A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD

A Phase 2A Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Varoglutamstat (PQ912) in Patients With Early Alzheimer's Disease With a Stage-Gate to Phase 2B (VIVA-MIND)

Status

Terminated

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03919162

Acronym

VIVA-MIND

Enrollment

112

Registered

2019-04-18

Start date

2021-11-15

Completion date

2024-08-12

Last updated

2025-12-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Alzheimer Disease

Keywords

Alzheimer's Disease, Mild Cognitive Impairment, Mild Alzheimer's Disease, Early Alzheimer's disease, MCI

Brief summary

This is a Phase 2A multi-center, randomized, double blind, placebo-controlled, parallel group study of varoglutamstat, with a stage gate to Phase 2B. In Phase 2A there will be adaptive dosing evaluation of three dose levels with exposure to varoglutamstat or placebo for a minimum of 24 weeks, with preliminary evaluation of both cognitive function and pharmacodynamic changes on EEG spectral analysis in approximately 180 participants. In the event that the stage gate for Phase 2B is reached, then Phase 2B will assesses efficacy and longer-term safety in a larger study group, i.e., 414.

Detailed description

The goal of this study is to advance a first-in-class, new small molecule treatment for early Alzheimer's disease (AD). Varoglutamstat (PQ912) is an oral, twice daily medication that addresses a novel and significantly differentiated amyloid target: N-terminal post-translationally modified Ab (pGlu-Ab), a particularly toxic subspecies of amyloid beta (Ab). The study is a Phase 2A multi-center, randomized, double-blind, parallel group trial, with a stage gate to Phase 2B. This study is conducted to further evaluate whether varoglutamstat's mechanism of action can result in a measurable therapeutic effect on cognition, function and relevant pharmacodynamic (PD) and biological markers in early AD. Phase 2A is designed to determine the highest dose that is both safe and well tolerated using a predefined Pocock safety stopping boundary based on the rate of adverse events of special interest (AESIs). During this phase there is an adaptive dosing evaluation with exposure to varoglutamstat or placebo for a minimum of 24 weeks (Phase 2A). Participants are randomized 1:1 to varoglutamstat or placebo, and randomization is stratified between mild AD and MCI, as well as by site. During Phase 2A participants are to be enrolled sequentially into one of three dose cohorts (labelled Cohort A, B and C, with 60 participants per cohort (n=30 active, n=30 placebo)) and treated at the originally assigned full dose until the Data Safety Monitoring Board (DSMB) provides a protocol-specified dose decision: Cohort A (600 mg): First 4 weeks 150 mg BID, week 5-8 300 mg BID, week 9-up to 72 600 mg BID; Cohort B (300 mg): First 4 weeks 150 mg BID, week 5-up to 72 300 mg BID; Cohort C (150 mg): up to 72 weeks on 150 mg BID. In addition, at the end of Phase 2A (after 24 weeks) an interim analysis for futility will be conducted evaluating both cognitive function (ADNI Battery Composite score) and pharmacodynamics changes on electroencephalogram (EEG) spectral analysis (EEG theta power) to inform a stage-gate decision on whether to proceed with Phase 2B (72 weeks). If the Phase 2A study meets the predefined criteria to proceed to Phase 2B, then Phase 2B will assess the longer-term efficacy and safety of varoglutamstat in a larger study group, using the dose level determined during Phase 2A. In Phase 2B, a composite cognitive and functional measure as well as PD biomarkers will be used to evaluate efficacy during the extended treatment period. According to the protocol, during Phase 2A the DSMB performs a continuous review of the safety data using a predefined Pocock safety stopping boundary to provide a dose decision. If Cohort A does not meet the safety stopping boundary until the last participant of the Cohort A reaches 8 weeks on full dose (600 mg BID) the DSMB will provide a dose decision as per protocol for the dose of Cohort A to be carried forward for all participants in the active arm for the remainder of the study. In case Cohort A meets the stopping boundary, all participants will be down-titrated to the next lower planned dose level (Cohort B) and the same review process by the DSMB will continue until either dose-selection, down-titration to the lowest dose level (Cohort C) or stage-gate decision. As pre-specified, the Pocock safety stopping boundary applies only until dose selection. If the first cohort (Cohort A) with the highest dose of PQ912 (600 mg BID) is selected to be carried forward, evaluation of other dose levels is no longer applicable and all data will be collected as one single active Arm/Group. All participants randomized to PQ912 will start at 150 mg BID and will be titrated to the dose level selected per protocol; all participants in the placebo group will receive matching placebo. Participants enrolled in Phase 2A remain in the study for seamless inclusion in the Phase 2B evaluation (up to 72 weeks).

