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    Clinical Trial Results:
    “ADAMANT” A 24-months randomised, placebo-controlled, parallel group, double blinded, multi centre, phase 2 study to assess safety and efficacy of AADvac1 applied to patients with mild Alzheimer’s disease

    Summary
    EudraCT number
    		 2015-000630-30
    Trial protocol
    		 AT   CZ   SE   DE   SK   SI  
    Global end of trial date
    25 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2020
    First version publication date
    11 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-AD-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02579252
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AXON NEUROSCIENCE SE
    Sponsor organisation address
    4, Arch. Makariou & Kalogreon, NICOLAIDES SEA VIEW CITY 5th floor, office 506, Larnaka, Cyprus, 6016
    Public contact
    Medical department, AXON Neuroscience CRM Services SE, 00421 220921620, adamant@axon-neuroscience.eu
    Scientific contact
    Medical department, AXON Neuroscience CRM Services SE, 00421 220921620, adamant@axon-neuroscience.eu
    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
    19 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate safety and tolerability of long-term AADvac1 treatment of patients with mild Alzheimer’s disease.
    Protection of trial subjects
    All the measurements of safety, tolerability, and efficacy used in this study are widely used and generally recognised as reliable, accurate, and relevant. The safety assessments were implemented appropriately based on the investigated condition and study population. The investigators assessed subjects safety on an ongoing basis. If the subject's safety or life was to be jeopardized, they were withdrawn from the study. This study was monitored regularly by a clinical monitor according to ICH GCP Guidelines and the respective standard operating procedures. The study safety data were regularly evaluated by an independent Data Safety Monitoring Board.
    Background therapy
    		 As per standard treatment of care of patients with mild Alzheimer’s disease, all patients enrolled in the study were required to be on treatment with a stable dose of acetylcholine esterase inhibitors for at least 3 months prior to screening (V01) and throughout the whole course of the study. If a study subject was on an add-on treatment with memantine, they must have been at a stable dose regimen for at least 3 months prior to screening (V01) and for the entire duration of the clinical study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jun 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 55
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Slovakia: 52
    Country: Number of subjects enrolled
    Slovenia: 10
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Czech Republic: 27
    Country: Number of subjects enrolled
    Germany: 22
    Worldwide total number of subjects
    196
    EEA total number of subjects
    196
    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)
    39
    From 65 to 84 years
    157
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The recruitment was performed at 42 investigational sites in 8 European countries from 16 Jun 2016 until 30 May 2017. The investigational sites were hospital units or out-patient clinics specialized in neurology or psychiatry with extensive experience in treating patients with Alzheimer’s disease (AD).

    Pre-assignment
    Screening details
    		 During the screening period, investigators continuously assessed patients’ eligibility, each time when receiving results from any examination or laboratory or imaging assessments. Eligibility was finally confirmed by the Sponsor, based on the investigator’s written justification of the diagnosis of AD, and eCRF, Laboratory and MRI data.

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    AADvac1 and placebo vials were identical in weight, viscosity and appearance. The allocation concealment was ensured by central randomised allocation of treatment codes performed by the IWRS, where only the unblinded biostatisticians at the Contract Research Organization and dedicated personnel at the IWRS provider had access to treatment codes. The treatment allocation was not to be revealed prior to the planned study unblinding after database lock, except in medical emergencies.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AADvac1
    Arm description
    		 AADvac1
    Arm type
    		 Experimental

    Investigational medicinal product name
    AADvac1
    Investigational medicinal product code
    AADvac1
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The active pharmaceutical ingredient is Axon Peptide 108 (coupled to KLH). One dose contains 40 µg Axon Peptide 108 formulated with aluminium hydroxide (0.5 mg Al3+/0.30 mL dose) in a phosphate buffer (in single-use vials). Six vaccinations of AADvac1 were administered as subcutaneous injections at intervals of 4 weeks, to complete the 6-dose primary vaccination series (Visit V02 to V07). Booster vaccinations with AADvac1 were administered at intervals of approximately 3 months (14 weeks) thereafter, at visits V08a (Week 34), V10 (Week 48), V11a (Week 62), V13 (Week 76) and V14a (Week 90).

