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    Clinical Trial Results:
    A Phase 2a Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel-group Safety and Tolerability Study of PQ912 in Subjects with Early Alzheimer’s Disease (SAPHIR)

    Summary
    EudraCT number
    		 2014-001967-11
    Trial protocol
    		 NL   FI   DE   SE   BE   ES  
    Global end of trial date
    22 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Apr 2018
    First version publication date
    12 Apr 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PBD 01071
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02389413
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Probiodrug AG
    Sponsor organisation address
    Weinbergweg 22, Halle, Germany, 06120
    Public contact
    Suzanne Bruins, Probiodrug AG, 0049 3455559900, info@probiodrug.de
    Scientific contact
    Suzanne Bruins, Probiodrug AG, 0049 3455559900, info@probiodrug.de
    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
    05 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the safety and tolerability of multiple doses of PQ912 compared with placebo in subjects with early stage AD.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with the International Council for Harmonisation E6 Good Clinical Practice guidelines and applicable national laws and regulatory requirements. Each patient who wanted to participate needed to have a study partner (friend or relative) who also consented to the study and needed to accompany the patient at each visit. A Safety Oversight Expert was responsible for making recommendations to the Steering Committee to either continue the study unchanged, or to continue with modifications or to (temporary) stop the study, based on observed safety.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Mar 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Sweden: 7
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Finland: 24
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 50
    Worldwide total number of subjects
    120
    EEA total number of subjects
    120
    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)
    25
    From 65 to 84 years
    94
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment started in March 2015 and stopped in December 2016.

    Pre-assignment
    Screening details
    		 Procedures at screening included documentation of medical history, physical and neurological examination, assessment of vital signs, electrocardiogram (ECG), Mini Mental State Exam (MMSE), Geriatric Depression Scale (GDS), neuropsychological test battery, Magnetic Resonance Imaging (MRI) and EEG. Blood, urine and CSF samples were collected.

    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
    To preserve the blinding of the study, batch numbers for placebo and PQ912 were the same. Emergency unblinding for (S)AEs could be done through Electronic Data Capture (EDC). This option was to be used only if the subject’s wellbeing required knowledge of the subject’s treatment assignment and only after the investigator had made an effort to contact the Sponsor (or delegate). All calls resulting in unblinding were to be recorded and reported by EDC.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects receiving placebo administered orally, BID, 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Week 1: Matching Placebo tablets. Weeks 2-12: Matching Placebo tablets. The tablet strength of PQ912 is 200 mg, therefore subjects were required to take 2 tablets per dosing (in Week 1) or 4 tablets per dosing (in Weeks 2-12).

    Arm title
    		 PQ912
    Arm description
    		 Subjects receiving PQ912 administered orally, BID, 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    PQ912
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Week 1: PQ912 400 mg BID (total daily dose 800 mg). Weeks 2-12: PQ912 800 mg BID (total daily dose 1600 mg). The tablet strength of PQ912 is 200 mg, therefore subjects were required to take 2 tablets per dosing (in Week 1) or 4 tablets per dosing (in Weeks 2-12).

    Number of subjects in period 1
    		Placebo PQ912
    Started
    60
    60
    Completed
    60
    55
    Not completed
    0
    5
         Consent withdrawn by subject
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo administered orally, BID, 12 weeks

    Reporting group title
    PQ912
    Reporting group description
    		 Subjects receiving PQ912 administered orally, BID, 12 weeks

    Reporting group values
    		 Placebo PQ912 Total
    Number of subjects
    		 60 60 120
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72 ( 6.7 ) 70.8 ( 7.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 36 64
        Male
    		 32 24 56
    ApoE genotype
    Apolipoprotein E (ApoE) is a class of proteins involved in the metabolism of fats in the body. APOE is polymorphic, with three major alleles: APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158). These differences alter APOE structure and function. The E4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups.
    Units: Subjects
        E4 positive
    		 43 38 81
        E4 negative
    		 16 20 36
        Missing
    		 1 2 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo administered orally, BID, 12 weeks

    Reporting group title
    PQ912
    Reporting group description
    		 Subjects receiving PQ912 administered orally, BID, 12 weeks

