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    Clinical Trial Results:
    A phase II a , Multicenter, Randomized , Third -party Unblinded , Long- term Extension study to Determine Safety, Tolerability and Immunogenicity of ACC-001 with and without QS21 Adjuvant in Subjects with Mild to Moderate Alzheimzer's Disease

    Summary
    EudraCT number
    2009-010922-21
    Trial protocol
    DE   FR   ES  
    Global end of trial date
    17 Dec 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    23 May 2016
    First version publication date
    05 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3134K1-2203-EU
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00955409
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd St, New York, United States,
    Public contact
    Pfizer ClinicalTrials.gov Call Center , Pfizer, Inc., 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center , Pfizer, Inc., 1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    03 Oct 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Dec 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the long-term safety and tolerability of doses of 3, 10, and 30 µg of ACC-001 (CRM-conjugated A-beta [1-7] antigen alone and in combination with QS-21 adjuvant) in subjects with mild to moderate AD. The Basic Results disclose pooled data from the extension studies 3134K1-2203-EU (B2571007) and 3434K1-2205-US (B2571008).
    Protection of trial subjects
    These studies were conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice guidelines. Pfizer/Janssen Alzheimer’s Immunotherapy (AI) data monitoring committee (DMC) and external DMC were involved for the ongoing monitoring of participants' safety. The table 'Number of subjects enrolled per age group' below reflects the number of enrolled subjects in the extension study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Nov 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 110
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 26
    Worldwide total number of subjects
    160
    EEA total number of subjects
    50
    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)
    40
    From 65 to 84 years
    117
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Planned duration was approximately 2 years (including 18 months of treatment + 6 months of follow-up). Participants who completed the lead-in 3134K1-200-EU (B2571004) study through Week 78 (Week 104 for Cohort 1 and 2) had the option to stay in the lead-in study or to roll-over into the extension protocol 3134K1-2203-EU (B2571007).

    Pre-assignment
    Screening details
    This extension study enrolled participants who completed lead-in study 3134K1-200-EU. All participants received active treatment in this extension study (ACC-001 with QS-21 adjuvant). Basic Results disclose pooled data from extension studies 3134K1-2203-EU (B2571007) and 3134K1-2205-US (B2571008). The row 'completed'=completed study in below table.

    Period 1
    Period 1 title
    Including treatment and follow up period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ACC 3 μg+QS-21 /ACC 3 μg+QS-21
    Arm description
    Participants received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study and extension study: ACC-001 3 μg and QS-21 50 μg. Intramuscular use.

    Arm title
    QS-21 / ACC 3 μg+QS-21
    Arm description
    Participants received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: QS-21 - 50 μg. Extension study: ACC-001 - 3 μg and QS-21 - 50 μg. Intramuscular use.

    Arm title
    ACC 10 μg+QS-21 /ACC 10 μg+QS-21
    Arm description
    Participants received 10 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    In both lead-in study and extension study: ACC-001 - 10 μg and QS-21 - 50 μg. Intramuscular use.

    Arm title
    ACC 10 μg / ACC 10 μg+QS-21
    Arm description
    Participants received 10 μg of ACC-001 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: ACC-001 - 10 μg. Extension study: 10 μg ACC-001 and 50 μg QS-21. Intramuscular use.

    Arm title
    QS-21 / ACC 10 μg+QS-21
    Arm description
    Participants received 50 μg of QS-21 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: 50 μg QS-21. Extension study: 10 μg ACC-001 and 50 μg QS-21 . Intramuscular use.

    Arm title
    PBS / ACC 10 μg+QS-21
    Arm description
    Participants received Phosphate buffered Saline (PBS) in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: PBS. Extension study: 10 μg ACC-001 and 50 μg QS-21 . Intramuscular use.

    Arm title
    ACC 30 μg+QS-21/ACC 30 μg+QS-21
    Arm description
    Participants received 30 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study and in extension study: 30 μg ACC-001 and 50 μg QS-21. Intramuscular use.