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    One dose of placebo contains aluminium hydroxide (0.5 mg Al3+/0.30 mL dose) in a phosphate buffer (in single-use vials). Six vaccinations of placebo were administered as subcutaneous injections at intervals of 4 weeks, to complete the 6-dose primary vaccination series (Visit V02 to V07). Booster vaccinations with placebo were administered at intervals of approximately 3 months (14 weeks) thereafter, at visits V08a (Week 34), V10 (Week 48), V11a (Week 62), V13 (Week 76) and V14a (Week 90).

    Number of subjects in period 1
    		AADvac1 Placebo
    Started
    117
    79
    Completed
    100
    63
    Not completed
    17
    16
         Adverse event, serious fatal
    2
    -
         Consent withdrawn by subject
    9
    10
         Physician decision
    2
    1
         Adverse event, non-fatal
    4
    2
         Unable to perform MRI examination
    -
    1
         Lost to follow-up
    -
    1
         Caregiver refused to accompany the patient
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AADvac1
    Reporting group description
    		 AADvac1

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 AADvac1 Placebo Total
    Number of subjects
    		 117 79 196
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 29 10 39
        From 65-84 years
    		 88 69 157
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.6 ± 8.37 72.7 ± 6.83 -
    Gender categorical
    Units: Subjects
        Female
    		 62 47 109
        Male
    		 55 32 87
    Subject analysis sets

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety set includes all subjects who have received at least one dose of study treatment and who have at least one post-Baseline value for safety. The Safety set was the primary data set of interest for the analysis of all safety variables. A conservative approach was used for the Safety set, any subjects that received AADvac1 at least once in the study was analysed in the AADvac1 group, and any subjects that received Placebo only was displayed in the Placebo group.

    Subject analysis set title
    Full Analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis set (FAS) was used for analyses of efficacy and included all randomised subjects who have received at least one dose of study treatment and who have at least one post-baseline value for efficacy. This population was the primary population of interest for the analysis of all efficacy variables. All subjects in the FAS was analysed according to the treatment they were randomised to receive and not according to what they actually received, in the event there is a discrepancy.

    Subject analysis sets values
    		 Safety set Full Analysis set
    Number of subjects
    196
    193
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    39
    39
        From 65-84 years
    157
    154
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    71.4 ± 7.84
    71.4 ± 7.83
    Gender categorical
    Units: Subjects
        Female
    109
    106
        Male
    87
    87

    End points

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    End points reporting groups
    Reporting group title
    AADvac1
    Reporting group description
    		 AADvac1

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety set includes all subjects who have received at least one dose of study treatment and who have at least one post-Baseline value for safety. The Safety set was the primary data set of interest for the analysis of all safety variables. A conservative approach was used for the Safety set, any subjects that received AADvac1 at least once in the study was analysed in the AADvac1 group, and any subjects that received Placebo only was displayed in the Placebo group.

    Subject analysis set title
    Full Analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The Full Analysis set (FAS) was used for analyses of efficacy and included all randomised subjects who have received at least one dose of study treatment and who have at least one post-baseline value for efficacy. This population was the primary population of interest for the analysis of all efficacy variables. All subjects in the FAS was analysed according to the treatment they were randomised to receive and not according to what they actually received, in the event there is a discrepancy.

