subjects
    48
    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)
    16
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Patients were recruited at 5 sites in 3 countries (Denmark, Finland, and Sweden). Cohort 1 FPFV - LPLV: 18Jan2010 - 05Sep2013 Cohort 2 FPFV - LPLV: 19May2011 - 03Nov2014 Cohort 3 FPFV - LPLV: 02May2012 - 14Nov2016 Cohort 4 FPFV - LPLV: 19May2014 - 16Oct2018 (FPFV = First patient first visit, LPLV = Last patient last visit)

    Pre-assignment
    Screening details
    Informed consent was obtained before a patient started any study-related procedures. 65 patients were screened and 48 patients were randomized to active treatment or placebo.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor
    Blinding implementation details
    The study was blinded to patients and site personnel, except to unblinded clinical personnel administrating/preparing the IMP, to pharmacists and to the unblinded CRAs. In emergency circumstances where the investigator was to identify an urgent clinical need to know whether the patient was receiving active medication or placebo, the IVRS was to allow the immediate unblinding of the patient by the investigator directly. Immediate unblinding was not required during the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    9 patients were planned to receive 7 doses of ACI-24 at 10μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    ACI-24
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    7 doses of ACI-24 at 10μg at weeks 0, 4, 8, 12, 24, 36, and 48.

    Arm title
    Cohort 2
    Arm description
    9 patients were planned to receive 7 doses of ACI-24 at 100μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    ACI-24
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    7 doses of ACI-24 at 100μg at weeks 0, 4, 8, 12, 24, 36, and 48.

    Arm title
    Cohort 3
    Arm description
    9 patients of Cohort 3 were planned to receive 7 doses of ACI-24 at 300μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks Data of these Cohort 3 patients including the Treatment and Follow-up period is reported under Cohort 3. A boosting dose (dose 8) of ACI-24 at 300 µg was offered to Cohort 3 patients after the 100 weeks Follow-up period: - 3 patients received this boosting dose 2.5 to 3.25 years after the last injection received at week 48. Follow-up period after boosting dose: 24 weeks. Data of these Cohort 3 patients for the boosting procedure is reported under Cohort 3 Booster where applicable.
    Arm type
    Experimental

    Investigational medicinal product name
    ACI-24
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    7 doses of ACI-24 at 300μg at weeks 0, 4, 8, 12, 24, 36, and 48 and one boosting dose (dose 8) of ACI-24 at 300 µg 2.5 to 3.25 years after the last injection received at week 48 (if applicable).

    Arm title
    Cohort 4
    Arm description
    9 patients of Cohort 4 were planned to receive 7 doses of ACI-24 at 1000μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period (7 doses): 52 weeks Follow-up period (7 doses): 100 weeks A boosting dose (dose 8) of ACI-24 at 1000μg at week 74 was offered to these patients: - 3 patients did not receive this boosting dose (2 patients did not give consent and treatment was discontinued in another patient after dose 6) and had Follow-up visits from week 64 to 152. These 3 patients plus the 9 patients until week 52 are reported under Cohort 4 (before/without Booster) where applicable. - 6 patients received this boosting dose and followed a different visit schedule from week 52. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of these patients from week 52 until study end is reported under Cohort 4 Booster where applicable. - Compiled data of Cohort 4 (before/without Booster) and Cohort 4 Booster is reported together under reporting group Cohort 4
    Arm type
    Experimental

    Investigational medicinal product name
    ACI-24
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    7 doses of ACI-24 at 1000μg at weeks 0, 4, 8, 12, 24, 36, and 48 and one boosting dose (dose 8) of ACI-24 at 1000μg at week 74 (if applicable). In Cohort 4, 2 concomitant injections were administered due to the higher volume of IMP needed.

    Arm title
    Placebo
    Arm description
    The placebo patients of the 4 dose-cohorts (3 placebo patients per dose-cohort) are pooled to represent one group (a total of 12 placebo patients). Placebo patients followed the same visit/administration schedule as the corresponding actively treated patients in the same dose-cohort: Cohort 1, 2, 3, and 4: 3 patients per dose-cohort were planned to receive 7 doses of placebo at weeks 0, 4, 8, 12, 24, 36, and 48. A boosting dose (dose 8) of placebo was offered to patients in Cohorts 3 and 4: - In Cohort 3, 1 patient received this boosting dose of placebo 3 years after the last injection of week 48. Data of this patient from the boosting procedure is reported under Placebo in Cohort 3 Booster where applicable. - In Cohort 4, 1 patient received this boosting dose (dose 8) of placebo at week 74. Data of this patient from the boosting procedure is reported under Placebo in Cohort 4 Booster where applicable.
    Arm type
    Placebo

    Investigational medicinal product name
    Phosphate buffered saline (PBS)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The volume of PBS administered to placebo patients was equivalent to the volume of ACI-24 administered to actively treated patients in each dose-cohort. In Cohort 4, 2 concomitant injections were administered due to the higher volume of IMP needed. Placebo patients followed the same visit/administration schedule as the corresponding actively treated patients in the same dose-cohort.

    Number of subjects in period 1
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Placebo
    Started
    9
    9
    9
    9
    12
    Completed
    8
    8
    6
    8
    9
    Not completed
    1
    1
    3
    1
    3
         Death
    -
    1
    -
    -
    1
         Other
    1
    -
    1
    -
    1
         Consent withdrawn
    -
    -
    2
    -
    1
         Adverse event
    -
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    9 patients were planned to receive 7 doses of ACI-24 at 10μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks

    Reporting group title
    Cohort 2
    Reporting group description
    9 patients were planned to receive 7 doses of ACI-24 at 100μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks

    Reporting group title
    Cohort 3
    Reporting group description
    9 patients of Cohort 3 were planned to receive 7 doses of ACI-24 at 300μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks Data of these Cohort 3 patients including the Treatment and Follow-up period is reported under Cohort 3. A boosting dose (dose 8) of ACI-24 at 300 µg was offered to Cohort 3 patients after the 100 weeks Follow-up period: - 3 patients received this boosting dose 2.5 to 3.25 years after the last injection received at week 48. Follow-up period after boosting dose: 24 weeks. Data of these Cohort 3 patients for the boosting procedure is reported under Cohort 3 Booster where applicable.