    Arm title
    ACC 30 μg / ACC 30 μg+QS-21
    Arm description
    Participants received 30 μg of ACC-001 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: 30 μg ACC-001. Extension study: 30 μg ACC-001 and 50 μg QS-21. Intramuscular use.

    Arm title
    QS-21 / ACC 30 μg+QS-21
    Arm description
    Participants received 50 μg of QS-21 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: 50 μg QS-21. Extension study: 30 μg ACC-001 and 50 μg QS-21. Intramuscular use.

    Arm title
    PBS / ACC 30 μg+QS-21
    Arm description
    Participants received PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.
    Arm type
    Experimental

    Investigational medicinal product name
    ACC-001 + QS-21 Adjuvant
    Investigational medicinal product code
    ACC-001 + QS-21 Adjuvant
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Lead-in study: PBS. Extension study: 30 μg ACC-001 and 50 μg QS-21 . Intramuscular use.

    Number of subjects in period 1
    ACC 3 μg+QS-21 /ACC 3 μg+QS-21 QS-21 / ACC 3 μg+QS-21 ACC 10 μg+QS-21 /ACC 10 μg+QS-21 ACC 10 μg / ACC 10 μg+QS-21 QS-21 / ACC 10 μg+QS-21 PBS / ACC 10 μg+QS-21 ACC 30 μg+QS-21/ACC 30 μg+QS-21 ACC 30 μg / ACC 30 μg+QS-21 QS-21 / ACC 30 μg+QS-21 PBS / ACC 30 μg+QS-21
    Started
    21
    6
    41
    25
    5
    9
    27
    6
    16
    4
    Completed Treatment
    12
    5
    15
    17
    3
    7
    4
    3
    2
    4
    Completed
    11
    5
    15
    17
    3
    6
    3
    2
    2
    3
    Not completed
    10
    1
    26
    8
    2
    3
    24
    4
    14
    1
         Physician decision
    -
    -
    1
    -
    -
    -
    -
    -
    -
    -
         Retrieval subjects; impacted by sponsor disc.
    2
    1
    13
    1
    2
    -
    16
    -
    8
    1
         Lack of efficacy
    1
    -
    -
    -
    -
    -
    -
    -
    -
    -
         Discontinuation of Study by Sponsor
    -
    -
    -
    -
    -
    -
    -
    1
    -
    -
         Caregiver Request
    2
    -
    6
    5
    -
    2
    3
    1
    3
    -
         Consent withdrawn by subject
    1
    -
    5
    2
    -
    -
    2
    -
    1
    -
         Adverse Event
    2
    -
    -
    -
    -
    1
    2
    -
    2
    -
         Lost to follow-up
    2
    -
    1
    -
    -
    -
    1
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ACC 3 μg+QS-21 /ACC 3 μg+QS-21
    Reporting group description
    Participants received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 3 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 10 μg+QS-21 /ACC 10 μg+QS-21
    Reporting group description
    Participants received 10 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 10 μg / ACC 10 μg+QS-21
    Reporting group description
    Participants received 10 μg of ACC-001 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 10 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    PBS / ACC 10 μg+QS-21
    Reporting group description
    Participants received Phosphate buffered Saline (PBS) in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 30 μg+QS-21/ACC 30 μg+QS-21
    Reporting group description
    Participants received 30 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 30 μg / ACC 30 μg+QS-21
    Reporting group description
    Participants received 30 μg of ACC-001 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 30 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    PBS / ACC 30 μg+QS-21
    Reporting group description
    Participants received PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group values
    ACC 3 μg+QS-21 /ACC 3 μg+QS-21 QS-21 / ACC 3 μg+QS-21 ACC 10 μg+QS-21 /ACC 10 μg+QS-21 ACC 10 μg / ACC 10 μg+QS-21 QS-21 / ACC 10 μg+QS-21 PBS / ACC 10 μg+QS-21 ACC 30 μg+QS-21/ACC 30 μg+QS-21 ACC 30 μg / ACC 30 μg+QS-21 QS-21 / ACC 30 μg+QS-21 PBS / ACC 30 μg+QS-21 Total
    Number of subjects
    21 6 41 25 5 9 27 6 16 4 160
    Age categorical
    Units: Subjects
        50 - 64 Years
    4 2 14 5 1 3 6 2 3 0 40
        ≥ 65 years
    17 4 27 20 4 6 21 4 13 4 120
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    68.7 ± 6.94 67.7 ± 9.52 69.7 ± 9.29 72.4 ± 9.12 75.2 ± 8.23 69.6 ± 7.94 71.3 ± 9.2 66.3 ± 9.42 69.5 ± 6.95 75.8 ± 7.89 -
    Gender categorical
    Units: Subjects
        Female
    11 4 21 12 3 8 16 3 14 2 94
        Male
    10 2 20 13 2 1 11 3 2 2 66
    Race/Ethnicity
    Units: Subjects
        Asian
    0 0 0 0 0 0 0 0 0 0 0
        Black or African American
    0 0 1 0 1 0 1 0 0 0 3
        Other
    1 0 0 0 0 0 0 0 0 0 1
        White
    20 6 40 25 4 9 26 6 16 4 156
    MMSE Ranges
    Units: Subjects
        MMSE score >26
    0 0 5 3 1 1 1 0 1 0 12
        MMSE score 21-26
    5 2 9 7 2 3 8 3 6 3 48
        MMSE score 16-20
    5 2 12 10 2 3 11 2 6 0 53
        MMSE score 10-15
    10 2 15 5 0 2 7 1 3 1 46
        MMSE score <10
    1 0 0 0 0 0 0 0 0 0 1
    MMSE Score
    Units: Score
        arithmetic mean (standard deviation)
    16.7 ± 4.64 18.3 ± 5.61 18.4 ± 5.92 19.6 ± 5.45 21.8 ± 4.21 20 ± 6.14 18.7 ± 4.98 20.5 ± 4.76 19.1 ± 4.84 20 ± 4.69 -