Interventions

DRUGPQ912

PQ912 150 mg tablets

OTHERPlacebo

Placebo tablets to mimic PQ912 150 mg tablets

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

50 Years to 89 Years

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: * Age 50-89 (inclusive) at screening * Diagnosed as having Mild Cognitive Impairment (MCI) due to Alzheimer's disease (AD) or Mild probable AD according to workgroups of the Diagnostic Guidelines of the National Institute on Aging and Alzheimer's Association (NIA-AA) * Mini-Mental State Examination (MMSE) score 20-30 inclusive at screening * Montreal Cognitive Assessment score (MoCA) \< 26 at screening * Clinical Dementia Rating global score 0.5 or 1 with memory score of \> 0.5 at screening * Positive cerebrospinal fluid (CSF) AD biomarker signature * A brain MRI scan within 6 months of screening consistent with a diagnosis of Alzheimer's disease * Participants must have a study partner who has frequent interaction with them (approximately \>3-4 times per week), will be present for all clinic visits, and can assist in compliance with study procedures. Key

Exclusion criteria

* Significant neurodegenerative diseases and causes of dementia, other than AD, including Parkinson's disease and Huntington's disease, vascular dementia, CJD (Creutzfeldt-Jakob disease), LBD (Lewy Body dementia), PSP (Progressive Supranuclear Palsy), AIDS (Acquired Immunodeficiency Syndrome), or NPH (normal pressure hydrocephalus) * Meeting Diagnostic Criteria for Possible AD according to workgroups of the Diagnostic Guidelines of the NIA-AA * Hepatic impairment defined as Child-Pugh class A or more severe liver impairment * History of moderate or severe skin reactions to medications or current moderate or severe disease of the skin and subcutaneous tissues * History of a major depressive episode within the past 6 months of screening * History of diagnosis of schizophrenia * History of uncontrolled bipolar disorder within past five years of screening * History of seizures within past two years of screening * Contraindication to lumbar puncture and MRI * Monoclonal antibody treatment with anti-amyloid or anti-tau agents intended to address the pathophysiologic processes associated with AD within the previous 180 days prior to baseline (BL) * Participants who are planning to receive treatment with aducanumab or any Amyloid Beta Antibody during the course of the study * Participation in another clinical trial for an investigational agent and having taken at least one dose of study drug, unless confirmed as having been on placebo, within 90 days prior to the baseline visit. The end of a previous investigational trial is defined as the date of the last dose of an investigational agent.