    Primary: Drug-related Treatment Emergent Adverse Events

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    End point title
    		 Drug-related Treatment Emergent Adverse Events [1]
    End point description
    The protocol-defined safety endpoint was mapped to the incidence of Drag-related Treatment-Emergent Adverse Events as primary endpoint for the purpose of results posting.
    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: The adverse events have been assessed by summarizing the counts for treatment group. No formal comparison for purpose of primary analysis was performed.
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    117
    79
    Units: Rate
        number (not applicable)
    29
    20
    No statistical analyses for this end point

    Secondary: Clinical Dementia Rating - Sum of Boxes (CDR-SB) - FAS

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    End point title
    		 Clinical Dementia Rating - Sum of Boxes (CDR-SB) - FAS
    End point description
    CDR assesses a subject's cognitive and functional performance in six areas. For the purpose of the CDR-SB, the scores of the six individual boxes are added to obtain a total score of 0–18. Mean change in CDR-SB score from baseline to Week 104 is assessed comparing AADvac1 and placebo treatment groups.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    96
    61
    Units: Score
        least squares mean (standard error)
    3.35 ± 0.314
    3.23 ± 3.939
    Statistical analysis title
    		 MMRM analysis of Change from Baseline
    Statistical analysis description
    Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score Mixed Model Repeated Measures (MMRM) Analysis of Change from Baseline after two years of treatment
    Comparison groups
    AADvac1 v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.806
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.504
    Notes
    [2] - A mixed model with repeated measures (MMRM) analysis was used to analyse change from baseline to V16 (Week 104) for CDR-SB. The MMRM model included fixed effect terms for treatment group, visit, pooled country, sex, age, years of education, ApoE4 status, baseline MRI hippocampal volume and baseline CDR-SB. The Least Squares (LS) mean treatment difference (AADvac1 – Placebo) at Week 104 (Visit V16) was presented along with the 95% CI and the two-sided p-value for treatment effect.

    Secondary: ADCS-MCI-ADL-24 - FAS

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    End point title
    		 ADCS-MCI-ADL-24 - FAS
    End point description
    The assessment of the subject’s everyday functioning was performed via the Alzheimer’s Disease Co-operative Study – Activities of Daily Living Score (Mild Cognitive Impairment Version) ADCS-MCI-ADL, a structured informant interview with the subject’s caregiver. The assessment included a total of 24 items. The scores from items were summed to provide a total score, with lower values corresponding to a more severe impairment.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    96
    61
    Units: Score
        least squares mean (standard error)
    -11.7 ± 1.14
    -10.2 ± 1.42
    Statistical analysis title
    		 MMRM analysis of Change from Baseline
    Statistical analysis description
    Alzheimer's Disease Co-operative Study — Activities of Daily Living (Mild Cognitive Impairment Version) (ADCS-MCI-ADL) Mixed Model Repeated Measures (MMRM) Analysis of Change from Baseline at Visit 16 (Week 104)
    Comparison groups
    AADvac1 v Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.431
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.1
         upper limit
    		 2.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.83
    Notes
    [3] - A mixed model with repeated measures (MMRM) analysis was used to analyse change from baseline to V16 (Week 104) for ADCS-MCI-ADL-24. The MMRM model included fixed effect terms for treatment group, visit, pooled country, sex, age, years of education, ApoE4 status, baseline MRI hippocampal volume, baseline CDR-SB and ADL. The Least Squares (LS) mean treatment difference (AADvac1 – Placebo) at Week 104 (Visit V16) was presented along with the 95% CI and the two-sided p-value for treatment effect.