    Primary: Safety primary composite endpoint

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    End point title
    		 Safety primary composite endpoint
    End point description
    The safety primary composite endpoint was based on: • Discontinuation of a subject due to SAE • Discontinuation of a subject due to AE with severity ≥ grade 3 according to CTCAE • Discontinuation of a subject due to an extreme laboratory parameter
    End point type
    Primary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: number of subjects
        Composite safety
    0
    6
        Discontinuation subject due to SAE
    0
    6
        Discontinuation subject due to AE ≥ CTCAE Grade 3
    0
    6
        Discontinuation subject due to extreme lab value
    0
    0
    Statistical analysis title
    		 Composite Safety
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.027
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.18
    Notes
    [1] - RR was not possible since 1 cell was zero.
    Statistical analysis title
    		 Discontinuation subject due to SAE
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.027
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.18
    Notes
    [2] - RR was not possible since 1 cell was zero .
    Statistical analysis title
    		 Discontinuation subject due to AE ≥ CTCAE Grade 3
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.027
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.18
    Notes
    [3] - RR was not possible since 1 cell was zero.
    Statistical analysis title
    		 Discontinuation subject due to extreme lab value
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0
         upper limit
    		 0
    Notes
    [4] - RR was not possible since both cells were zero.

    Primary: Tolerability primary composite endpoint

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    End point title
    		 Tolerability primary composite endpoint
    End point description
    A composite tolerability endpoint composed of: 1) The number of subjects who experienced a dose adjustment, defined as a reduction of dose from 800 BID to 400 BID, and 2) The number of subjects experiencing non-adherence to randomized treatment, defined as using less than 75% of the prescribed dose in 4 consecutive weeks including at least one week with less than 50%, or three or more consecutive days in total or seven days of interrupted use during the full 12 weeks.
    End point type
    Primary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: number of subjects
        Dose adjustment during treatment period
    5
    5
        Non-adherence to randomised treatment
    2
    26
    Statistical analysis title
    		 Composite tolerability
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2
         upper limit
    		 10.11
    Statistical analysis title
    		 Dose adjustment during treatment period
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 3.28
    Statistical analysis title
    		 Non-adherence to randomised treatment
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.23
         upper limit
    		 52.35

    Secondary: Number of SAEs

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    End point title
    		 Number of SAEs
    End point description
    The number of SAEs occurring during the study was recorded.
    End point type
    Secondary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: number of events
        Number of SAEs
    5
    13
    No statistical analyses for this end point

    Secondary: Number of AEs with severity ≥ grade 3 according to CTCAE

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    End point title
    		 Number of AEs with severity ≥ grade 3 according to CTCAE
    End point description
    The number of AEs with severity ≥ grade 3 according to CTCAE occurring during the study was recorded.
    End point type
    Secondary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: number of events
        Number of AEs of ≥ CTCAE Grade 3
    3
    9
    No statistical analyses for this end point

    Secondary: Time to dose adjustment (time in days after randomisation)

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    End point title
    		 Time to dose adjustment (time in days after randomisation)
    End point description
    The time to dose adjustment (time in days after randomisation) was recorded during the study. Dose adjustment, i.e. reduction, was defined as a reduction of dose from 800 mg BID to 400 mg BID. If applicable, median survival time is reported. Median survival time cannot be assessed because less than 50 % of subjects showed an event before the end of study. In this case, 0 = NA.
    End point type
    Secondary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: days
    median (standard deviation)
        Time to dose adjustment
    0 ( 0 )
    0 ( 0 )
    Attachments
    		 Time to dose adjustment
    No statistical analyses for this end point

    Secondary: Time to non-adherence (time in weeks after randomisation)

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    End point title
    		 Time to non-adherence (time in weeks after randomisation)
    End point description
    Time to non-adherence (time in weeks after randomisation) was recorded during the study. Non-adherence was defined as using <75% of the prescribed dose in 4 consecutive weeks including at least 1 week with <80%, or ≥3 consecutive days in total or 7 days of interrupted use during the full 12 weeks. If applicable, median survival time is reported. Median survival time cannot be assessed because less than 50 % of subjects showed an event before the end of study. In this case, 0 = NA.
    End point type
    Secondary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: weeks
    median (standard deviation)
        Time to non-adherence
    0 ( 0 )
    0 ( 0 )
    Attachments
    		 Untitled (Filename: Figure 14.4.2.jpg)
    No statistical analyses for this end point

    Secondary: Time to non-adherence, dose adjustment, discontinuation due to SAE, AE-CTCAE3+ or extreme lab (time in weeks after randomisation).