    Reporting group title
    Cohort 4
    Reporting group description
    9 patients of Cohort 4 were planned to receive 7 doses of ACI-24 at 1000μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period (7 doses): 52 weeks Follow-up period (7 doses): 100 weeks A boosting dose (dose 8) of ACI-24 at 1000μg at week 74 was offered to these patients: - 3 patients did not receive this boosting dose (2 patients did not give consent and treatment was discontinued in another patient after dose 6) and had Follow-up visits from week 64 to 152. These 3 patients plus the 9 patients until week 52 are reported under Cohort 4 (before/without Booster) where applicable. - 6 patients received this boosting dose and followed a different visit schedule from week 52. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of these patients from week 52 until study end is reported under Cohort 4 Booster where applicable. - Compiled data of Cohort 4 (before/without Booster) and Cohort 4 Booster is reported together under reporting group Cohort 4

    Reporting group title
    Placebo
    Reporting group description
    The placebo patients of the 4 dose-cohorts (3 placebo patients per dose-cohort) are pooled to represent one group (a total of 12 placebo patients). Placebo patients followed the same visit/administration schedule as the corresponding actively treated patients in the same dose-cohort: Cohort 1, 2, 3, and 4: 3 patients per dose-cohort were planned to receive 7 doses of placebo at weeks 0, 4, 8, 12, 24, 36, and 48. A boosting dose (dose 8) of placebo was offered to patients in Cohorts 3 and 4: - In Cohort 3, 1 patient received this boosting dose of placebo 3 years after the last injection of week 48. Data of this patient from the boosting procedure is reported under Placebo in Cohort 3 Booster where applicable. - In Cohort 4, 1 patient received this boosting dose (dose 8) of placebo at week 74. Data of this patient from the boosting procedure is reported under Placebo in Cohort 4 Booster where applicable.

    Reporting group values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Placebo Total
    Number of subjects
    9 9 9 9 12 48
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    3 5 1 5 2 16
        From 65-84 years
    6 4 8 4 10 32
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.4 ± 8.7 65.2 ± 8.3 71.1 ± 4.9 62.2 ± 8.5 69.1 ± 4.8 -
    Gender categorical
    Units: Subjects
        Female
    5 4 6 3 5 23
        Male
    4 5 3 6 7 25
    Race
    Units: Subjects
        Hispanic or Latino
    1 0 0 0 0 1
        White
    8 9 9 9 12 47

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    9 patients were planned to receive 7 doses of ACI-24 at 10μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks

    Reporting group title
    Cohort 2
    Reporting group description
    9 patients were planned to receive 7 doses of ACI-24 at 100μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks

    Reporting group title
    Cohort 3
    Reporting group description
    9 patients of Cohort 3 were planned to receive 7 doses of ACI-24 at 300μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period: 52 weeks Follow-up period: 100 weeks Data of these Cohort 3 patients including the Treatment and Follow-up period is reported under Cohort 3. A boosting dose (dose 8) of ACI-24 at 300 µg was offered to Cohort 3 patients after the 100 weeks Follow-up period: - 3 patients received this boosting dose 2.5 to 3.25 years after the last injection received at week 48. Follow-up period after boosting dose: 24 weeks. Data of these Cohort 3 patients for the boosting procedure is reported under Cohort 3 Booster where applicable.

    Reporting group title
    Cohort 4
    Reporting group description
    9 patients of Cohort 4 were planned to receive 7 doses of ACI-24 at 1000μg at weeks 0, 4, 8, 12, 24, 36, and 48. Treatment period (7 doses): 52 weeks Follow-up period (7 doses): 100 weeks A boosting dose (dose 8) of ACI-24 at 1000μg at week 74 was offered to these patients: - 3 patients did not receive this boosting dose (2 patients did not give consent and treatment was discontinued in another patient after dose 6) and had Follow-up visits from week 64 to 152. These 3 patients plus the 9 patients until week 52 are reported under Cohort 4 (before/without Booster) where applicable. - 6 patients received this boosting dose and followed a different visit schedule from week 52. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of these patients from week 52 until study end is reported under Cohort 4 Booster where applicable. - Compiled data of Cohort 4 (before/without Booster) and Cohort 4 Booster is reported together under reporting group Cohort 4

    Reporting group title
    Placebo
    Reporting group description
    The placebo patients of the 4 dose-cohorts (3 placebo patients per dose-cohort) are pooled to represent one group (a total of 12 placebo patients). Placebo patients followed the same visit/administration schedule as the corresponding actively treated patients in the same dose-cohort: Cohort 1, 2, 3, and 4: 3 patients per dose-cohort were planned to receive 7 doses of placebo at weeks 0, 4, 8, 12, 24, 36, and 48. A boosting dose (dose 8) of placebo was offered to patients in Cohorts 3 and 4: - In Cohort 3, 1 patient received this boosting dose of placebo 3 years after the last injection of week 48. Data of this patient from the boosting procedure is reported under Placebo in Cohort 3 Booster where applicable. - In Cohort 4, 1 patient received this boosting dose (dose 8) of placebo at week 74. Data of this patient from the boosting procedure is reported under Placebo in Cohort 4 Booster where applicable.

    Subject analysis set title
    Cohort 3 Booster (Safety Analysis Set)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Cohort 3 Booster (Safety Analysis Set) (3 patients who received a boosting dose (dose 8) of ACI-24 at 300μg 2.5 to 3.25 years after the last injection of week 48). Safety events that occurred after booster injection are reported.

    Subject analysis set title
    Placebo in Cohort 3 Booster (Safety Analysis Set)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Placebo in Cohort 3 Booster (Safety Analysis Set) (1 patient who received a boosting dose (dose 8) of placebo 3 years after the last injection of week 48). Safety events that occurred after booster injection are reported.

    Subject analysis set title
    Cohort 4 Booster (Safety Analysis Set)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Cohort 4 Booster (Safety Analysis Set) (6 patients who received a boosting dose (dose 8) of ACI-24 at 1000 μg at week 74). These patients followed a different visit schedule from week 52 than Cohort 4 patients who did not receive a boosting dose. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of these patients from week 52 until study end is reported.

    Subject analysis set title
    Placebo in Cohort 4 Booster (Safety Analysis Set)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Placebo in Cohort 4 Booster (Safety Analysis Set) (1 patient who received a boosting dose (dose 8) of placebo at week 74. One patient of the other 2 patients did not consent for a boosting dose and the other patient died during the study). This patient followed a different visit schedule from week 52 than Cohort 4 patients who did not receive a boosting dose. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of this patient from week 52 until study end is reported.