    Secondary: Custom Cognitive Battery Composite z-score - FAS

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    End point title
    		 Custom Cognitive Battery Composite z-score - FAS
    End point description
    A battery of 8 cognitive tests was used to assess subjects’ cognition, these comprised of measures of memory, executive function, attention and processing speed. The tests were administered as both computerised tests and ‘paper and pencil’ cognitive tests. The primary task scores from the individual tests were used to calculate a composite z-score for each subject for analysis at specific visit. The composite z-score was defined as the arithmetic mean of the individual z-scores obtained for each individual test from subjects within the relevant Analysis set. No weighting of tests was performed.
    End point type
    Secondary
    End point timeframe
    24-months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    91
    56
    Units: z-score
        least squares mean (standard error)
    -0.3537 ± 0.05533
    -0.3017 ± 0.06975
    Statistical analysis title
    		 MMRM analysis of Change from Baseline
    Statistical analysis description
    Custom Cognitive Battery (CCB) Composite z-Score Mixed Model Repeated Measures (MMRM) Analysis of Change from Baseline at Visit 16 (Week 104)
    Comparison groups
    AADvac1 v Placebo
    Number of subjects included in analysis
    147
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.561
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.0519
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2282
         upper limit
    		 0.1244
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08919
    Notes
    [4] - A mixed model with repeated measures (MMRM) analysis was used to analyse change from baseline to V16 (Week 104) for CCB composite z-score. The MMRM model included fixed effect terms for treatment group, visit, pooled country, sex, age, years of education, ApoE4 status, baseline MRI hippocampal volume and baseline CDR-SB. The Least Squares (LS) mean treatment difference (AADvac1 – Placebo) at Week 104 (Visit V16) was presented along with the 95% CI and the two-sided p-value for treatment effect.

    Secondary: Antibody Responders Rates - FAS

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    End point title
    		 Antibody Responders Rates - FAS [5]
    End point description
    Number of AADvac1-treated subjects who developed an IgG antibody response against the “Axon Peptide 108” component of AADvac1. A subject was defined as having an IgG antibody response if the subject had detectable Anti Axon Peptide 108 IgG antibodies (positive titres) at any post-Baseline visit i.e. > 100.
    End point type
    Secondary
    End point timeframe
    24 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The antibody response was assess by presenting the values over time. No statistical tests were performed.
    End point values
    		 AADvac1
    Number of subjects analysed
    116
    Units: Number of subjects
    114
    No statistical analyses for this end point

    Secondary: Mean IgG antibody titres against Axon peptide 108 Week 24 - FAS

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    End point title
    		 Mean IgG antibody titres against Axon peptide 108 Week 24 - FAS [6]
    End point description
    Geometric mean titre of AADvac1-induced IgG antibodies against Axon Peptide 108 after 6 initial vaccinations in 1-month intervals at Visit 8 (Week 24).
    End point type
    Secondary
    End point timeframe
    24 weeks
    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: The antibody response was assess by presenting the values over time. No statistical tests were performed.
    End point values
    		 AADvac1
    Number of subjects analysed
    114
    Units: Antibody titres
        geometric mean (confidence interval 95%)
    17349.8 (12809.1 to 23500.1)
    No statistical analyses for this end point

    Secondary: Mean IgG antibody titres against Axon peptide 108 Week 104 - FAS

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    End point title
    		 Mean IgG antibody titres against Axon peptide 108 Week 104 - FAS [7]
    End point description
    Geometric mean titre of AADvac1-induced IgG antibodies against Axon Peptide 108 after 6 initial vaccinations in 1-month intervals and 5 additional boosters in 3-month intervals at Visit 16 (Week 104).
    End point type
    Secondary
    End point timeframe
    104 weeks
    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: The antibody response was assess by presenting the values over time. No statistical tests were performed.
    End point values
    		 AADvac1
    Number of subjects analysed
    98
    Units: Titres
        geometric mean (confidence interval 95%)
    10351.3 (7287.7 to 14702.9)
    No statistical analyses for this end point