    End points

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    End points reporting groups
    Reporting group title
    ACC 3 μg+QS-21 /ACC 3 μg+QS-21
    Reporting group description
    Participants received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 3 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 10 μg+QS-21 /ACC 10 μg+QS-21
    Reporting group description
    Participants received 10 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 10 μg / ACC 10 μg+QS-21
    Reporting group description
    Participants received 10 μg of ACC-001 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 10 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    PBS / ACC 10 μg+QS-21
    Reporting group description
    Participants received Phosphate buffered Saline (PBS) in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 30 μg+QS-21/ACC 30 μg+QS-21
    Reporting group description
    Participants received 30 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    ACC 30 μg / ACC 30 μg+QS-21
    Reporting group description
    Participants received 30 μg of ACC-001 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 30 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    PBS / ACC 30 μg+QS-21
    Reporting group description
    Participants received PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Subject analysis set title
    ACC 3 μg+QS-21 / ACC 3 μg+QS-21
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Subject analysis set title
    QS-21 / ACC 3 μg+QS-21
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Subject analysis set title
    Active / ACC 10 μg+QS-21
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 10 μg of ACC-001 and 50 μg of QS-21 or 10 μg of ACC-001 alone in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Subject analysis set title
    Control / ACC 10 μg+QS-21
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of the study drug were included in the safety population. Subjects received 50 μg of QS-21 or PBS in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Subject analysis set title
    Active / ACC 30 μg+QS-21
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of the study drug were included in the safety population. Subjects received 30 μg of ACC-001 and 50 μg of QS-21 or 30 μg of ACC-001 alone in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Subject analysis set title
    Control / ACC 30 μg+QS-21
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of the study drug were included in the safety population. Subjects in this group received 50 μg of QS-21 or PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Primary: Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs)