    Subject analysis set title
    Cohort 4 Booster (Full Analysis Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Cohort 4 Booster (Safety Analysis Set) (6 patients who received a boosting dose (dose 8) of ACI-24 at 1000 μg at week 74). These patients followed a different visit schedule from week 52 than Cohort 4 patients who did not receive a boosting dose. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of these patients from week 52 until study end is reported.

    Subject analysis set title
    Cohort 4 (before/without Booster) (Full Analysis Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This reporting group comprises data of 9 patients of Cohort 4 until week 52 (9 patients who were planned to receive 7 doses of ACI-24 at 1000μg at weeks 0, 4, 8, 12, 24, 36, and 48) as well as data of 3 patients of Cohort 4 who did not receive a boosting dose who had additional Follow-up visit from week 64 to 152 (Follow-up period: 100 weeks). Of these 3 patients, 2 patients did not give consent for a boosting dose and treatment was discontinued in another patient after dose 6. Data of the other 6 patients (out of 9 patients) of Cohort 4 who received a boosting dose (dose 8) is not included in this reporting group. These patients followed a different visit schedule from week 52 and are reported under Cohort 4 Booster.

    Subject analysis set title
    Placebo in Cohort 4 Booster (Full Analysis Set)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo in Cohort 4 Booster (Safety Analysis Set) (1 patient who received a boosting dose (dose 8) of placebo at week 74. Of the other 2 patients, 1 patient did not consent for a boosting dose and the other patient died during the study). This patient followed a different visit schedule from week 52 than Cohort 4 patients who did not receive a boosting dose. Treatment period (8 doses): 76 weeks Follow-up period (8 doses): 50 weeks Data of this patient from week 52 until study end is reported.

    Primary: Overview of Adverse Events (Safety Analysis Set)

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    End point title
    Overview of Adverse Events (Safety Analysis Set) [1]
    End point description
    No hypothesis testing performed. Observations are given for the safety population (all randomized patients who received at least one dose of ACI-24 or placebo and who have at least one post-dosing safety assessment). Safety events that occurred during the Booster procedure in Cohort 3 are listed separately in the table. Categorical data are presented with the number of patients with at least one event for the following selections: - Treatment-emergent adverse events (TEAEs) - Deaths - Serious TEAEs - TEAEs leading to withdrawal of IMP - Severe and life threatening adverse events (AEs) - TEAEs possibly/probably related to IMP - Serious TEAEs possibly/probably related to IMP
    End point type
    Primary
    End point timeframe
    The safety reporting period was defined as the interval between the time of first dosing and the end of the designated Follow-up period. Adverse events falling into this time window were classified as treatment-emergent Adverse Events (TEAEs).
    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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Placebo Cohort 3 Booster (Safety Analysis Set) Placebo in Cohort 3 Booster (Safety Analysis Set)
    Number of subjects analysed
    9
    9
    9
    9
    12
    3
    1
    Units: Number of patients
        Treatment-emergent adverse events (TEAEs)
    8
    9
    9
    9
    12
    2
    1
        Deaths
    0
    1
    0
    1
    1
    0
    0
        Serious TEAEs
    2
    1
    0
    3
    4
    0
    0
        TEAEs leading to withdrawal of IMP
    0
    0
    0
    1
    0
    0
    0
        Severe and life threatening AEs
    1
    1
    0
    3
    3
    0
    0
        TEAEs possibly/probably related to IMP
    5
    4
    5
    8
    6
    0
    1
        Serious TEAEs possibly/probably related to IMP
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Global assessment of tolerability in Cohorts 1-4 and Placebo (Safety Analysis Set)

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    End point title
    Global assessment of tolerability in Cohorts 1-4 and Placebo (Safety Analysis Set) [2]
    End point description
    No hypothesis testing performed. Results are reported for the safety population (all randomized patients who received at least one dose of ACI-24 or placebo and who have at least one post-dosing safety assessment). Data for Cohorts 1-4 and Placebo until week 52 are reported in this table. Tolerability data are tabulated with descriptive statistics and counts. For each visit, the count of patients in the tolerability categories "very good", "good", and "moderate" are given. Tolerability was never assessed as "poor" and this category is therefore not listed. Note: The number of patients provided in the table ("number of subjects analysed") shows the number of patients planned to be analyzed. The actual number of patients analyzed per data point (week) is the sum of listed patients per data point (week). Data for patients of Cohort 3 and 4 who received dose 8 are reported in separate tables.
    End point type
    Primary
    End point timeframe
    Tolerability was assessed at weeks 2, 4, 6, 8, 10, 12, 14, 18, 24, 26, 30, 36, 38, 42, 48 & 52. In addition, Cohort 4 patients receiving dose 8 were assessed at weeks 74 & 76 and Cohort 3 patients receiving dose 8 at weeks 2, 4 & 12 after boosting dose.
    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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Placebo
    Number of subjects analysed
    9
    9
    9
    9
    12
    Units: Number of patients
        Week 2 – Very Good
    8
    8
    7
    5
    7
        Week 2 – Good
    1
    1
    2
    4
    5
        Week 2 – Moderate
    0
    0
    0
    0
    0
        Week 4 – Very Good
    9
    8
    7
    3
    9
        Week 4 – Good
    0
    1
    2
    6
    3
        Week 4 – Moderate
    0
    0
    0
    0
    0
        Week 6 – Very Good
    8
    9
    8
    5
    9
        Week 6 – Good
    1
    0
    1
    4
    3
        Week 6 – Moderate
    0
    0
    0
    0
    0
        Week 8 – Very Good
    8
    7
    7
    6
    8
        Week 8 – Good
    1
    2
    2
    3
    4
        Week 8 – Moderate
    0
    0
    0
    0
    0
        Week 10 – Very Good
    9
    6
    7
    2
    6
        Week 10 – Good
    0
    3
    1
    4
    5
        Week 10 – Moderate
    0
    0
    1
    0
    0
        Week 12 – Very Good
    9
    6
    7
    4
    8
        Week 12 – Good
    0
    3
    2
    5
    4
        Week 12 – Moderate
    0
    0
    0
    0
    0
        Week 14 – Very Good
    8
    6
    7
    4
    8
        Week 14 – Good
    1
    2
    1
    5
    3
        Week 14 – Moderate
    0
    1
    1
    0
    0
        Week 18 – Very Good
    7
    5
    6
    4
    5
        Week 18 – Good
    1
    2
    3
    5
    6
        Week 18 – Moderate
    1
    2
    0
    0
    0
        Week 24 – Very Good
    7
    7
    7
    4
    6
        Week 24 – Good
    2
    0
    2
    5
    5
        Week 24 – Moderate
    0
    2
    0
    0
    0
        Week 26 – Very Good
    4
    7
    8
    4
    6
        Week 26 – Good
    5
    0
    1
    5
    4
        Week 26 – Moderate
    0
    2
    0
    0
    1
        Week 30 – Very Good
    6
    7
    5
    4
    7
        Week 30 – Good
    3
    1
    2
    4
    4
        Week 30 – Moderate
    0
    1
    1
    1
    0
        Week 36 – Very Good
    4
    7
    5
    3
    3
        Week 36 – Good
    4
    1
    4
    5
    8
        Week 36 – Moderate
    1
    1
    0
    1
    0
        Week 38 – Very Good
    5
    6
    6
    3
    6
        Week 38 – Good
    4
    1
    3
    6
    4
        Week 38 – Moderate
    0
    2
    0
    0
    0
        Week 42 – Very Good
    6
    7
    5
    3
    4
        Week 42 – Good
    3
    1
    2
    6
    5
        Week 42 – Moderate
    0
    1
    1
    0
    0
        Week 48 – Very Good
    3
    6
    7
    1
    3
        Week 48 – Good
    6
    1
    2
    7
    7
        Week 48 – Moderate
    0
    2
    0
    0
    0
        Week 52 – Very Good
    4
    6
    8
    3
    3
        Week 52 – Good
    5
    3
    1
    6
    6
        Week 52 – Moderate
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Primary: Global assessment of tolerability in Cohort 3 Booster and Placebo in Cohort 3 Booster (Safety Analysis Set)