    Other pre-specified: p-Tau 181 in cerebrospinal fluid - FAS

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    End point title
    		 p-Tau 181 in cerebrospinal fluid - FAS
    End point description
    Increased phosphorylated-tau 181 (p-Tau 181) in cerebrospinal fluid (CSF) indicates the presence of tau pathology in the brain. CSF sampling was included as an optional part of the study and was collected in subjects that provided informed consent for this part of the study.
    End point type
    Other pre-specified
    End point timeframe
    24 months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    19
    7
    Units: ng/L
        least squares mean (standard error)
    -10.8 ± 3.52
    1.3 ± 6.13
    Statistical analysis title
    		 MMRM analysis of Change from Baseline
    Statistical analysis description
    p-Tau 181 Mixed Model Repeated Measures (MMRM) Analysis of Change from Baseline at Visit 16 (Week 104)
    Comparison groups
    AADvac1 v Placebo
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.076
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -12.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.6
         upper limit
    		 1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.55
    Notes
    [8] - A mixed model with repeated measures (MMRM) analysis was used to analyse change from baseline to V16 (Week 104). The MMRM model included fixed effect terms for treatment group, visit, pooled country, sex, age, years of education, ApoE4 status, baseline MRI hippocampal volume and baseline CDR-SB. The Least Squares (LS) mean treatment difference (AADvac1 – Placebo) at Week 104 (Visit V16) was presented along with the 95% CI and the two-sided p-value for treatment effect.

    Other pre-specified: Total Tau in cerebrospinal fluid - FAS

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    End point title
    		 Total Tau in cerebrospinal fluid - FAS
    End point description
    Increased total Tau in cerebrospinal fluid (CSF) indicates the ongoing neurodegenerative processes (intensity of neuronal damage) in the brain. CSF sampling was included as an optional part of the study and was collected in subjects that provided informed consent for this part of the study.
    End point type
    Other pre-specified
    End point timeframe
    24 months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    19
    7
    Units: ng/L
        least squares mean (standard error)
    -56.0 ± 42.30
    82.5 ± 69.72
    Statistical analysis title
    		 MMRM analysis of Change from Baseline
    Comparison groups
    Placebo v AADvac1
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.078
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -138.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -293.7
         upper limit
    		 16.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    75.1
    Notes
    [9] - A mixed model with repeated measures (MMRM) analysis was used to analyse change from baseline to V16 (Week 104). The MMRM model included fixed effect terms for treatment group, visit, pooled country, sex, age, years of education, ApoE4 status, baseline MRI hippocampal volume and baseline CDR-SB. The Least Squares (LS) mean treatment difference (AADvac1 – Placebo) at Week 104 (Visit V16) was presented along with the 95% CI and the two-sided p-value for treatment effect.

    Other pre-specified: Neurofilament light chain protein (NfL) in plasma - FAS

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    End point title
    		 Neurofilament light chain protein (NfL) in plasma - FAS
    End point description
    Neurofilament light chain protein (NfL) is a sensitive marker of neuroaxonal damage and its increased levels in plasma are thought to reflect ongoing neurodegeneration in patient with Alzheimer's disease.
    End point type
    Other pre-specified
    End point timeframe
    24 months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    99
    62
    Units: pg/mL
        least squares mean (standard error)
    2.094 ± 0.6881
    5.067 ± 0.8120
    Statistical analysis title
    		 ANCOVA analysis of Change from Baseline
    Statistical analysis description
    ANCOVA Analysis of Change from Baseline in Neurofilament light chain protein (NfL) Assay at Week 104
    Comparison groups
    AADvac1 v Placebo
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.972
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.849
         upper limit
    		 -1.096
    Notes
    [10] - The ANCOVA modelled the change from Baseline to Week 104 result including terms for treatment group, pooled country, sex, age, years of education, ApoE4 status, Baseline MRI hippocampal volume, and Baseline CDR SB. The LS mean treatment difference (AADvac1 – Placebo) was presented along with the 95 % CI and the two-sided p value for treatment effect.