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    End point title
    Percentage of Participants With Treatment-emergent adverse events (AEs) or serious adverse events (SAEs) [1]
    End point description
    An AE was any untoward, undesired, or unplanned clinical event in the form of signs, symptoms, disease, or laboratory or physiologic observations occurring in a person given study drug or in a sponsor's clinical study. The event did not need to be causally related to the study drug or the clinical studies. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.
    End point type
    Primary
    End point timeframe
    24 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed for this endpoint.
    End point values
    ACC 3 μg+QS-21 / ACC 3 μg+QS-21 QS-21 / ACC 3 μg+QS-21 Active / ACC 10 μg+QS-21 Control / ACC 10 μg+QS-21 Active / ACC 30 μg+QS-21 Control / ACC 30 μg+QS-21
    Number of subjects analysed
    21
    6
    65
    14
    33
    20
    Units: Percentage of participants
    number (not applicable)
        With TEAEs
    100
    100
    93.8
    92.9
    78.8
    90
        With serious TEAEs
    28.6
    0
    24.6
    14.3
    12.1
    20
    No statistical analyses for this end point

    Other pre-specified: Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104

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    End point title
    Geometric Mean Titers (GMTs) of Anti-A-beta Immunoglobulin G (IgG) Total Using an Enzyme-linked Immunosorbent Assay (ELISA) at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104
    End point description
    The lower limit of quantification (LLOQ) was 100 U/mL and when the assay result was below LLOQ (100 U/mL), 50 U/mL was imputed for IgG.
    End point type
    Other pre-specified
    End point timeframe
    Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104
    End point values
    ACC 3 μg+QS-21 /ACC 3 μg+QS-21 QS-21 / ACC 3 μg+QS-21 ACC 10 μg+QS-21 /ACC 10 μg+QS-21 ACC 10 μg / ACC 10 μg+QS-21 QS-21 / ACC 10 μg+QS-21 PBS / ACC 10 μg+QS-21 ACC 30 μg+QS-21/ACC 30 μg+QS-21 ACC 30 μg / ACC 30 μg+QS-21 QS-21 / ACC 30 μg+QS-21 PBS / ACC 30 μg+QS-21
    Number of subjects analysed
    21
    6
    41
    24
    5
    9
    27
    6
    16
    4
    Units: U/ml
    geometric mean (confidence interval 95%)
        Screening Lead-in (N:21,6,41,24,5,9,27,6,16,4)
    50 (-99999 to 99999)
    50 (-99999 to 99999)
    50 (-99999 to 99999)
    50 (575.1 to 3808.2)
    50 (-99999 to 99999)
    50 (-99999 to 99999)
    50 (-99999 to 99999)
    50 (-99999 to 99999)
    58.8 (41.6 to 83.3)
    50 (-99999 to 99999)
        Screening Extension (N:21,6,41,24,5,9,27,6,16,4)
    836.5 (362.2 to 1932.3)
    50 (-99999 to 99999)