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    End point title
    Global assessment of tolerability in Cohort 3 Booster and Placebo in Cohort 3 Booster (Safety Analysis Set) [3]
    End point description
    Please refer to the description for the end point “Global assessment of tolerability in Cohorts 1-4 and Placebo (Safety Analysis Set)”.
    End point type
    Primary
    End point timeframe
    As stated above (end point “Global assessment of tolerability in Cohorts 1-4 and Placebo (Safety Analysis Set)”), tolerability in Cohort 3 Booster patients who received dose 8 (ACI-24 or placebo) was assessed at weeks 2, 4 & 12 after boosting dose.
    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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 3 Booster (Safety Analysis Set) Placebo in Cohort 3 Booster (Safety Analysis Set)
    Number of subjects analysed
    3
    1
    Units: Number of patients
        Week 2 – Very Good
    2
    0
        Week 2 – Good
    0
    0
        Week 2 – Moderate
    1
    1
        Week 4 – Very Good
    3
    0
        Week 4 – Good
    0
    1
        Week 4 – Moderate
    0
    0
        Week 12 – Very Good
    3
    0
        Week 12 – Good
    0
    1
        Week 12 – Moderate
    0
    0
    No statistical analyses for this end point

    Primary: Global assessment of tolerability in Cohort 4 Booster and Placebo in Cohort 4 Booster (Safety Analysis Set)

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    End point title
    Global assessment of tolerability in Cohort 4 Booster and Placebo in Cohort 4 Booster (Safety Analysis Set) [4]
    End point description
    Please refer to the description for the end point “Global assessment of tolerability in Cohorts 1-4 and Placebo (Safety Analysis Set)”.
    End point type
    Primary
    End point timeframe
    As stated above (end point “Global assessment of tolerability in Cohorts 1-4 and Placebo (Safety Analysis Set)”), tolerability in Cohort 4 patients who received dose 8 (ACI-24 or placebo) was assessed at weeks 74 & 76.
    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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 4 Booster (Safety Analysis Set) Placebo in Cohort 4 Booster (Safety Analysis Set)
    Number of subjects analysed
    6
    1
    Units: Number of patients
        Week 74 – Very Good
    2
    0
        Week 74 – Good
    3
    1
        Week 74 – Moderate
    0
    0
        Week 76 – Very Good
    2
    0
        Week 76 – Good
    4
    0
        Week 76 – Moderate
    0
    1
    No statistical analyses for this end point

    Primary: Descriptive measures of anti-Abeta1-42 IgG in serum: Responder analysis (Full Analysis Set)

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    End point title
    Descriptive measures of anti-Abeta1-42 IgG in serum: Responder analysis (Full Analysis Set) [5]
    End point description
    The Aβ1-42 IgG antibody response in serum was studied in patients at the prespecified timepoints of Week 26 and Week 52 by enzyme-linked immunosorbent assay (ELISA) detecting the free fraction of IgG response. A patient was defined as a responder if the antibody response at 26 and/or 52 weeks of treatment was at least doubled compared to the Baseline value of antibody response. The Baseline value was defined as the mean of the anti-Aβ1-42 IgG titer values at the Screening Visit (Week -4 to 0) and visit 1 (Week 0). Note: The number of patients provided in the table ("number of subjects analysed") shows the number of patients planned to be analyzed. Table does not allow entering the number of patients analyzed per data point (actual numbers are recorded below). Actual number of patients analyzed (n): - at Week 26: n = 9 (Cohort 1, Cohort 2, Cohort 3, Cohort 4), n = 11 (Placebo) - at Week 52: n = 9 (Cohort 1, Cohort 2, Cohort 4), n = 8 (Cohort 3, Placebo)
    End point type
    Primary
    End point timeframe
    End point was assessed at weeks 26 and 52 after first dose.
    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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Cohort 4 Placebo
    Number of subjects analysed
    9
    9
    9
    9
    12
    Units: Number of patients
        Week 26 – IgG Responder
    0
    0
    0
    0
    0
        Week 52 – IgG Responder
    0
    0
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Descriptive measures of brain Aβ levels assessed by Positron Emission Tomography (PET) in Cohorts 1-4 and Placebo (Full Analysis Set)

