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
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EudraCT number |
2019-003532-23 |
Trial protocol |
DK DE NL ES PL |
Global end of trial date |
12 Jan 2024
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Feb 2025
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First version publication date |
15 Feb 2025
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PBD 01180
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04498650 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Vivoryon Therapeutics N.V.
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Sponsor organisation address |
Weinbergweg 22, Halle, Germany, 06120
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Public contact |
CBO, Vivoryon Therapeutics N.V., +49 345 5559900, info@vivoryon.com
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Scientific contact |
CBO, Vivoryon Therapeutics N.V., +49 345 5559900, info@vivoryon.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
15 Feb 2024
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
12 Jan 2024
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Jan 2024
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
• To assess the safety and tolerability of PQ912
• To evaluate the efficacy of PQ912 on working memory and attention
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
13 Jul 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Netherlands: 41
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Country: Number of subjects enrolled |
Poland: 4
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Country: Number of subjects enrolled |
Spain: 65
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Country: Number of subjects enrolled |
Denmark: 85
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Country: Number of subjects enrolled |
Germany: 64
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Worldwide total number of subjects |
259
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EEA total number of subjects |
259
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
74
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From 65 to 84 years |
185
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85 years and over |
0
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Recruitment
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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
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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
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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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.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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).
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Oral use
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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).
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Baseline characteristics reporting groups
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Reporting group title |
PQ912
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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
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Reporting group description |
Subjects receiving placebo administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
PQ912
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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
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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
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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.
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who had taken at least one dose of PQ912 or placebo.
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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
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End point type |
Primary
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End point timeframe |
From baseline up to Week 48 or Week 96 (depending on the time of randomisation).
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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.
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Comparison groups |
PQ912 v Placebo
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Number of subjects included in analysis |
259
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.8194 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Slope (weeks) difference | |||||||||||||||||||||
Point estimate |
-0.0003
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.0028 | |||||||||||||||||||||
upper limit |
0.0022 |
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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
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End point type |
Secondary
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End point timeframe |
From baseline up to Week 48 or Week 96 (depending on the time of randomisation).
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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.
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Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
259
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.9619 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Slope (weeks) difference | |||||||||||||||||||||
Point estimate |
0
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.002 | |||||||||||||||||||||
upper limit |
0.0019 |
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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
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End point type |
Secondary
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End point timeframe |
From baseline up to Week 48 or Week 96 (depending on the time of randomisation).
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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.
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Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
259
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||||||||
P-value |
= 0.7709 | |||||||||||||||||||||
Method |
Mixed models analysis | |||||||||||||||||||||
Parameter type |
Slope (weeks) difference | |||||||||||||||||||||
Point estimate |
0.0002
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Confidence interval |
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level |
95% | |||||||||||||||||||||
sides |
2-sided
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lower limit |
-0.0013 | |||||||||||||||||||||
upper limit |
0.0017 |
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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
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End point type |
Secondary
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End point timeframe |
From baseline up to EOT (depending on the time of randomisation).
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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.
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Comparison groups |
PQ912 v Placebo
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Number of subjects included in analysis |
252
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.1872 | |||||||||||||||
Method |
ANCOVA | |||||||||||||||
Parameter type |
Difference in LS Means | |||||||||||||||
Point estimate |
-1.5523
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-3.8639 | |||||||||||||||
upper limit |
0.7594 |
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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
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End point type |
Secondary
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End point timeframe |
From baseline to Week 48.
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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.
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Comparison groups |
Placebo v PQ912
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Number of subjects included in analysis |
163
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||||||||
P-value |
= 0.7281 | |||||||||||||||
Method |
Mixed models analysis | |||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||
Point estimate |
0.0026
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
-0.0121 | |||||||||||||||
upper limit |
0.0173 |
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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
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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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
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End point type |
Secondary
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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)
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No statistical analyses for this end point |
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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
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End point type |
Secondary
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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).
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No statistical analyses for this end point |
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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
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End point type |
Secondary
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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).
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No statistical analyses for this end point |
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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.
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End point type |
Other pre-specified
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End point timeframe |
From baseline up to EOT (depending on the time of randomisation).
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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.
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Comparison groups |
PQ912 v Placebo
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Number of subjects included in analysis |
258
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Analysis specification |
Pre-specified
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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
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Confidence interval |
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level |
95% | |||||||||||||||
sides |
2-sided
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lower limit |
1.07 | |||||||||||||||
upper limit |
4.22 |
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Adverse events information
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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).
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Adverse event reporting additional description |
The frequency threshold for reporting non-serious adverse events is 5% in any treatment group.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
26.1
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Reporting groups
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Reporting group title |
PQ912
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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
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Reporting group description |
Subjects receiving placebo administered orally, 48 to 96 weeks (depending on the time of randomisation) or discontinued earlier. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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). |
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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. |
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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.
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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. |
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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.
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Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |