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    Clinical Trial Results:
    A Phase 2b Multicentre, Randomised, Double-blind, Placebo-controlled, Parallel Group Dose Finding, Safety, Tolerability and Efficacy Study of PQ912 in Subjects with Mild Cognitive Impairment and Mild Dementia due to Alzheimer’s Disease

    Summary
    EudraCT number
    		 2019-003532-23
    Trial protocol
    		 DK   DE   NL   ES   PL  
    Global end of trial date
    12 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Feb 2025
    First version publication date
    15 Feb 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PBD 01180
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04498650
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vivoryon Therapeutics N.V.
    Sponsor organisation address
    Weinbergweg 22, Halle, Germany, 06120
    Public contact
    CBO, Vivoryon Therapeutics N.V., +49 345 5559900, info@vivoryon.com
    Scientific contact
    CBO, Vivoryon Therapeutics N.V., +49 345 5559900, info@vivoryon.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To assess the safety and tolerability of PQ912 • To evaluate the efficacy of PQ912 on working memory and attention
    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 could accompany the patient at each visit. A Data Safety Monitoring Board (DSMB) conducted several unblinded safety assessments of the study and 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 the observed safety profile, and provided recommendations for the dose selection of PQ912 after the first 90 subjects who reached Week 24.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Jul 2020
    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
    Netherlands: 41
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 65
    Country: Number of subjects enrolled
    Denmark: 85
    Country: Number of subjects enrolled
    Germany: 64
    Worldwide total number of subjects
    259
    EEA total number of subjects
    259
    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)
    74
    From 65 to 84 years
    185
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at study sites in Spain, Denmark, Poland, Germany and The Netherlands. The first ICF was signed on 13 July 2020. The last ICF was signed on 07 October 2022.

    Pre-assignment
    Screening details
    		 Documentation of medical history, physical and neurological examination, vital signs, ECG, MMSE, GDS, neuropsychological test battery, WAIS-IV, WLA, A-IADL-Q, and MRI. Blood, urine and CSF sample collection. 670 subjects were screened. -Not meeting inclusion criteria: 397 subjects -Consent withdrawn by subject: 10 subjects -Other: 4 subjects

    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
    		 Investigator, Monitor, Data analyst, Carer, Subject
    Blinding implementation details
    To preserve blinding, PQ912 and placebo tablets were identical in appearance. Emergency unblinding for (S)AEs could be done through EDC. This option was only to be used 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 in the EDC.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PQ912
    Arm description
    		 Subjects receiving PQ912 administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.
    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 1-2: PQ912 50 mg QD (total daily dose 50 mg) Weeks 3-4: PQ912 50 mg BID (total daily dose 100 mg) Weeks 5-8: PQ912 150 mg BID (total daily dose 300 mg) Weeks 9-12: PQ912 300 mg BID (total daily dose 600 mg) Weeks 13-48 (up to maximum Week 96): PQ912 300 mg or 600 mg BID (total daily dose 600 mg or 1200 mg) The tablet strength of PQ912 is 50 mg and 150 mg, therefore, subjects were required to take 1 tablet per dosing (Weeks 1-8), 2 tablets per dosing (Weeks 9-12), and 2 or 4 tablets per dosing (Weeks 13-48, up to maximum Week 96).

    Arm title
    		 Placebo
    Arm description
    		 Subjects receiving placebo administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.
    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 1-2: Matching Placebo tablets, 1 tablet QD Weeks 3-4: Matching Placebo tablets, 1 tablet BID Weeks 5-8: Matching Placebo tablets, 1 tablet BID Weeks 9-12: Matching Placebo tablets, 2 tablets BID Weeks 13-48 (up to maximum Week 96): Matching Placebo tablets, 2 or 4 tablets BID The tablet strength of PQ912 is 50 mg and 150 mg, therefore, subjects were required to take 1 tablet per dosing (Weeks 1-8), 2 tablets per dosing (Weeks 9-12), and 2 or 4 tablets per dosing (Weeks 13-48, up to maximum Week 96).

    Number of subjects in period 1
    		PQ912 Placebo
    Started
    142
    117
    Completed
    122
    106
    Not completed
    20
    11
         Consent withdrawn by subject
    15
    7
         Physician decision
    -
    1
         Adverse event, non-fatal
    4
    3
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PQ912
    Reporting group description
    		 Subjects receiving PQ912 administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.