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    End point title
    Descriptive measures of brain Aβ levels assessed by Positron Emission Tomography (PET) in Cohorts 1-4 and Placebo (Full Analysis Set) [6]
    End point description
    The brain Aβ levels were quantified by Amyloid Positron Emission Tomography (PET) using Florbetaben as the PET tracer at 3 different time points (Baseline or Screening (weeks -4 or week 0) and 2 later timepoints (weeks 26 & 52 or weeks 52 & 76) depending on the cohort/patient). The change from Baseline in composite summary (CompSum) Standardized Uptake Value Ratio (SUVR) using the Mean Cerebellum Gray (MCG) as reference region is tabulated. Note: The number of patients provided in the table ("number of subjects analysed") shows the number of patients planned to be analyzed. Table does not allow entering the number of patients analyzed per data point (actual numbers are recorded below). Actual number of patients analyzed (n): - at Week 26: n = 9 (Cohort 2-3), n = 3 (Cohort 4), n = 7 (Placebo) - at Week 52: n = 9 (Cohort 2-3), n = 7 (Cohort 4), n = 8 (Placebo) Data of patients in Cohort 4 Booster is listed in a separate table. PET Imaging was not done in Cohort 1.
    End point type
    Secondary
    End point timeframe
    Cohorts 2-3 patients were planned to be scanned at weeks 0, 26 & 52. Patients 1-4 in Cohort 4 were planned to be scanned at weeks -4 (Screening), 26 & 52. Patients 5-12 in Cohort 4 were planned to be scanned at weeks -4 (Screening), 52 & 76.
    Notes
    [6] - 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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 2 Cohort 3 Placebo Cohort 4 (before/without Booster) (Full Analysis Set)
    Number of subjects analysed
    9
    9
    12
    9
    Units: Composite Summary SUVR (MCG)
    arithmetic mean (standard deviation)
        Change from Baseline (CompSum SUVR) – Week 26
    0.02 ± 0.21
    0.02 ± 0.19
    0.02 ± 0.28
    -0.10 ± 0.10
        Change from Baseline (CompSum SUVR) – Week 52
    0.08 ± 0.25
    -0.03 ± 0.22
    0.06 ± 0.22
    -0.07 ± 0.07
    No statistical analyses for this end point

    Secondary: Descriptive measures of brain Aβ levels assessed by Positron Emission Tomography (PET) in Cohort 4 Booster and Placebo in Cohort 4 Booster at Week 76 (Full Analysis Set)

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    End point title
    Descriptive measures of brain Aβ levels assessed by Positron Emission Tomography (PET) in Cohort 4 Booster and Placebo in Cohort 4 Booster at Week 76 (Full Analysis Set)
    End point description
    Please refer to the description for the end point "Descriptive measures of brain Aβ levels assessed by Positron Emission Tomography (PET) in Cohorts 1-4 and Placebo (Full Analysis Set)". Note: The number of patients in the table ("number of subjects analysed") shows the actual number of patients analyzed at week 76. As data for only 1 placebo patient is available, a standard deviation (SD) is not applicable. Since the table does not allow to enter "not applicable", a "0.0" was entered as SD for the placebo patient.
    End point type
    Secondary
    End point timeframe
    As stated above (end point "Descriptive measures of brain Aβ levels assessed by Positron Emission Tomography (PET) in Cohorts 1-4 and Placebo (Full Analysis Set)", Cohort 4 patients 5-12 were planned to be scanned at Week 76.
    End point values
    Cohort 4 Booster (Full Analysis Set) Placebo in Cohort 4 Booster (Full Analysis Set)
    Number of subjects analysed
    4
    1
    Units: Composite Summary SUVR (MCG)
    arithmetic mean (standard deviation)
        Change from Baseline (CompSum SUVR) – Week 76
    0.06 ± 0.11
    -0.17 ± 0.0
    No statistical analyses for this end point

    Secondary: Assessment of global function as measured by the Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) in Cohorts 1-4 and Placebo (Full Analysis Set)

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    End point title
    Assessment of global function as measured by the Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) in Cohorts 1-4 and Placebo (Full Analysis Set) [7]
    End point description
    The CDR was assessed in 6 categories: memory, orientation, judgement/problem solving, community affairs, home/hobbies, personal care. It is based on a semi-structured interview conducted with the patient and caregiver, by a rater without access to the results of the cognitive tests. Each category has scores from 0 (no symptoms) to 3 (severe), and the sum of these items (sum of boxes) may range from 0 to 18 points. An increase in the CDR - SB indicates a decline in functioning. The change from Baseline in CDR - SB is tabulated. Note: The number of patients provided in the table ("number of subjects analysed") shows the number of patients planned to be analyzed. Table does not allow entering the number of patients analyzed per data point, for the actual number of patients analyzed per data point refer to the attachment. Data for Cohort 4 Booster is presented in a separate table. Data for Cohort 3 Booster is not presented due to the small sample size.
    End point type
    Secondary
    End point timeframe
    The Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) was assessed at weeks 0, 26, 36, 52, 76, 100 & 152 (Cohorts 1-3 and 4 (before/without Booster)). Patients in Cohort 4 Booster were assessed at weeks 76, 87, 100 & 126.
    Notes
    [7] - 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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Placebo Cohort 4 (before/without Booster) (Full Analysis Set)
    Number of subjects analysed
    9
    9
    9
    12
    9
    Units: CDR – SB
    arithmetic mean (standard deviation)
        Change from Baseline (CDR-SB) – Week 26
    1.8 ± 1.7
    0.6 ± 1.5
    0.8 ± 1.3
    1.1 ± 1.3
    0.1 ± 0.5
        Change from Baseline (CDR-SB) – Week 36
    2.3 ± 1.6
    1.3 ± 2.7
    0.7 ± 0.8
    1.4 ± 2.4
    0.3 ± 0.8
        Change from Baseline (CDR-SB) – Week 52
    2.9 ± 2.0
    2.6 ± 3.6
    0.9 ± 1.7
    2.0 ± 2.9
    1.0 ± 1.0
        Change from Baseline (CDR-SB) – Week 76
    3.5 ± 3.0
    3.4 ± 4.2
    1.9 ± 1.8
    3.9 ± 4.3
    1.7 ± 0.8
        Change from Baseline (CDR-SB) – Week 100
    5.7 ± 2.5
    3.6 ± 3.9
    3.1 ± 2.5
    4.4 ± 4.7
    3.0 ± 2.1
        Change from Baseline (CDR-SB) – Week 152
    7.2 ± 3.5
    4.4 ± 2.9
    5.4 ± 4.0
    4.4 ± 3.7
    8.5 ± 0.0
    Attachments
    Attachment_CDR-Sum of boxes (FAS)
    No statistical analyses for this end point