Design outcomes

Primary

Measure	Time frame	Description
Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)	From first dose to completion of 8 weeks on the full dose (Week 16)	The proportion of participants, who experience any AESI during the safety evaluation period, which is from first dose to completion of 8 weeks at the full originally assigned dose. Per protocol, if the first cohort (Cohort A) does not meet the pre-specified Pocock safety stopping boundary within the active arm, that dose will be selected as safe. The dose selected as safe will be the dose carried forward for all participants in the active arm for the remainder of the study. The Pocock boundary is only valid until dose selection. If a higher dose is selected as safe, assignment to lower doses will stop, and all current participants on a lower dose will be titrated up to the selected dose according to uptitration schedule. If Cohort A does not meet the Pocock boundary only evaluation of Cohort A is required for this endpoint.
Phase 2A: Median Estimated Target Occupancy (TO) of PQ912 in Cerebrospinal Fluid (CSF) at Week 24	Week 24, pre-dose (trough level) and 2-3h post-dose	The pharmacokinetics (PK) endpoints in Phase 2A are the derived median values of PQ912 levels in plasma and the corresponding calculated target occupancy (TO) in CSF, following at least 8 weeks of treatment at the dose level being tested. TO in CSF was estimated from plasma PQ912 concentrations.
Phase 2A: Median Plasma Concentrations of PQ912 at Week 24	Week 24, pre-dose (trough level) and 2-3h post-dose	The pharmacokinetics (PK) endpoints in Phase 2A are the derived median values of PQ912 levels in plasma and the corresponding calculated target occupancy (TO) in CSF, following at least 8 weeks of treatment at the dose level being tested. Blood samples were obtained and PQ912 plasma concentrations were determined using a validated high-pressure liquid chromatography hyphenated with tandem mass spectrometry (LC-MS/MS) method.
Phase 2A: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) Score	24 weeks	The within-participant change from baseline in the composite mean of standardized scores from a set of ADNI neuropsychological test measures, the ADNI Battery Composite (ABC, 9-item). The ABC score was calculated from the following 9 measures from the ADNI-1 Neuropsychological Test Battery: Auditory Verbal Learning Test (AVLT)-Immediate Recall, AVLT-Delayed Recall, Number Span Forward, Number Span Backward, Category Fluency, Trail Making Test A, Trail Making Test B, Digit Symbol Substitution, Boston Naming Test. Standardized scores (Z-scores) were calculated using the overall mean and standard deviation of all participants in the modified Intent-to-Treat (mITT) population at baseline as reference. The ABC score for each participant was the mean of the standardized subtest values. Range: -3 to 3; higher scores indicate less impairment.
Phase 2A: Change From Baseline in Quantitative Electroencephalogram (qEEG)	24 weeks	The within-participant change from baseline of global relative theta wave power (4-8 Hz) in qEEG. qEEG was used to assess resting-state brain activity, including global relative theta power (4-8 Hz), based on spectral analysis of signals from 21 electrode positions. Higher theta power indicates greater impairment.
Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score	72 weeks	The within-participant change from baseline in CDR-SB scores. The CDR-SB is a composite rating of cognition and everyday function which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview three cognitive domains (memory, orientation, and judgement/problem solving) and three everyday functional domains (community affairs, home and hobbies, and personal care). Level of impairment in each of the six domains is rated from none (score=0) to severe (score=3). The six domain scores are then summed to create the CDR-SB. Range: 0-18; higher scores indicate greater impairment.