    1623.4 (1015.3 to 2595.7)
    180.2 (-99999 to 99999)
    50 (-99999 to 99999)
    50 (-99999 to 99999)
    1718.3 (1101.2 to 2681.3)
    424.2 (70.9 to 2539.4)
    59.5 (41 to 86.3)
    50 (-99999 to 99999)
        Week 4 (N:21,6,41,24,5,9,27,5,16,4)
    4523.7 (2070.2 to 9885)
    50 (-99999 to 99999)
    6219.3 (3853.2 to 10038.2)
    517.9 (76.4 to 425.3)
    50 (-99999 to 99999)
    60.6 (38.9 to 94.4)
    8436.2 (5569.8 to 12778)
    4223 (185 to 96408.3)
    144.7 (67.9 to 308)
    100.1 (11 to 912.6)
        Week 12 (N:21,6,41,23,4,9,27,5,16,4)
    2540.3 (1060.5 to 6084.8)
    50 (-99999 to 99999)
    4251 (2709.7 to 6669.2)
    425.4 (166.8 to 1607.6)
    50 (-99999 to 99999)
    62 (37.8 to 101.7)
    3604.3 (2009.6 to 6464.5)
    761.6 (33.2 to 17472.9)
    89.3 (43.7 to 182.5)
    87.9 (14.6 to 529.8)
        Week 24 (N:21,6,39,24,4,9,27,5,15,3)
    1466.6 (607.2 to 3542.4)
    50 (-99999 to 99999)
    3058.1 (1887.1 to 4955.9)
    280.3 (137 to 1320.6)
    50 (-99999 to 99999)
    57.5 (41.7 to 79.2)
    2146.4 (1309 to 3519.7)
    541.1 (31.3 to 9362.1)
    78.9 (42.6 to 146.1)
    50 (-99999 to 99999)
        Week 30 (N:18,6,38,20,4,6,24,5,14,3)
    3780.6 (1941.7 to 7360.9)
    477.1 (85.4 to 2664.5)
    8682 (5670.1 to 13293.8)
    1574.5 (100.2 to 784.4)
    552.2 (37.8 to 8075.8)
    317 (27.5 to 3654.9)
    12939.5 (8634.4 to 19391.2)
    1374.9 (54.4 to 34722.9)
    1889.4 (570.8 to 6254.5)
    4360.1 (30.3 to 627361.8)
        Week 36 (N:18,6,36,20,4,9,25,5,14,3)
    2927.8 (1368.7 to 6262.8)
    267.1 (53.6 to 1331.2)
    5946.6 (3807.1 to 9288.6)
    1029.4 (568.2 to 4363.1)
    282.9 (43.5 to 1838.7)
    428 (83.8 to 2186.8)
    6228.9 (3794.3 to 10225.7)
    706.7 (33.6 to 14852.3)
    1018.5 (297.8 to 3483.6)
    1164.2 (23.4 to 57811.5)
        Week 50 (N:17,6,37,20,4,8,20,5,13,3)
    1843.8 (776.1 to 4380)
    141.3 (24.5 to 813.2)
    3146.6 (1945.8 to 5088.4)
    512.4 (346.4 to 3059.1)
    169.6 (35.8 to 804.5)
    333.6 (63 to 1767)
    2439 (1369.5 to 4343.8)
    527.7 (33.4 to 8348.8)
    651.3 (189.9 to 2233.5)
    401.4 (4.5 to 35461.1)
        Week 56 (N:17,6,32,19,4,8,12,4,5,3)
    4958.8 (2257.8 to 10891)
    1441.4 (159.3 to 13045.1)
    10412.4 (6365.4 to 17032.7)
    4562.2 (176.5 to 1487.4)
    1720 (108.1 to 27356.9)
    3451 (478.9 to 24871.3)
    5241.2 (2459.3 to 11170.1)
    2216.1 (38 to 129086.9)
    578.3 (26.6 to 12559.5)
    8033.5 (584.5 to 110404.7)
        Week 66 (N:17,6,30,19,4,7,8,5,3,3)
    2765 (1190.8 to 6420.3)
    701.5 (86 to 5719.3)
    6627.7 (3946.1 to 11131.5)
    2049.2 (2233.3 to 9319.8)
    891 (32.6 to 24385.5)
    1989.2 (152.1 to 26014.2)
    4341.1 (1677.8 to 11232.1)
    1315.8 (117.1 to 14780.6)
    968.4 (43 to 21784.1)