    Secondary: Assessment of global function as measured by the Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) in Cohort 4 Booster and Placebo in Cohort 4 Booster (Full Analysis Set)

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    End point title
    Assessment of global function as measured by the Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) in Cohort 4 Booster and Placebo in Cohort 4 Booster (Full Analysis Set)
    End point description
    Please refer to the description for the end point "Assessment of global function as measured by the Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) in Cohorts 1-4 and Placebo (Full Analysis Set)". Note: As data for only 1 placebo patient is available, a standard deviation (SD) is not applicable. Since the table does not allow to enter "not applicable", a "0.0" was entered as SD for the placebo patient.
    End point type
    Secondary
    End point timeframe
    As stated above (end point "Assessment of global function as measured by the Clinical Dementia Rating (CDR) Scale - sum of boxes (SB) in Cohorts 1-4 and Placebo (Full Analysis Set)", patients in Cohort 4 Booster were assessed at weeks 76, 87, 100 & 126.
    End point values
    Cohort 4 Booster (Full Analysis Set) Placebo in Cohort 4 Booster (Full Analysis Set)
    Number of subjects analysed
    6
    1
    Units: CDR – SB
    arithmetic mean (standard deviation)
        Change from Baseline (CDR-SB) – Week 76
    1.0 ± 1.4
    5.0 ± 0.0
        Change from Baseline (CDR-SB) – Week 87
    1.1 ± 1.2
    4.0 ± 0.0
        Change from Baseline (CDR-SB) – Week 100
    1.4 ± 1.7
    6.0 ± 0.0
        Change from Baseline (CDR-SB) – Week 126
    3.1 ± 3.4
    7.0 ± 0.0
    No statistical analyses for this end point

    Secondary: Assessment of cognitive function as measured by Mini-Mental State Examination (MMSE) in Cohorts 1-4 and Placebo (Full Analysis Set)

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    End point title
    Assessment of cognitive function as measured by Mini-Mental State Examination (MMSE) in Cohorts 1-4 and Placebo (Full Analysis Set) [8]
    End point description
    The MMSE was performed to evaluate cognitive function, assessing memory, orientation, and praxis in a short series of tests. The score is from 0 to 30 with 30 being the best possible and 0 being the worst possible score. The change from Baseline in MMSE total scores is tabulated. Note: The number of patients provided in the table ("number of subjects analysed") shows the number of patients planned to be analyzed. Table does not allow entering the number of patients analyzed per data point, for the actual number of patients analyzed per data point refer to the attachment. Data for Cohort 4 Booster is presented in a separate table. Data for Cohort 3 Booster is not presented due to the small sample size.
    End point type
    Secondary
    End point timeframe
    The Mini-Mental State Examination (MMSE) was performed at weeks -4, 0, 26, 36, 52, 76, 100 & 152 (Cohorts 1-3 and 4 (before/without Booster)). Patients in Cohort 4 Booster were assessed at weeks 76, 87, 100 & 126.
    Notes
    [8] - 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: All data obtained in this study are listed and summarized with descriptive statistics or frequency tables where appropriate. No hypothesis testings have been performed as per the statistical analysis plan.
    End point values
    Cohort 1 Cohort 2 Cohort 3 Placebo Cohort 4 (before/without Booster) (Full Analysis Set)
    Number of subjects analysed
    9
    9
    9
    12
    9
    Units: MMSE total score
    arithmetic mean (standard deviation)
        Change from Baseline (MMSE total score) – Week 26
    -2.9 ± 2.0
    -2.1 ± 3.6
    -1.3 ± 1.2
    -1.3 ± 3.3
    0.8 ± 1.4
        Change from Baseline (MMSE total score) – Week 36
    -4.5 ± 3.4
    -2.0 ± 2.8
    -2.1 ± 1.9
    -1.5 ± 3.3
    0.8 ± 1.4
        Change from Baseline (MMSE total score) – Week 52
    -3.0 ± 4.4
    -2.9 ± 5.6
    -3.0 ± 3.3
    -2.9 ± 2.1
    0.2 ± 1.9
        Change from Baseline (MMSE total score) – Week 76
    -4.4 ± 4.3
    -3.9 ± 2.3
    -5.1 ± 3.4
    -4.4 ± 2.5
    -1.7 ± 2.9
        Change from Baseline (MMSE total score) – Week 100
    -6.4 ± 4.0
    -4.3 ± 2.3
    -5.9 ± 2.6
    -7.1 ± 3.8
    -2.5 ± 2.1
        Change from Baseline (MMSE total score) – Week 152
    -10.0 ± 4.7
    -8.5 ± 4.1
    -6.2 ± 4.2
    -9.1 ± 3.2
    -11 ± 0.0
    Attachments
    Attachment_MMSE (FAS)
    No statistical analyses for this end point

    Secondary: Assessment of cognitive function as measured by Mini-Mental State Examination (MMSE) in Cohort 4 Booster and Placebo in Cohort 4 Booster (Full Analysis Set)

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    End point title
    Assessment of cognitive function as measured by Mini-Mental State Examination (MMSE) in Cohort 4 Booster and Placebo in Cohort 4 Booster (Full Analysis Set)
    End point description
    Please refer to the description for the end point "Assessment of cognitive function as measured by Mini-Mental State Examination (MMSE) in Cohorts 1-4 and Placebo (Full Analysis Set)". Note: As data for only 1 placebo patient is available, a standard deviation (SD) is not applicable. Since the table does not allow to enter "not applicable", a "0.0" was entered as SD for the placebo patient.
    End point type
    Secondary
    End point timeframe
    As stated above (end point "Assessment of cognitive function as measured by Mini-Mental State Examination (MMSE) in Cohorts 1-4 and Placebo (Full Analysis Set)", patients in Cohort 4 Booster were assessed at weeks 76, 87, 100 & 126.
    End point values
    Cohort 4 Booster (Full Analysis Set) Placebo in Cohort 4 Booster (Full Analysis Set)
    Number of subjects analysed
    6
    1
    Units: MMSE total score
    arithmetic mean (standard deviation)
        Change from Baseline (MMSE total score) – Week 76
    -0.2 ± 1.9
    -2.0 ± 0.0
        Change from Baseline (MMSE total score) – Week 87
    -1.8 ± 4.0
    -3.0 ± 0.0
        Change from Baseline (MMSE total score) – Week 100
    -0.8 ± 2.6
    1.0 ± 0.0
        Change from Baseline (MMSE total score) – Week 126
    -3.0 ± 4.4
    -9.0 ± 0.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For the purpose of safety reporting, the study period was defined as the interval between the time of first dosing and the end of the designated Follow-up period.
    Adverse event reporting additional description
    Determination of AEs was based on: - the signs or symptoms detected during the physical examination and on clinical evaluation of the patient - the interview of the patient and their caregiver
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Cohort 1 (Safety Analysis Set)
    Reporting group description
    Cohort 1 Safety Analysis Set (9 patients who received at least 1 dose of ACI-24 at 10μg)