    Reporting group values
    		 PQ912 Placebo Total
    Number of subjects
    		 142 117 259
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 68.6 ( 7.08 ) 68.3 ( 7.78 ) -
    Gender categorical
    Units: Subjects
        Female
    		 69 62 131
        Male
    		 73 55 128
    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 homozygous
    		 36 30 66
        E4 heterozygous
    		 61 51 112
        E4 negative
    		 33 26 59
        Not detected
    		 4 3 7
        Missing
    		 8 7 15

    End points

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    End points reporting groups
    Reporting group title
    PQ912
    Reporting group description
    		 Subjects receiving PQ912 administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects randomly assigned to study treatment, who received at least one treatment dose (PQ912 or placebo), and with at least one post-baseline value. Subjects who discontinued treatment before Week 48 were included in the analysis.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who had taken at least one dose of PQ912 or placebo.

    Primary: Change with time on working memory and attention as measured by the combined Z-score of the Detection test, Identification test and the ‘One Back’ test (attention and working memory domains) of the neuropsychological test battery (NTB)

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    End point title
    		 Change with time on working memory and attention as measured by the combined Z-score of the Detection test, Identification test and the ‘One Back’ test (attention and working memory domains) of the neuropsychological test battery (NTB)
    End point description
    The CogState NTB is composed of cognitive tests indexing executive function (Detection test), attention (Identification test), and working memory (One Back test); key cognitive skills known to be compromised early in the AD process. The primary efficacy endpoint was derived as the combined Z-score calculated as the arithmetic mean of the 3 Z-scores of the Detection test, Identification test, and the One Back test (attention and working memory domains), with a higher Z-score indicating a better performance. The rate of change of the combined Z-score over time was analysed via a random coefficients model to estimate the total slope (weeks; ie change in Z-score per week) in each treatment group with the difference in total slope and its associated standard error, CI, and 2-sided p-value. Population: Full Analysis Set
    End point type
    Primary
    End point timeframe
    From baseline up to Week 48 or Week 96 (depending on the time of randomisation).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Not applicable
    least squares mean (standard error)
        Baseline
    -1.3321 ( 0.0778 )
    -1.2195 ( 0.0859 )
        Week 96
    -1.6175 ( 0.1011 )
    -1.4768 ( 0.1120 )
        Change from baseline at Week 96
    -0.2853 ( 0.0816 )
    -0.2573 ( 0.0917 )
    Statistical analysis title
    		 Primary total slope random coefficients analysis
    Statistical analysis description
    The difference in total slope (active vs placebo) was estimated using the random coefficients model. Random, subject-specific intercepts and slopes were assumed, taken from a bivariate normal distribution, centered at (0,0). The covariance structure was unrestricted. All valid observations were used. For missed baseline data at the individual test level, the most recent screening assessments were used.
    Comparison groups
    PQ912 v Placebo
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8194
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope (weeks) difference
    Point estimate
    -0.0003
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0028
         upper limit
    		 0.0022

    Secondary: Change with time in overall cognition as measured by the combined Z-score of the CogState Brief Battery (CBB)

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    End point title
    		 Change with time in overall cognition as measured by the combined Z-score of the CogState Brief Battery (CBB)
    End point description
    The CBB includes the 3 tests of the primary endpoint (Detection test, Identification test and the ‘One Back’ test [attention and working memory domains]) plus the ‘One Card Learning’ test, testing the episodic visual memory. A combined Z-score was derived as the arithmetic mean of the 4 Z-scores, with a high combined Z-score indicating a better performance. The rate of change of the combined Z score over time was analysed via a random coefficients model to estimate the total slope (weeks; ie change in Z-score per week) in each treatment group, similar as done for the primary efficacy endpoint. Population: Full Analysis Set
    End point type
    Secondary
    End point timeframe
    From baseline up to Week 48 or Week 96 (depending on the time of randomisation).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Not applicable
    least squares mean (standard error)
        Baseline
    -1.3220 ( 0.0635 )
    -1.2262 ( 0.0701 )
        Week 96
    -1.5900 ( 0.0826 )
    -1.4896 ( 0.0915 )
        Change from baseline at Week 96
    -0.2680 ( 0.0640 )
    -0.2634 ( 0.0721 )
    Statistical analysis title
    		 CBB total slope random coefficients analysis
    Statistical analysis description
    The difference in total slope (active vs placebo) was estimated using the random coefficients model. Random, subject-specific intercepts and slopes were assumed, taken from a bivariate normal distribution, centered at (0,0). The covariance structure was unrestricted. All observations were used. For missed baseline data at the individual test level, the most recent screening assessments were used.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9619
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope (weeks) difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.002
         upper limit
    		 0.0019