Secondary

Measure	Time frame	Description
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Rates of All Treatment-emergent Serious Adverse Events (SAEs)	76 weeks	Longer-term safety and tolerability of PQ912 compared between the active and placebo arm as measured by rates of all treatment-emergent SAEs, presented as numbers of participants with at least one SAE and percentages
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Suicidality on the Columbia-Suicide Severity Rating Scale (C-SSRS)	Up to 72 weeks	Assessment of the longer-term safety and tolerability of PQ912 via the C-SSRS. The C-SSRS is an instrument designed to assess the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the corresponding assessment period. The scale includes suggested questions to elicit the type of information needed to determine if a suicide-related thought or behavior occurred. In this study it was used to 'detect' the appearance of new suicidal ideation or behavior as either present or not present. The tables reflect the total number of participants (and percentage) experiencing Any suicidality, Any suicidal ideation, Any suicidal behavior, and Any self-injurious behavior at screening and subsequent time points.
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Mortality Rates	76 weeks	Longer-term safety and tolerability of PQ912 compared between the active and placebo arm as measured by rates of fatal treatment-emergent serious adverse events (SAEs), presented as numbers of participants with a treatment emergent SAE leading to death and percentages.
Phase 2B: Key Secondary Efficacy: Change From Baseline in Cognitive Functional Composite-2 (CFC2) Score, a Cognitive Functional Composite	72 weeks	The within-participant change from baseline in CFC2 scores. The CFC2 is a novel composite outcome measure of cognition and everyday function that has been derived from measures used in Alzheimer's Disease Neuroimaging Initiative (ADNI) and optimized for detecting change in early Alzheimer's disease (doi.org/10.1016/j.jalz.2012.05.2187). CFC2 is comprised of selected subtests from the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) (Word Recall, Delayed Word Recall, and Orientation), Clinical Dementia Rating (CDR) sum of the Cognitive Boxes (Memory, Orientation, Judgement, and Problem Solving), and the Functional Activities Questionnaire (FAQ). The total score for each component subtest was multiplied by -1 so that higher scores indicate better performance. The CFC2 score was then calculated as the sum of the transformed raw scores for the component subtests. Range: -67 to 0; higher scores indicate less impairment.
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Rates of All Adverse Events of Special Interest (AESIs)	76 weeks	Longer-term safety and tolerability of PQ912 compared between the active and placebo arm as measured by rates of all AESIs presented as numbers of participants with at least one AESI and percentages .
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Drug Discontinuation Rates	72 weeks	Longer-term safety and tolerability of PQ912 compared between the active and placebo arm as measured by rates of drug discontinuation due to treatment-emergent adverse events (TEAEs), presented as numbers of participants with a TEAE leading to drug discontinuation and percentages.
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Rates of All Treatment-emergent Adverse Events (TEAEs)	76 weeks	Longer-term safety and tolerability of PQ912 compared between the active and placebo arm as measured by rates of all TEAEs, presented as numbers of participants with at least one TEAE and percentages
Phase 2B: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC, 9-item) Score	72 weeks	The within-participant change from baseline in the composite sum of standardized scores from a set of ADNI neuropsychological test measures, the ADNI Battery Composite (ABC, 9-item). The ABC score is calculated from the following 9 measures from the ADNI-1 Neuropsychological Test Battery: Auditory Verbal Learning Test (AVLT)-Immediate Recall, AVLT-Delayed Recall, Number Span Forward, Number Span Backward, Category Fluency, Trail Making Test A, Trail Making Test B, Digit Symbol Substitution, Boston Naming Test. Standardized scores (Z-scores) were calculated using the overall mean and standard deviation of all participants in the modified intent-to-treat (mITT) population at baseline as reference. The ABC score for each participant was the mean of the standardized subtest values. Range: -3 to 3; higher scores indicate less impairment.
Phase 2B: Change From Baseline in Quantitative Electroencephalogram (qEEG)	72 weeks	The within-participant change from baseline of global relative theta wave power (4-8 Hz) in qEEG. qEEG was used to assess resting-state brain activity, including global relative theta power (4-8 Hz), based on spectral analysis of signals from 21 electrode positions. Higher theta power indicates greater impairment.
Phase 2B: Change From Baseline in Functional Activities Questionnaire (FAQ)	72 weeks	The within-participant change from baseline in FAQ.The FAQ is a validated 10-item questionnaire, completed as a structured interview with the study partner, which rates the study participant's ability to carry out ten complex activities of daily living (doi.org/10.1093/geronj/37.3.323). Each item is rated on a scale from 0 (no impairment) to 3 (dependent). Scores are summed across items to provide a total score. Range: 0 to 30; higher scores indicate greater impairment.
Phase 2B: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13)	72 weeks	The within-participant change from baseline in ADAS-Cog-13. The ADAS-Cog-13 is a structured scale that evaluates memory (immediate and delayed word recall; immediate word recognition), receptive and expressive language, orientation, ideational praxis (preparing a letter for mailing), constructional praxis (copying figures), and attention (number cancellation). Ratings of spoken language, language comprehension, word finding difficulty, and ability to remember test instructions also are obtained. The ADAS-Cog total score is calculated by summing the scores of the 13 component subtests. Range: 0-85; higher scores indicate greater impairment.
Phase 2B: Change From Baseline in Neuropsychiatric Inventory (NPI)	72 weeks	The within-participant change from baseline in NPI. The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in Alzheimer's disease dementia based on the results of an interview with the study partner. Frequency and severity of 12 neuropsychiatric symptoms are assessed. Range: 0 to 144; higher scores indicate greater impairment.

Countries

United States

Participant flow

Recruitment details

Participants were enrolled at 22 study centers in the US between 2021 and 2024. The first participant was screened on November 10, 2021 and the last participant had his last visit on August 12, 2024. Of 253 screened participants, 112 met inclusion criteria and were randomized to treatment.

Pre-assignment details

Participants were randomized 1:1 to PQ912 or matching placebo. All participants randomized to PQ912 started at 150 mg BID and were up-titrated to 600 mg BID. Therefore, all data from the participants randomized to PQ912 were collected as one single active Arm/Group and separation of doses is not applicable. Participants enrolled in Phase 2A remained in the study for seamless inclusion in the Phase 2B evaluation (up to 72 weeks). No new participants were enrolled in Phase 2B.