    Reporting group title
    Cohort 2 (Safety Analysis Set)
    Reporting group description
    Cohort 2 Safety Analysis Set (9 patients who received at least 1 dose of ACI-24 at 100μg)

    Reporting group title
    Cohort 3 (Safety Analysis Set)
    Reporting group description
    Cohort 3 Safety Analysis Set (9 patients who received at least 1 dose of ACI-24 at 300μg)

    Reporting group title
    Cohort 4 (Safety Analysis Set)
    Reporting group description
    Cohort 4 Safety Analysis Set (9 patients who received at least 1 dose of ACI-24 at 1000μg). Note: For 1 patient the SAE "Neoplasm malignant" was reported during the study. This patient completed the study but died shortly (arround 1 month) after the last safety Follow-up visit. Although this event (Death) did not occur in the official safety reporting period of the study, this outcome is however reported in the table for SAEs.

    Reporting group title
    Placebo (pooled) (Safety Analysis Set)
    Reporting group description
    Placebo (pooled) Safety Analysis Set (12 patients who received at least 1 dose of placebo)

    Reporting group title
    Cohort 3 Booster (Safety Analysis Set)
    Reporting group description
    Cohort 3 Booster (Safety Analysis Set) (3 patients who received a boosting dose (dose 8) of ACI-24 at 300μg 2.5 to 3.25 years after the last injection received at week 48). Events that occurred after booster injection are reported.

    Reporting group title
    Placebo in Cohort 3 Booster (Safety Analysis Set)
    Reporting group description
    Placebo in Cohort 3 Booster (Safety Analysis Set) (1 patient who received a boosting dose (dose 8) of placebo 2.5 to 3.25 years after the last injection received at week 48). Events that occurred after booster injection are reported.