    5403.5 (171.1 to 170698.5)
        Week 76 (N:14,5,23,19,4,7,5,5,3,3)
    2802.1 (1334.8 to 5882.6)
    842.5 (107.7 to 6592.3)
    3373.8 (1763.5 to 6454.6)
    1479.9 (852.2 to 4927.5)
    628.5 (26.6 to 1478.7)
    1235.3 (116.5 to 13096.6)
    2030.7 (576.9 to 7147.4)
    875 (94.7 to 8083.3)
    494.1 (1.2 to 198416.2)
    2042.8 (107.4 to 38841.8)
        Week 82 (N:13,5,16,18,3,7,4,4,2,3)
    6831.1 (3436.2 to 13579.9)
    5104.3 (540.8 to 48180.8)
    12261.1 (6635.8 to 22655.2)
    5771.4 (587.2 to 4172.5)
    2768.5 (79 to 97040.9)
    4779.6 (706.4 to 32339.3)
    1902 (35 to 103340.7)
    3736.1 (594.2 to 23491.3)
    1617.1 (3 to 868223.9)
    9922.5 (2059.8 to 47798.6)
        Week 104 (N:12,5,14,17,2,5,5,2,2,3)
    2951.6 (1259.3 to 6918.3)
    1061 (77.8 to 14476)
    6644.4 (2583.6 to 17088.1)
    1565.2 (3264.4 to 10203.5)
    1128.4 (0.1 to 25253974)
    832.4 (56.5 to 12268.2)
    1447.6 (548.5 to 3820.9)
    3654.5 (11.3 to 1181935)
    321.9 (0 to 12636639)
    1340.5 (421.5 to 4263.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 24 months, starting from Day 1, inclusive 18 months of dosing and 6 months of follow-up after the last dose.
    Adverse event reporting additional description
    Treatment emergent SAEs and non-SAEs are presented. Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as nonserious in another participant, or 1 participant may have experienced both a serious and nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    ACC 3 μg+QS-21 / ACC 3 μg+QS-21
    Reporting group description
    Participants received 3 μg of ACC-001 and 50 μg of QS-21 in the lead-in study and in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    QS-21 / ACC 3 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 in the lead-in study and 3 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    Active / ACC 10 μg+QS-21
    Reporting group description
    Participants received 10 μg of ACC-001 and 50 μg of QS-21 or 10 μg of ACC-001 alone in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    Control / ACC 10μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 or PBS in the lead-in study and 10 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    Active / ACC 30 μg+QS-21
    Reporting group description
    Participants received 30 μg of ACC-001 and 50 μg of QS-21 or 30 μg of ACC-001 alone in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Reporting group title
    Control / ACC 30 μg+QS-21
    Reporting group description
    Participants received 50 μg of QS-21 or PBS in the lead-in study and 30 μg of ACC-001 and 50 μg of QS-21 in the extension study. Test article was given by intramuscular injection into the deltoid muscle at 0, 6, 12, and 18 months.