    Other pre-specified: DTI Fracional anisotrophy of fornix - FAS

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    End point title
    		 DTI Fracional anisotrophy of fornix - FAS
    End point description
    Fractional anisotropy as the main parameter of white matter integrity measured by Diffusion Tensor Imaging (DTI), a MRI imaging method. The increase in Fractional anisotropy implies a greater degree of white matter organisation and integrity. Region Fornix includes pathway which originates from the hippocampus and connects regions affected severely in the disease.
    End point type
    Other pre-specified
    End point timeframe
    24 months
    End point values
    		 AADvac1 Placebo
    Number of subjects analysed
    12
    7
    Units: degree
        least squares mean (standard error)
    0.035 ± 0.0181
    -0.046 ± 0.0250
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    ANCOVA Analysis of Change from Baseline in Fractional anisotrophy of Fornix of Corpus callosum at Visit 16 (Week 104)
    Comparison groups
    Placebo v AADvac1
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.048
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.081
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.001
         upper limit
    		 0.162
    Notes
    [11] - The ANCOVA modelled the change from Baseline to Week 104 result including terms for treatment group, pooled country, sex, age, years of education, ApoE4 status, Baseline MRI hippocampal volume, and Baseline CDR SB. The LS mean treatment difference (AADvac1 – Placebo) was presented along with the 95 % CI and the two-sided p value for treatment effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months
    Adverse event reporting additional description
    The protocol-defined safety endpoint was mapped to the incidence of drug-related AEs as primary endpoint for the purpose of results posting.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    AADvac1
    Reporting group description
    		 AADvac1