    Serious adverse events
    Cohort 1 (Safety Analysis Set) Cohort 2 (Safety Analysis Set) Cohort 3 (Safety Analysis Set) Cohort 4 (Safety Analysis Set) Placebo (pooled) (Safety Analysis Set) Cohort 3 Booster (Safety Analysis Set) Placebo in Cohort 3 Booster (Safety Analysis Set)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    3 / 9 (33.33%)
    4 / 12 (33.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    1
    0
    1
    1
    0
    0
         number of deaths resulting from adverse events
    0
    1
    0
    1
    1
    0
    0
    Injury, poisoning and procedural complications
    Compression fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Cohort 1 (Safety Analysis Set) Cohort 2 (Safety Analysis Set) Cohort 3 (Safety Analysis Set) Cohort 4 (Safety Analysis Set) Placebo (pooled) (Safety Analysis Set) Cohort 3 Booster (Safety Analysis Set) Placebo in Cohort 3 Booster (Safety Analysis Set)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 9 (88.89%)
    9 / 9 (100.00%)
    9 / 9 (100.00%)
    9 / 9 (100.00%)
    12 / 12 (100.00%)
    2 / 3 (66.67%)
    1 / 1 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    3
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vein disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Surgical and medical procedures
    Hernia repair
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hip arthroplasty
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Tooth extraction
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Colon cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Keratoacanthoma
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Leiomyoma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Neoplasm malignant
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Prostate cancer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    General disorders and administration site conditions
    Cardiac death
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    Death
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    5 / 9 (55.56%)
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    10
    4
    0
    0
    Feeling cold
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Injection site haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Injection site reaction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Injection site swelling
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Irritability
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    7
    0
    0
    0
    Nodule
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Affective disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Aggression
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Agitation
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    1
    Anger
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    1
    0
    0
    Confusional state
         subjects affected / exposed
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    2
    1
    0
    1
    0
    1
    Delirium
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Delusion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 9 (33.33%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    0
    1
    3
    0
    0
    Depressive symptom
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    1
    1
    1
    0
    0
    Erectile dysfunction
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Hallucination, auditory
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Hallucination, visual
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    2
    1
    1
    0
    0
    Rapid eye movements sleep abnormal
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    Restlessness
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Compression fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    1
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Limb injury
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Post lumbar puncture syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Road traffic accident
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Thermal burn
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    Wound
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Wrist fracture
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood acid phosphatase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cardiac disorders
    Extrasystoles
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Rales
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    0
    Cognitive disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    3
    0
    0
    Dyskinesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Head titubation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    4 / 9 (44.44%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    3
    14
    1
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Lacunar infarction
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Parkinson's disease
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Presyncope
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Sensory disturbance
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Syncope
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Eye disorders
    Accommodation disorder
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Macular degeneration
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Vitreous detachment
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    0
    Vertigo positional
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 9 (33.33%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    0
    1
    3
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    1
    4
    1
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    0
    Paraesthesia oral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    2 / 9 (22.22%)
    1 / 9 (11.11%)
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    2
    3
    2
    0
    0
    Vomiting projectile
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Actinic keratosis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    Blepharitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Ecchymosis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Eczema asteatotic
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    1
    2
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Papule
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Rosacea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    1
    0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    Arthropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Back pain
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    1
    1
    2
    0
    0
    Costochondritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Monarthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    Pain in jaw
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Periarthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Tendonitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Gout
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    0
    Cystitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Erythema migrans
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    Gingival infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    Laryngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 9 (22.22%)
    2 / 9 (22.22%)
    4 / 9 (44.44%)
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    3
    6
    2
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 9 (0.00%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 9 (11.11%)
    1 / 9 (11.11%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    2
    1
    1
    0
    0
    Wound infection
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    0 / 9 (0.00%)
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Sep 2009
    Amendment 2: Major Changes • Added a requirement for 24 hours of hospitalization after first IMP injection • Added the requirement to obtain approval before commencement of Step 2 Minor Changes • Updated study contact details and Sponsor Medical Director • Clarification on planned interim analysis provided
    25 Sep 2009
    Amendment 1: Major Changes • Added DSMB meetings for safety evaluation • Added T-cell measurement at V4 (Week 6) • Additional description of the Informed Consent procedure added • Added patient safety supervision and monitoring after injections • Included coagulation assessment prior to lumbar puncture • Defined randomization process (eg, the 4 first patients of each dose-cohort [Step 1], were randomized in an interval of more or equal (≥) than 7 days) • Removed cross-reactivity measurement • Removed PET imaging in the case of dose-Cohort 1 (10 μg) (Step 1) Minor Changes • Included additional investigational medicinal product storage information • Updated study contact details • Updated site personnel responsibilities regarding psychometric tests and Clinical rating scales • Re-organized psychometric test battery • Updated visits time window • Updated laboratory assessments and schedule
    10 Sep 2010
    Amendment 3: Major Changes • Removed EEG recording • Changed the ligand to be used for PET imaging
    22 Mar 2011
    Amendment 4: Major Changes • Added additional T-cell measurements at V2 (Week 2), V6 (Week 10), V11 (Week 26), and V14 (Week 38) • Addition of TLR4 expression assessments at V1 (Week 0) and 17 (Week 52) • Updated blood sample volumes to be taken Minor Changes • Added clarifications on wording • Updated study plan with new laboratory assessments • Updated study contact details
    23 Sep 2011
    Amendment 5: Major Changes • Addition of TLRs and NLRs expression assessments at V1 (Week 0) and 17 (Week 52) • Added clarification that vital signs were measured at every visit • Allowed the use of Memantine in the Follow-up period (after Week 52) • Addition of coagulation indices measurement at Screening visit • Updated blood sample volumes to be taken (10 mL for biomarkers assessments instead of 20 mL and 20 mL for T-cell profile assessment instead of 10 mL) Minor Changes • Added clarifications on wording
    17 Jan 2012
    Amendment 6: Minor Changes • Listed the changes of responsible persons/organizations and contact details
    04 May 2012
    Amendment 7: Minor Changes • Listed the changes of responsible persons/organizations and contact details
    10 Jul 2012
    Amendment 8: Major Changes • Added an interim analysis in Step 1 to see antibody anti-Aβ1-42 titers for all patients in Cohort 1 and patients of Cohort 2 up to 6 months of treatment • Updated patient information with additional details that further described the use of Florbetaben as radiolabeled agent in PET imaging
    04 Oct 2013
    Amendment 9: Major Changes • Replacement of PET imaging by measurement of Aβ1-42 in blood in the interim analysis at 26 weeks of treatment in the highest dose group and in all corresponding sections • Added clarification that the unblinding could have been done using the IVRS and there were no sealed code break envelops on site • Added a clarification on the SAE reporting procedure and safety officer email address • Updated the Data Handling section after the change of system from Oracle Clinical to Omnicomm Minor Changes • Included changes on the background information related to the IB update • Added clarification on the responsibilities on the packaging and labeling of investigational medicinal product • Added clarification that MRI was part of the Screening visit and not Baseline visit • Added clarifications on wording
    18 Mar 2014
    Amendment 10: Major Changes • Added Cohort 4 to assess the immunogenicity of a higher dose (1000 μg) of ACI-24 • Added PET imaging as an inclusion criterion • Added performance of Baseline CSF sampling at least 3 days prior to administration of investigational medicinal product Minor Changes • Change of safety reporting company to Product Life Ltd
    04 Jul 2014
    Amendment 11: Major Changes • Changed inclusion criterion number 2 with raising the MMSE upper limit from 26 to 28
    02 Apr 2015
    Amendment 12: Major Changes • Added analysis of additional testing in the first 4 patients of Cohort 4: Aβ1-42 and Aβ1-40 in plasma and Aβ1-42 in CSF; IgM anti-Aβ; inflammatory markers
    26 Jun 2015
    Amendment 13: Major Changes • Added analysis of additional testing in the 12 patients of Cohort 3: Aβ1-42 and Aβ1-40 in plasma and Aβ1-42 in CSF; IgM anti-Aβ in serum; inflammatory markers (cytokines)
    30 Nov 2015
    Amendment 14: Major Changes • Expanded Cohort 4 from 4 to 12 patients • Added a late booster injection at 18 months for patients in Cohort 4 • Added an inclusion criterion as requested by the Swedish MPA in order to comply with Swedish law 1992:859 13b §. This additional criterion was only applicable in Sweden. Minor Changes • Updated study contact details
    03 Mar 2016
    Amendment 15: Major Changes • Added a late booster injection at 2.5 to 3.25 years after last dose for patients in Cohort 3 Minor Changes • Corrected the visit schedule for Study Plan number 2 for Cohort 4 to state that PET imaging was done at the Screening Visit, not at V1
    17 Oct 2016
    Amendment 16: Major Changes • Clarified content for the full interim analysis of Step 1 data, namely: - to specify that subsequent Interim analyses could have been conducted if needed at later timepoints than V11 (Week 26) for all patients enrolled in Cohort 4 - planned to unblind data of patients participating in Cohort 1, 2, 3, and 4 after booster after data for these cohorts had been locked - all data available for any visit in all cohorts up to the data-cut date (ie, the last patient completing Week 26 in Cohort 4) was to be included in the full interim analysis • Implemented changes to improve consistency between sections of the study protocol, by clarifying the study objectives and endpoints classifications in Sections 7.1 and 7.2 of the study protocol • Clarified the term “Inflammatory marker” to delineate between collection of cytokines alone or cytokines and CRP • Clarified that the version of ADAS-Cog to be used was ADAS-Cog12 Minor Changes • A number of administrative changes were added, including modification of the contact list to include additional vendors and update information, modification of the headers in some pages to align with the section concerned, modification of the signature page, an update of Section 6.2, and clarification of what procedure/analysis was to be performed for each cohort when the wording was confusing
    17 Jul 2017
    Amendment 17: Minor Changes • Reduced the safety Follow-up period of patients in Cohort 4 who received a booster injection at 18 months from 2 years to 1 year

    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.
    Small sample size allowed only descriptive statistics.
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