    Serious adverse events
    ACC 3 μg+QS-21 / ACC 3 μg+QS-21 QS-21 / ACC 3 μg+QS-21 Active / ACC 10 μg+QS-21 Control / ACC 10μg+QS-21 Active / ACC 30 μg+QS-21 Control / ACC 30 μg+QS-21
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    0 / 6 (0.00%)
    16 / 65 (24.62%)
    2 / 14 (14.29%)
    4 / 33 (12.12%)
    4 / 20 (20.00%)
         number of deaths (all causes)
    2
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Raynaud's phenomenon
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gallbladder cancer metastatic
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Device dislocation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic mass
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Agitated depression
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Agitation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Fall
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Hand fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Rib fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Road traffic accident
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Spinal compression fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Atrial fibrillation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Bradyarrhythmia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Bradycardia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Cyanosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Mitral valve prolapse
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Ventricular tachycardia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Pulmonary embolism
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Nervous system disorders
    Cerebral haemosiderin deposition
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Epilepsy
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Ischaemic stroke
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Partial seizures
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    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
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    1 / 14 (7.14%)
    2 / 33 (6.06%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Vasogenic cerebral oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Diarrhoea
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 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
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Petechiae
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Skin exfoliation
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Skin fissures
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Skin haemorrhage
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Hypoglycaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ACC 3 μg+QS-21 / ACC 3 μg+QS-21 QS-21 / ACC 3 μg+QS-21 Active / ACC 10 μg+QS-21 Control / ACC 10μg+QS-21 Active / ACC 30 μg+QS-21 Control / ACC 30 μg+QS-21
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 21 (90.48%)
    6 / 6 (100.00%)
    55 / 65 (84.62%)
    13 / 14 (92.86%)
    23 / 33 (69.70%)
    17 / 20 (85.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    3
    0
    0
    1
    Haemorrhage
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    0 / 14 (0.00%)
    2 / 33 (6.06%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    3
    0
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    5 / 65 (7.69%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Face oedema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 6 (16.67%)
    4 / 65 (6.15%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    7
    0
    1
    0
    Induration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Inflammation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Injection site bruising
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    2 / 33 (6.06%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    2
    0
    2
    1
    Injection site erythema
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 6 (0.00%)
    5 / 65 (7.69%)
    1 / 14 (7.14%)
    5 / 33 (15.15%)
    4 / 20 (20.00%)
         occurrences all number
    8
    0
    5
    1
    9
    6
    Injection site haemorrhage
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    1
    0
    0
    1
    0
    4
    Injection site hypersensitivity
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injection site induration
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    4
    0
    1
    0
    0
    0
    Injection site inflammation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    3
    0
    1
    1
    Injection site pain
         subjects affected / exposed
    4 / 21 (19.05%)
    0 / 6 (0.00%)
    11 / 65 (16.92%)
    2 / 14 (14.29%)
    5 / 33 (15.15%)
    6 / 20 (30.00%)
         occurrences all number
    7
    0
    15
    2
    9
    8
    Injection site pruritus
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 6 (66.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    4
    0
    0
    0
    0
    Injection site swelling
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 6 (0.00%)
    5 / 65 (7.69%)
    0 / 14 (0.00%)
    4 / 33 (12.12%)
    1 / 20 (5.00%)
         occurrences all number
    3
    0
    6
    0
    7
    1
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Aggression
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 6 (16.67%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    5
    0
    0
    1
    Agitation
         subjects affected / exposed
    3 / 21 (14.29%)
    4 / 6 (66.67%)
    5 / 65 (7.69%)
    2 / 14 (14.29%)
    3 / 33 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    5
    4
    7
    2
    3
    1
    Anxiety
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 6 (0.00%)
    4 / 65 (6.15%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    5
    1
    3
    0
    Confusional state
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    4 / 65 (6.15%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    4
    0
    0
    0
    Delirium
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Delusional perception
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Depression
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    3 / 14 (21.43%)
    2 / 33 (6.06%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    3
    3
    2
    0
    Irritability
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Nightmare
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Contusion
         subjects affected / exposed
    3 / 21 (14.29%)
    1 / 6 (16.67%)
    2 / 65 (3.08%)
    1 / 14 (7.14%)
    2 / 33 (6.06%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    2
    1
    2
    1
    Corneal abrasion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Eye contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fall
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 6 (16.67%)
    7 / 65 (10.77%)
    2 / 14 (14.29%)
    2 / 33 (6.06%)
    2 / 20 (10.00%)
         occurrences all number
    6
    1
    8
    2
    2
    6
    Hip fracture
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    1 / 14 (7.14%)
    2 / 33 (6.06%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    3
    1
    2
    1
    Limb injury
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Periorbital contusion
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Investigations
    Bartonella test positive
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vitamin B1 decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 6 (16.67%)