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    End point title
    		 Time to non-adherence, dose adjustment, discontinuation due to SAE, AE-CTCAE3+ or extreme lab (time in weeks after randomisation).
    End point description
    Time to non-adherence, dose adjustment, discontinuation due to SAE, AE-CTCAE3+ or extreme laboratory values were recorded during the study. Dose adjustment, i.e. reduction, was defined as a reduction of dose from 800 mg BID to 400 mg BID. Non-adherence was defined as using <75% of the prescribed dose in 4 consecutive weeks including at least 1 week with <80%, or ≥3 consecutive days in total or 7 days of interrupted use during the full 12 weeks. If applicable, median survival time is reported. In this case, 0 = NA.
    End point type
    Secondary
    End point timeframe
    From screening to last study visit. Screening to randomization: up to 12 weeks. Randomization to last study visit: 16 weeks.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    60
    60
    Units: weeks
    median (standard deviation)
        Time to event
    0 ( 0 )
    0 ( 0 )
    Attachments
    		 Time to event
    No statistical analyses for this end point

    Secondary: Glutaminyl cyclase (QC) activity in cerebrospinal fluid (CSF)

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    End point title
    		 Glutaminyl cyclase (QC) activity in cerebrospinal fluid (CSF)
    End point description
    QC activity is the primary target of the QC inhibitor PQ912.
    End point type
    Secondary
    End point timeframe
    CSF samples for biomarker assessment were obtained at screening and V5/End-of-treatment (EoT) visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    41
    26
    Units: mU/L
    median (inter-quartile range (Q1-Q3))
        Baseline
    120.8 (101.3 to 140.2)
    110.2 (94.8 to 134.2)
        End of treatment (EoT)
    120.3 (104.1 to 137.5)
    35.6 (29.7 to 63.2)
        Change over time
    -0.6 (-5.5 to 4.3)
    -68.9 (-87 to -56.4)
    Statistical analysis title
    		 QC activity
    Statistical analysis description
    An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001
    Method
    		 ANCOVA
    Parameter type
    		 mean difference in log-transformed value
    Point estimate
    -0.454
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.507
         upper limit
    		 -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.027
    Notes
    [5] - 65 subjects were included in this Per Protocol (PP) analysis.

    Secondary: Target Occupancy (TO)

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    End point title
    		 Target Occupancy (TO) [6]
    End point description
    The target of PQ912, the QC enzyme, is present in the CSF and its activity can be measured ex vivo in CSF samples. Based on the measured QC activities pre- and post-dosing the TO can be calculated. The TO will give important information about the dose-relatedness of QC inhibition as a prerequisite for any effect on disease related pathological pathways and on cognition. TO was calculated for CSF samples taken within 24 hours after last intake at Visit 5/EOT, where the corresponding QC activity at screening was available. Measurement of QC activity in vitro required a sample dilution and is sensitive to substrate concentration relative to Michaelis Menten constant (Km).
    End point type
    Secondary
    End point timeframe
    CSF samples for biomarker assessment were obtained at screening and V5/End-of-treatment (EoT) visits.
    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: TO was not calculated for the placebo group.
    End point values
    		 PQ912
    Number of subjects analysed
    25
    Units: percent
    median (full range (min-max))
        TO
    92 (82 to 96)
    No statistical analyses for this end point

    Secondary: pGlu-A-beta oligomer

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    End point title
    		 pGlu-A-beta oligomer
    End point description
    The production of the toxic species pGlu-A-beta might be reduced by using the QC inhibitor PQ 912 and was therefore selected as biomarker in this study.
    End point type
    Secondary
    End point timeframe
    CSF samples for biomarker assessment were obtained at screening and V5/E0T visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    42
    25 [7]
    Units: AU
    median (inter-quartile range (Q1-Q3))
        Baseline
    0.01 (0 to 0.54)
    0.51 (0.22 to 0.99)
        EoT
    0.26 (0 to 0.58)
    0.44 (0 to 1.42)
        Change over time
    0 (-0.23 to 0.4)
    0 (-0.31 to 0.85)
    Notes
    [7] - 25 subjects were analysed at baseline and for change over time, 26 subjects were analysed at EoT
    Statistical analysis title
    		 pGlu-A-beta oligomer
    Statistical analysis description
    The data was dichotomized (yes/no LLOQ), reported in cross tables for baseline and EOT assessments per group and analysed using Mantel Haenszel statistics with treatment andV5/EOT as variables and V1 as confounder.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.369
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 6.04
    Notes
    [8] - 68 subjects were included in this PP analysis