    Secondary: Change with time of overall cognition as measured by the combined Z-score of the complete neuropsychological test battery (NTB)

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    End point title
    		 Change with time of overall cognition as measured by the combined Z-score of the complete neuropsychological test battery (NTB)
    End point description
    The complete NTB included 8 tests (Detection test, Identification test, One Back test [attention and working memory domains], One Card Learning test, International Shopping List test [Immediate and Delayed Recall tests], Category Fluency test, and Letter Fluency test ). A combined Z-score was derived as the arithmetic mean of the 8 Z-scores, with a high combined Z-score indicating a better performance. The rate of change of the combined Z score over time was analysed via a random coefficients model to estimate the total slope (weeks; ie change in Z-score per week) in each treatment group, similar as done for the primary efficacy endpoint. Population: Full Analysis Set
    End point type
    Secondary
    End point timeframe
    From baseline up to Week 48 or Week 96 (depending on the time of randomisation).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Not applicable
    least squares mean (standard error)
        Baseline
    -1.5072 ( 0.0515 )
    -1.4655 ( 0.0568 )
        Week 96
    -1.8680 ( 0.0681 )
    -1.8472 ( 0.0753 )
        Change from baseline at Week 96
    -0.3608 ( 0.0480 )
    -0.3818 ( 0.0538 )
    Statistical analysis title
    		 NTB total slope random coefficients analysis
    Statistical analysis description
    The difference in total slope (active vs placebo) was estimated using the random coefficients model. Random, subject-specific intercepts and slopes were assumed, taken from a bivariate normal distribution, centered at (0,0). The covariance structure was unrestricted. All observations were used. For missed baseline data at the individual test level, the most recent screening assessments were used.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    259
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7709
    Method
    		 Mixed models analysis
    Parameter type
    		 Slope (weeks) difference
    Point estimate
    0.0002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0013
         upper limit
    		 0.0017

    Secondary: Change from baseline in daily activities as measured by Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) total score at End of Treatment (EOT)

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    End point title
    		 Change from baseline in daily activities as measured by Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) total score at End of Treatment (EOT)
    End point description
    The A-IADL-Q long version total score is derived via a closed algorithm based on 70 items addressing household/leisure time/work-related topics with a higher total score indicating a better performance. The subject’s study partner completed the questionnaire. Since EOT occurred at different visits for different subjects, an analysis of covariance (ANCOVA) was used to estimate and compare the change from baseline at EOT between the active and placebo groups. Population: Full Analysis Set
    End point type
    Secondary
    End point timeframe
    From baseline up to EOT (depending on the time of randomisation).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    138
    114
    Units: Score
    least squares mean (standard error)
        Change from baseline at EOT
    -8.3975 ( 0.7817 )
    -6.8452 ( 0.8615 )
    Statistical analysis title
    		 A-IADL-Q total score at EOT - ANCOVA
    Statistical analysis description
    An ANCOVA was used to estimate and compare the change from baseline at EOT between the active and placebo groups. All observations were used.
    Comparison groups
    PQ912 v Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1872
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.5523
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8639
         upper limit
    		 0.7594

    Secondary: Change from baseline in global relative theta (4-8 Hz) power in the electroencephalogram (EEG) at Week 48

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    End point title
    		 Change from baseline in global relative theta (4-8 Hz) power in the electroencephalogram (EEG) at Week 48
    End point description
    Quantitative EEG measurements were used to evaluate brain functional network activity and connectivity. In AD, eyes closed resting state EEG shows distinct changes reflecting abnormalities of brain oscillatory activity. With disease progression, 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 regarded as the most sensitive oscillatory activity marker in the earliest stages of AD. The change from baseline at Week 48 was analysed using a mixed model with repeated measurements, using all observations. Population: Full Analysis Set
    End point type
    Secondary
    End point timeframe
    From baseline to Week 48.
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    98
    65
    Units: Hz
    least squares mean (confidence interval 95%)
        Change from baseline at Week 48
    0.0168 (0.0076 to 0.0260)
    0.0142 (0.0029 to 0.0255)
    Statistical analysis title
    		 Global relative theta power - MMRM
    Statistical analysis description
    A mixed model with repeated measurements (MMRM) was used to estimate and compare the change from baseline at Week 48 between the active and placebo groups. The estimated difference between the treatment groups at Week 48 is the main result. All observations were used. Subjects without baseline values were automatically excluded.
    Comparison groups
    Placebo v PQ912
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7281
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.0026
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.0121
         upper limit
    		 0.0173