    3 / 65 (4.62%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    3
    1
    3
    0
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Cognitive disorder
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Dementia Alzheimer's type
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 6 (0.00%)
    5 / 65 (7.69%)
    2 / 14 (14.29%)
    2 / 33 (6.06%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    6
    2
    2
    2
    Headache
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    6 / 65 (9.23%)
    1 / 14 (7.14%)
    3 / 33 (9.09%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    9
    1
    4
    1
    Hyperreflexia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Myoclonus
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 6 (16.67%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Syncope
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 6 (0.00%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Tremor
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Glaucoma
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Heterophoria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Retinal degeneration
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    2 / 33 (6.06%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    0
    2
    2
    Dental caries
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    4 / 21 (19.05%)
    1 / 6 (16.67%)
    3 / 65 (4.62%)
    1 / 14 (7.14%)
    2 / 33 (6.06%)
    0 / 20 (0.00%)
         occurrences all number
    5
    1
    3
    1
    2
    0
    Faeces soft
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    2
    0
    3
    0
    0
    3
    Periodontal disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    4
    0
    1
    1
    1
    4
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    0
    0
    0
    1
    Erythema
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    2 / 65 (3.08%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    4
    0
    1
    1
    Rash
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    4 / 65 (6.15%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    5
    0
    0
    0
    Rosacea
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Skin lesion
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    2 / 14 (14.29%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    2
    0
    1
    2
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    4 / 65 (6.15%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    6
    0
    1
    1
    Back pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    4 / 65 (6.15%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    5
    2
    1
    2
    Muscle spasms
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    4 / 65 (6.15%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    4
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    1
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    4 / 65 (6.15%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    1 / 14 (7.14%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    3
    1
    1
    0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vitamin D deficiency
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    3 / 65 (4.62%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 21 (14.29%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    3
    0
    1
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 6 (33.33%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 6 (16.67%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    0
    Infected bites
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Influenza
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Localised infection
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lyme disease
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 21 (9.52%)
    1 / 6 (16.67%)
    6 / 65 (9.23%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    4
    1
    9
    0
    1
    0
    Onychomycosis
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 6 (16.67%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    2 / 65 (3.08%)
    0 / 14 (0.00%)
    1 / 33 (3.03%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    3
    0
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    1 / 65 (1.54%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    4
    0
    1
    1
    0
    0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    1 / 14 (7.14%)
    0 / 33 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 6 (0.00%)
    3 / 65 (4.62%)
    2 / 14 (14.29%)
    1 / 33 (3.03%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    3
    2
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 6 (66.67%)
    9 / 65 (13.85%)
    1 / 14 (7.14%)
    2 / 33 (6.06%)
    1 / 20 (5.00%)
         occurrences all number
    2
    4
    10
    1
    2
    3
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Wound infection
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 6 (0.00%)
    0 / 65 (0.00%)
    0 / 14 (0.00%)
    0 / 33 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Feb 2010
    The following major changes were made in protocol amendment 1: - Study design was revised to clarify the study population, inclusion/exclusion criteria, concomitant medications, and procedures. - Protocol inconsistencies, omissions and errors were corrected.
    30 Jun 2010
    The following major changes were made in protocol amendment 2: - Study design was revised to clarify the study population, inclusion/exclusion criteria, concomitant medications, and procedures. - Protocol inconsistencies, omissions and errors were corrected.
    13 Jan 2012
    Protocol amendment 3 was made to update: - Exclusion criteria, inclusion of suicidality assessment, addition of direct and indirect bilirubin testing, and to update information and instructions pertaining to retrieval subjects, CSF sample collection, AEs/SAEs, discontinuation of investigational product due to injection site reactions, and reporting of safety issues.
    14 Jun 2012
    Protocol amendment 4 was made to update: - Adverse events, adverse events of special interest, concomitant treatments, and to add cerebral hemorrhage as an adverse drug reaction.
    17 Dec 2013
    The following major changes were made in protocol amendment 5: - CSF assays for anti-A-beta antibodies and IgG subtype analysis were listed as exploratory objectives and it was clarified that the analysis will not be conducted. - Specific protocol section was revised to clarify the inconsistency with the Investigator Brochure regarding the adverse events of special circumstance.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Jul 2013
    This study was prematurely terminated. In July 2013 the Alliance made a decision that ACC-001 would not be further developed in mild to moderate AD. Consequently, on 12 July 2013, dosing in the long-term extension studies was terminated and all remaining subjects were followed for safety for up to 6 months following their last administration of investigational product in accordance with the study protocols.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The following endpoints are not presented as these were not analyzed: GMTs of Anti-A-beta IgM and IgG Subtypes (where an IgG total response was measurable) using ELISA at Weeks 0, 4, 12, 24, 30, 36, 50, 56, 66, 76, 82, and 104.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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