    Secondary: Neurogranin

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    End point title
    		 Neurogranin
    End point description
    Neurogranin is a biomarker associated with synaptic dysfunction. Increases are seen in patients with AD.
    End point type
    Secondary
    End point timeframe
    CSF samples for biomarker assessment were obtained at screening and V5/EoT visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    41 [9]
    26
    Units: pg/ml
    median (inter-quartile range (Q1-Q3))
        Baseline
    419 (348 to 583)
    422 (314 to 530)
        EoT
    411 (328 to 517)
    391 (298 to 516)
        Change over time
    0 (-31.5 to 16)
    -22.5 (-45 to 12)
    Notes
    [9] - 41 subjects were analysed at baseline and EoT, 40 subjects were analysed for change over time
    Statistical analysis title
    		 Neurogranin
    Statistical analysis description
    An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.194
    Method
    		 ANCOVA
    Parameter type
    		 mean difference in log-transformed value
    Point estimate
    -0.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.054
         upper limit
    		 0.011
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.016
    Notes
    [10] - 64 subjects were included in this PP analysis

    Secondary: YKL40

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    End point title
    		 YKL40
    End point description
    YKL-40, a marker of astrocyte activation (inflammation), has been shown to be increased in subjects with AD and mild cognitive impairment due to AD, compared to matched controls and is evaluated for its potential as therapeutic marker.
    End point type
    Secondary
    End point timeframe
    CSF samples for biomarker assessment were obtained at screening and V5/EoT visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    41 [11]
    26
    Units: pg/ml
    median (inter-quartile range (Q1-Q3))
        Baseline
    367 (295 to 476)
    292 (232 to 412)
        EoT
    353 (274 to 469)
    297 (219 to 384)
        Change over time
    -8 (-28.5 to 20)
    -3.5 (-28 to 3)
    Notes
    [11] - 41 subjects were analysed at baseline and EoT, 40 subjects were analysed for change over time
    Statistical analysis title
    		 YKL40
    Statistical analysis description
    An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 = 0.025
    Method
    		 ANCOVA
    Parameter type
    		 mean difference in log-transformed value
    Point estimate
    -0.032
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.059
         upper limit
    		 -0.004
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.014
    Notes
    [12] - 64 subjects were included in this PP analysis

    Secondary: Relative theta power

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    End point title
    		 Relative theta power
    End point description
    It has been widely established that in AD, eyes closed resting state EEG shows distinct changes reflecting abnormalities of brain oscillatory activity. In the earliest phase of AD, especially in late onset AD as opposed to young onset AD (< 65 years), the EEG can be normal. With progression of the disease, there is a gradual, diffuse slowing of brain activity. First, theta power increases and beta power decreases, followed by slowing and diminished reactivity of the alpha peak frequency. In later stages, alpha power decreases and finally delta power increases. An increase in relative theta power is thus regarded as the most sensitive oscillatory activity marker in the earliest stages of AD.
    End point type
    Secondary
    End point timeframe
    EEG endpoints were assessed at screening and V5/EoT visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    48
    28
    Units: not applicable
    median (inter-quartile range (Q1-Q3))
        Baseline
    0.1282 (0.1028 to 0.1886)
    0.1547 (0.103 to 0.23)
        EoT
    0.1622 (0.1081 to 0.2018)
    0.1446 (0.1078 to 0.2145)
        Change over time
    0.016 (-0.0036 to 0.0338)
    -0.0018 (-0.0285 to 0.0113)
    Statistical analysis title
    		 Relative theta power
    Statistical analysis description
    An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.002
    Method
    		 ANCOVA
    Parameter type
    		 mean difference in log-transformed value
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.114
         upper limit
    		 -0.026
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.022
    Notes
    [13] - 74 subjects were included in this PP analysis

    Secondary: One Back Test

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    End point title
    		 One Back Test
    End point description
    The One Back Test is designed to assess working memory.
    End point type
    Secondary
    End point timeframe
    Neuropsychological endpoints were assessed at screening, baseline and V5/EoT visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    56
    35
    Units: log10 ms
    median (inter-quartile range (Q1-Q3))
        Baseline
    2.992 (2.907 to 3.089)
    3.045 (2.92 to 3.153)
        EoT
    3.024 (2.916 to 3.12)
    3.047 (2.92 to 3.128)
        Change over time
    0.004 (-0.041 to 0.069)
    -0.025 (-0.087 to 0.025)
    Statistical analysis title
    		 One Back Test
    Statistical analysis description
    An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.144
    Method
    		 ANCOVA
    Parameter type
    		 mean difference in log-transformed value
    Point estimate
    -0.027
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.063
         upper limit
    		 0.009
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.018
    Notes
    [14] - 88 subjects were included in this PP analysis