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs) with severity ≥ grade 3 according to CTCAE

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAEs) with severity ≥ grade 3 according to CTCAE
    End point description
    The number of subjects with TEAEs with severity ≥ grade 3 (according to CTCAE v5.0) during the study. Population: Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    All ≥ grade 3 AEs that occurred or worsened after the first administration of the study treatment and up to the last visit (up to 52 to 100 weeks; 48 to 96 weeks treatment + 4 weeks of follow-up)
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Subjects
        Any TEAE of ≥ CTCAE Grade 3
    22
    9
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent serious adverse events (SAEs)

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    End point title
    		 Number of subjects with treatment-emergent serious adverse events (SAEs)
    End point description
    The number of subjects with treatment-emergent SAEs during the study. Population: Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    All SAEs that occurred or worsened after the first administration of the study treatment and up to the last visit (up to 52 to 100 weeks; 48 to 96 weeks treatment + 4 weeks of follow-up)
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Subjects
        Any treatment-emergent SAE
    18
    10
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events (TEAEs) leading to treatment discontinuation

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    End point title
    		 Number of subjects with treatment-emergent adverse events (TEAEs) leading to treatment discontinuation
    End point description
    The number of subjects with TEAEs leading to treatment discontinuation during the study. Population: Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    All AEs leading to treatment discontinuation that occurred or worsened after the first administration of the study treatment and up to the last visit (up to 52 to 100 weeks; 48 to 96 weeks treatment + 4 weeks of follow-up).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Number of subjects
        Any TEAE leading to treatment discontinuation
    6
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events of special interest (AESI)

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    End point title
    		 Number of subjects with treatment-emergent adverse events of special interest (AESI)
    End point description
    The number of subjects with treatment-emergent AESIs. An AESI is defined as an SAE, discontinuation due to TEAE or SAE, or any ≥ grade 3 AE (according to CTCAE) defined within either the system organ class Skin and Subcutaneous Tissue Disorders or Hepatobiliary Disorders, or a discontinuation due to an extreme liver laboratory parameter related to the liver and/or bile organ system, as defined below. • Alanine-amino transferase (ALT) or asparagine-amino transferase (AST) >8x upper limit of normal (ULN) • ALT or AST >5xULN for more than 2 weeks • ALT or AST >3xULN and (total bilirubin [T-BiL] >2xULN or international normalised ratio [INR] >1.5) • ALT or AST >3xULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%). Population: Safety Analysis Set
    End point type
    Secondary
    End point timeframe
    All AESIs after the first administration of the study treatment and up to the last visit (up to 52 to 100 weeks; 48 to 96 weeks treatment + 4 weeks of follow-up).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    142
    117
    Units: Number of subjects
        Any treatment-emergent AESI
    3
    0
    No statistical analyses for this end point

    Other pre-specified: Change with time of estimated glomerular filtration rate (eGFR)

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    End point title
    		 Change with time of estimated glomerular filtration rate (eGFR)
    End point description
    The eGFR is a relevant renal function parameter commonly used in clinical practice to estimate creatinine clearance, with higher scores indicating a better renal function. eGFR was estimated with the Modification of Diet in Renal Disease (MDRD) method using the equation: 32788 × [serum creatinine]^(-1.154) × (age)^(-0.203) × (1.212 if black) x (0.742 if female). The change over time in eGFR was estimated using random coefficients mixed effects modelling. Population: Full Analysis Set; all subjects who received at least one dose, with at least one post-baseline value, a baseline eGFR value, and no missing covariate values.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to EOT (depending on the time of randomisation).
    End point values
    		 PQ912 Placebo
    Number of subjects analysed
    141
    117
    Units: mL/min/1.73m²/year
    least squares mean (standard error)
        Change from baseline at EOT
    0.83 ( 0.519 )
    -1.82 ( 0.606 )
    Statistical analysis title
    		 Change with time of eGFR
    Statistical analysis description
    A random coefficients analysis model was used to estimate and compare the change from baseline through EOT between the active and placebo groups. All eGFR data were used, whether scheduled or unscheduled. For missing eGFR data, no imputations were made, rather missing data were handled implicitly by use of mixed modelling.
    Comparison groups
    PQ912 v Placebo
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.001
    Method
    		 random coefficients mixed effects model
    Parameter type
    		 Difference in annualized rate of change
    Point estimate
    2.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.07
         upper limit
    		 4.22

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events that occurred or worsened after the first administration of the study treatment and up to the last visit (up to 52 to 100 weeks; 48 to 96 weeks treatment + 4 weeks of follow-up).
    Adverse event reporting additional description
    The frequency threshold for reporting non-serious adverse events is 5% in any treatment group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    PQ912
    Reporting group description
    		 Subjects receiving PQ912 administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receiving placebo administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier.