Participants by arm

Arm	Count
PQ912 All participants started at 150 mg BID and were up-titrated to 600 mg BID administered orally for up to 72 weeks and therefore, all data from these participants were collected as one single active Arm/Group. Participants enrolled in Phase 2A remained in the study for seamless inclusion in the Phase 2B evaluation (up to 72 weeks). No new participants were enrolled in Phase 2B. PQ912: 150 mg tablets	52
Placebo All participants received matching placebo BID administered orally for up to 72 weeks Participants enrolled in Phase 2A remained in the study for seamless inclusion in the Phase 2B evaluation (up to 72 weeks). No new participants were enrolled in Phase 2B. Placebo: PQ912 matching placebo tablet	57
Total	109

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	2
Overall Study	Death	2	0
Overall Study	Lost to Follow-up	1	0
Overall Study	Missing	1	1
Overall Study	Screen failure	1	0
Overall Study	Study terminated by Sponsor	20	24
Overall Study	Withdrawal by Subject	12	12

Baseline characteristics

Characteristic	Placebo	PQ912	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	46 Participants	44 Participants	90 Participants
Age, Categorical Between 18 and 65 years	11 Participants	8 Participants	19 Participants
Age, Continuous	70.8 Years STANDARD_DEVIATION 7.4	72.9 Years STANDARD_DEVIATION 8.3	71.8 Years STANDARD_DEVIATION 7.9
Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) score	0.00 Z-scores STANDARD_DEVIATION 0.58	-0.01 Z-scores STANDARD_DEVIATION 0.65	-0.00 Z-scores STANDARD_DEVIATION 0.61
Apolipoprotein E (APOE) genotyping E4 carrier - heterozygous	30 Participants	23 Participants	53 Participants
Apolipoprotein E (APOE) genotyping E4 carrier - homozygous	14 Participants	11 Participants	25 Participants
Apolipoprotein E (APOE) genotyping Non-carrier	11 Participants	18 Participants	29 Participants
Clinical Dementia Rating - Sum of Boxes (CDR-SB)	2.99 Box scores (0-18) STANDARD_DEVIATION 1.7	3.35 Box scores (0-18) STANDARD_DEVIATION 1.53	3.16 Box scores (0-18) STANDARD_DEVIATION 1.62
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	2 Participants	2 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	57 Participants	50 Participants	107 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Initial diagnosis Mild cognitive impairment due to Alzheimer's disease	38 Participants	30 Participants	68 Participants
Initial diagnosis Mild probable Alzheimer's disease	19 Participants	22 Participants	41 Participants
Quantitative EEG (qEEG)	0.13596 Proportion (0-1) STANDARD_DEVIATION 0.05351	0.18952 Proportion (0-1) STANDARD_DEVIATION 0.09281	0.16171 Proportion (0-1) STANDARD_DEVIATION 0.07902
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	4 Participants	1 Participants	5 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) White	52 Participants	51 Participants	103 Participants
Region of Enrollment United States	57 participants	52 participants	109 participants
Sex: Female, Male Female	30 Participants	24 Participants	54 Participants
Sex: Female, Male Male	27 Participants	28 Participants	55 Participants
Site Banner Sun Health Research Institute (BSHRI)	5 Participants	4 Participants	9 Participants
Site Lowcountry Center for Veterans Research (RJVA)	3 Participants	3 Participants	6 Participants
Site Northern Light Acadia Hospital (AHEMMC)	4 Participants	5 Participants	9 Participants
Site Northwestern University Feinberg School of Medicine (NWU)	5 Participants	3 Participants	8 Participants
Site Ohio State University (OSU)	8 Participants	9 Participants	17 Participants
Site Pooled sites	15 Participants	12 Participants	27 Participants
Site The University of Iowa Carver College of Medicine (UI)	5 Participants	5 Participants	10 Participants
Site The University of Kentucky Sanders-Brown Center on Aging (UKY)	3 Participants	3 Participants	6 Participants
Site University of California, Irvine (UCI)	3 Participants	4 Participants	7 Participants
Site University of California San Diego (UCSD) Alzheimer's Disease Research Center	6 Participants	4 Participants	10 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	2 / 53	0 / 56
other Total, other adverse events	46 / 53	47 / 56
serious Total, serious adverse events	11 / 53	6 / 56