    Secondary: Detection Test

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    End point title
    		 Detection Test
    End point description
    The Detection Test is designed to assess psychomotor speed.
    End point type
    Secondary
    End point timeframe
    Neuropsychological endpoints were assessed at screening, baseline and V5/EoT visits.
    End point values
    		 Placebo PQ912
    Number of subjects analysed
    56
    35
    Units: log10 ms
    median (inter-quartile range (Q1-Q3))
        Baseline
    2.562 (2.45 to 2.675)
    2.533 (2.449 to 2.603)
        EoT
    2.597 (2.507 to 2.661)
    2.537 (2.425 to 2.587)
        Change over time
    0.008 (-0.029 to 0.081)
    0.002 (-0.039 to 0.055)
    Statistical analysis title
    		 Detection Test
    Statistical analysis description
    An analysis of covariance(ANCOVA) with treatment, gender, ApoE (E4 allele present or not) and country(stratification) as factors and time between screening and baseline, baseline measure of the endpoint and age as covariates, was performed. The assumption of normally distributed residuals was not met and therefore data were log transformed.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.397
    Method
    		 ANCOVA
    Parameter type
    		 mean difference in log-transformed value
    Point estimate
    -0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.083
         upper limit
    		 0.033
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.029
    Notes
    [15] - 88 subjects were included in this PP analysis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening to end of study. Screening to randomization: between 4 and 12 weeks. Randomization to end of study: 16 weeks.
    Adverse event reporting additional description
    Note: the frequency threshold is => 3 subjects (2.5%) reporting in total.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo administered orally, BID, 12 weeks. All non-serious adverse events reported here are treatment-emergent.

    Reporting group title
    PQ912
    Reporting group description
    		 Subjects receiving PQ912 administered orally, BID, 12 weeks. All non-serious adverse events reported here are treatment-emergent.

    Serious adverse events
    		 Placebo PQ912
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 60 (5.00%)
    8 / 60 (13.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrilation
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Optic ischaemic neuropathy
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis toxic
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (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
    Gastroenteritis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 60 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo PQ912
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 60 (66.67%)
    45 / 60 (75.00%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 60 (6.67%)
         occurrences all number
    4
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 60 (5.00%)
         occurrences all number
    2
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 60 (6.67%)
    2 / 60 (3.33%)
         occurrences all number
    4
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    3
    1
    Constipation
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 60 (5.00%)
         occurrences all number
    0
    3
    Diarrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    5 / 60 (8.33%)
         occurrences all number
    1
    6
    Nausea
         subjects affected / exposed
    4 / 60 (6.67%)
    8 / 60 (13.33%)
         occurrences all number
    5
    8
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 60 (6.67%)
         occurrences all number
    2
    5
    Urticaria
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 60 (6.67%)
         occurrences all number
    0
    5
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 60 (1.67%)
         occurrences all number
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 60 (5.00%)
         occurrences all number
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 60 (6.67%)
         occurrences all number
    4
    4
    Viral upper respiratory tract infection
         subjects affected / exposed
    8 / 60 (13.33%)
    1 / 60 (1.67%)
         occurrences all number
    8
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 60 (6.67%)
         occurrences all number
    1
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2014
    Reason for amendment: Protocol has been updated after comments from regulatory authorities Main changes: - Statistical considerations section updated to be aligned with protocol - Baseline MRI, EEG and Lumbar Puncture moved to Screening MRI, EEG and Lumbar Puncture - Added to the protocol that treatment with Standard of Care AD treatment may be started during the course of the study in case of clinical worsening - Hepatitis A and C assessments in blood added
    12 Feb 2015
    Reason for amendment: Protocol has been updated after comments from regulatory authorities. Main changes: - Definition of primary safety endpoint (composite endpoint) made more clear - Added information on the power calculations - Clarified that in Sweden no study partner would be used - Clarification on dose-adjustments during the study - GnRH and TRH measurements were added
    08 Dec 2015
    Reason for amendment: to improve recruitment/eligibility and changed on request of regulatory authorities Main changes: - The per patient screening period extended - To allow for re-screening - Tau/A-beta ratio added to inclusion criteria - Use of Souvenaid is allowed - Added: precautionary measures due to photo toxicity - Added prohibited mediation for inclusion

    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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