    Serious adverse events
    		 PQ912 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 142 (12.68%)
    10 / 117 (8.55%)
         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
    0 / 142 (0.00%)
    2 / 117 (1.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive lobular breast carcinoma
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delusion
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (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 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stoma complication
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enterovesical fistula
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         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
    Exostosis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint stiffness
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (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
    Pneumonia
         subjects affected / exposed
    1 / 142 (0.70%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 142 (0.00%)
    1 / 117 (0.85%)
         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 / 142 (0.70%)
    0 / 117 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 PQ912 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    81 / 142 (57.04%)
    59 / 117 (50.43%)
    Nervous system disorders
    Dementia Alzheimer's type
         subjects affected / exposed
    13 / 142 (9.15%)
    8 / 117 (6.84%)
         occurrences all number
    13
    8
    Headache
         subjects affected / exposed
    7 / 142 (4.93%)
    11 / 117 (9.40%)
         occurrences all number
    9
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 142 (5.63%)
    4 / 117 (3.42%)
         occurrences all number
    9
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 142 (6.34%)
    11 / 117 (9.40%)
         occurrences all number
    10
    14
    Nausea
         subjects affected / exposed
    12 / 142 (8.45%)
    4 / 117 (3.42%)
         occurrences all number
    13
    5
    Constipation
         subjects affected / exposed
    5 / 142 (3.52%)
    6 / 117 (5.13%)
         occurrences all number
    5
    8
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 142 (2.82%)
    10 / 117 (8.55%)
         occurrences all number
    5
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 142 (8.45%)
    3 / 117 (2.56%)
         occurrences all number
    15
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    38 / 142 (26.76%)
    21 / 117 (17.95%)
         occurrences all number
    40
    22
    Urinary tract infection
         subjects affected / exposed
    10 / 142 (7.04%)
    5 / 117 (4.27%)
         occurrences all number
    12
    6
    Nasopharyngitis
         subjects affected / exposed
    9 / 142 (6.34%)
    6 / 117 (5.13%)
         occurrences all number
    9
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Dec 2020
    Reason for amendment: Clarifications to blood/urine sampling, electroencephalogram (EEG) assessments, and washout periods for concomitant medication, an exploratory objective was added to evaluate serum biomarkers, correction of the WAIS IV Coding Test and widening of the range of cognitive impairment in the inclusion criteria, and updates for the use of intrauterine devices (IUDs) in association with magnetic resonance imaging (MRI).
    17 Jun 2022
    Reason for amendment: Administrative updates and clarifications on electroencephalogram (EEG) assessments, inclusion criteria, concomitant medication use, adverse event (AE) reporting, and rescreening procedures, addition of local requirements for COVID-19 testing, and addition of brain magnetic resonance imaging (MRI) in case of neuropsychiatric AEs.
    07 Jul 2023
    Reason for amendment: Administrative updates concerning the coordinating investigator, and adjustments to the endpoint ordering and analyses as specified below. - Tests were added to the exploratory efficacy objectives and endpoints: pen-and-pencil Letter and Category Fluency tests, CogState brief battery tests. - Secondary efficacy objectives and endpoints were reordered to emphasise the importance of cognition objectives. - The category ‘Other Pre-specified Analyses’ was added to the efficacy parameters.
    06 Oct 2023
    Reason for amendment: Administrative updates (change in biostatistician), the method of MRI reading for amyloid-related imaging abnormalities was changed to central reading, minor adjustments of exploratory endpoints, and of the proposed model for analysis of cognitive change, and a clarification was added regarding PQ912 and varoglutamstat being synonymous.
    01 Dec 2023
    Reason for amendment: Clarifications to the proposed model for analysis of cognitive change, renal safety markers were added in ‘Other safety endpoints’ and to blood chemistry parameters, and a reference to the investigational medicinal product handling guide was added.

    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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