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Serious adverse events
    		 AADvac1 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 117 (17.09%)
    19 / 79 (24.05%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    B-cell lymphoma
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleomorphic adenoma
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hospitalisation
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular swelling
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottic cyst
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Neuropsychiatric symptoms
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sternal fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Motor dysfunction
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive disorder
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenic infarction
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Keratitis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Incarcerated inguinal hernia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 79 (2.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Septic encephalopathy
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomembranous colitis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 79 (1.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 79 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AADvac1 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 117 (84.62%)
    64 / 79 (81.01%)
    Investigations
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    11 / 117 (9.40%)
    4 / 79 (5.06%)
         occurrences all number
    12
    4
    Blood folate decreased
         subjects affected / exposed
    7 / 117 (5.98%)
    7 / 79 (8.86%)
         occurrences all number
    7
    7
    Fibrin D dimer increased
         subjects affected / exposed
    7 / 117 (5.98%)
    10 / 79 (12.66%)
         occurrences all number
    8
    12
    C-reactive protein increased
         subjects affected / exposed
    6 / 117 (5.13%)
    1 / 79 (1.27%)
         occurrences all number
    6
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    7 / 117 (5.98%)
    3 / 79 (3.80%)
         occurrences all number
    9
    3
    Fall
         subjects affected / exposed
    6 / 117 (5.13%)
    2 / 79 (2.53%)
         occurrences all number
    7
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 117 (9.40%)
    6 / 79 (7.59%)
         occurrences all number
    15
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    22 / 117 (18.80%)
    13 / 79 (16.46%)
         occurrences all number
    55
    23
    Dizziness
         subjects affected / exposed
    12 / 117 (10.26%)
    9 / 79 (11.39%)
         occurrences all number
    17
    10
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 117 (11.11%)
    6 / 79 (7.59%)
         occurrences all number
    25
    13
    Injection site erythema
         subjects affected / exposed
    38 / 117 (32.48%)
    14 / 79 (17.72%)
         occurrences all number
    129
    37
    Injection site nodule
         subjects affected / exposed
    28 / 117 (23.93%)
    5 / 79 (6.33%)
         occurrences all number
    90
    9
    Injection site swelling
         subjects affected / exposed
    25 / 117 (21.37%)
    6 / 79 (7.59%)
         occurrences all number
    69
    14
    Injection site pain
         subjects affected / exposed
    18 / 117 (15.38%)
    10 / 79 (12.66%)
         occurrences all number
    36
    21
    Injection site pruritus
         subjects affected / exposed
    9 / 117 (7.69%)
    1 / 79 (1.27%)
         occurrences all number
    23
    3
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    9 / 117 (7.69%)
    2 / 79 (2.53%)
         occurrences all number
    14
    5
    Diarrhoea
         subjects affected / exposed
    8 / 117 (6.84%)
    10 / 79 (12.66%)
         occurrences all number
    10
    14
    Nausea
         subjects affected / exposed
    7 / 117 (5.98%)
    5 / 79 (6.33%)
         occurrences all number
    18
    9
    Psychiatric disorders
    Depression
         subjects affected / exposed
    7 / 117 (5.98%)
    3 / 79 (3.80%)
         occurrences all number
    7
    3
    Confusional state
         subjects affected / exposed
    6 / 117 (5.13%)
    0 / 79 (0.00%)
         occurrences all number
    7
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 117 (5.98%)
    3 / 79 (3.80%)
         occurrences all number
    7
    5
    Back pain
         subjects affected / exposed
    7 / 117 (5.98%)
    5 / 79 (6.33%)
         occurrences all number
    8
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 117 (16.24%)
    12 / 79 (15.19%)
         occurrences all number
    34
    15
    Urinary tract infection
         subjects affected / exposed
    14 / 117 (11.97%)
    12 / 79 (15.19%)
         occurrences all number
    21
    22
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 117 (7.69%)
    7 / 79 (8.86%)
         occurrences all number
    14
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2016
    AC-AD-003_Clinical study protocol_v3.0_29Apr2016 included the following changes: • Exclusion criteria were revised. • The options for re-screening were adjusted. • Text for the packaging and labelling of the IMP was revised to be consistent with the IMPD. • Storage and accountability of the IMP were revised. • Minor corrections and clarifications in Prior and concomitant therapy sections were made. • The description of medical history was revised. • The wording for subject information and informed consent was corrected in line with GCP and local legislations.
    10 Nov 2016
    AC-AD-003_Clinical study protocol_v4.0_19Sep2016 included the following changes: • Inclusion criterion 4 was expanded to allow biomarker evidence of the AD pathophysiological process to be satisfied either by medial temporal lobe atrophy seen in MRI, or by a positive AD biomarker signature in the CSF. • Exclusion criteria were revised. • Safety procedures were clarified. • Additional safety procedures related to eventual meningoencephalitis were included: a meningoencephalitis emergency treatment plan was included in the protocol. • Minor corrections were implemented and various changes were made to improve wording, consistency and clarity throughout the document. • Sponsor details were updated.
    05 Jan 2017
    AC-AD-003_Clinical study protocol_v5.0_19Dec2016 included the following changes: • The vaccination regimen was changed to administer 5 booster vaccinations at intervals of approximately 3 months, instead of the planned 2 booster vaccinations at intervals of 6 months. • Vaccine administration instructions were adjusted. • Clarification was provided for the order of assessments at Screening and subsequent visits. • Minor corrections were implemented and various changes were made to improve wording, consistency and clarity throughout the document.
    17 Aug 2017
    AC-AD-003_Clinical study protocol_v6.0_21Jun2017 included the following changes: • The storage, handling, and administration section was updated and Instructions for administration of the vaccine were updated. • Packaging and Labelling of Investigational Medicinal Product was updated. • The secondary endpoints regarding immunogenicity were revised to include a definition of a responder. • Exploratory endpoints were expanded. • The visit windows for some visits were expanded. • Additional preclinical study data was included. • The possibility to arrange unscheduled visits for purposes other than safety assessment was included.
    09 Mar 2018
    AC-AD-003_CT PROTOCOL_7.0_FINAL_2018-01-24 included the following changes: • Visit windows were broaden for some procedures. • Minor revisions were made to the text for endpoints and exclusion criteria and end of study definition to improve clarity. • Various formal changes were made to improve wording, consistency and clarity throughout the document.
    14 Aug 2018
    AC-AD-003_CT PROTOCOL_8.0_FINAL_2018-06-18 included the following changes: • The list of visits where CSF sampling may be performed was expanded. • Visit window for some procedures was clarified. • Various formal changes were made to improve wording, consistency and clarity throughout the document.

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

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