Outcome results

Primary

Phase 2A: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) Score

The within-participant change from baseline in the composite mean of standardized scores from a set of ADNI neuropsychological test measures, the ADNI Battery Composite (ABC, 9-item). The ABC score was calculated from the following 9 measures from the ADNI-1 Neuropsychological Test Battery: Auditory Verbal Learning Test (AVLT)-Immediate Recall, AVLT-Delayed Recall, Number Span Forward, Number Span Backward, Category Fluency, Trail Making Test A, Trail Making Test B, Digit Symbol Substitution, Boston Naming Test. Standardized scores (Z-scores) were calculated using the overall mean and standard deviation of all participants in the modified Intent-to-Treat (mITT) population at baseline as reference. The ABC score for each participant was the mean of the standardized subtest values. Range: -3 to 3; higher scores indicate less impairment.

Time frame: 24 weeks

Population: The mITT population, including all randomized participants who took at least one dose of the study medication and who have a baseline assessment of the primary endpoint for phase 2B (CDR-SB)

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
PQ912	Phase 2A: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) Score	-0.156 Z-scores	Standard Error 0.036
Placebo	Phase 2A: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) Score	-0.214 Z-scores	Standard Error 0.039

Comparison: Initially after Phase 2A, a futility analysis was planned with a sample size of 90 participants per treatment group to test the 1-sided hypothesis that the rate of decrease of ABC score is greater for the PQ912 group than for the Placebo group. The test should be carried out at a 1-sided 40% significance level, using the mixed effects model. Due to early termination of the study and limited sample size, analysis of Phase 2A data was done in the same manner as final analysis of Phase 2B data.p-value: 0.226195% CI: [-0.036, 0.152]Mixed Models Analysis

Primary

Phase 2A: Change From Baseline in Quantitative Electroencephalogram (qEEG)

The within-participant change from baseline of global relative theta wave power (4-8 Hz) in qEEG. qEEG was used to assess resting-state brain activity, including global relative theta power (4-8 Hz), based on spectral analysis of signals from 21 electrode positions. Higher theta power indicates greater impairment.

Time frame: 24 weeks

Population: The modified intent-to-treat (mITT) population, including all randomized participants who took at least one dose of the study medication and who have a baseline assessment of the primary endpoint for phase 2B (CDR-SB). Only paired EEGs (at least 1 evaluable Baseline and 1 evaluable Follow-up EEG) were analyzed.

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
PQ912	Phase 2A: Change From Baseline in Quantitative Electroencephalogram (qEEG)	0.01749 Proportion (0-1)	Standard Error 0.00649
Placebo	Phase 2A: Change From Baseline in Quantitative Electroencephalogram (qEEG)	0.02275 Proportion (0-1)	Standard Error 0.00619

Comparison: Initially after Phase 2A, a futility analysis was planned with a sample size of 90 participants per treatment group to test the hypothesis that increase in EEG theta power is greater for Placebo than for PQ912 (1-sided, alpha = 0.05). Higher theta power is worse; hence this alternative hypothesis indicates benefit of the drug.~Due to early termination of the study and limited sample size, analysis of Phase 2A data was done in the same manner as final analysis of Phase 2B data.p-value: 0.481495% CI: [-0.02017, 0.00964]Mixed Models Analysis

Primary

Phase 2A: Median Estimated Target Occupancy (TO) of PQ912 in Cerebrospinal Fluid (CSF) at Week 24

Time frame: Week 24, pre-dose (trough level) and 2-3h post-dose

Population: Pharmacokinetic population, including all randomized participants who have received at least 1 dose of the study drug, and who provided sufficient PK samples to reliably estimate 1 plasma PK concentration post-baseline

Arm	Measure	Group	Value (MEDIAN)
PQ912	Phase 2A: Median Estimated Target Occupancy (TO) of PQ912 in Cerebrospinal Fluid (CSF) at Week 24	Week 24 (Visit 7) - pre-dose	55.3 Percent (%)
PQ912	Phase 2A: Median Estimated Target Occupancy (TO) of PQ912 in Cerebrospinal Fluid (CSF) at Week 24	Week 24 (Visit 7) - 2-3h post-dose	94.3 Percent (%)

Primary

Phase 2A: Median Plasma Concentrations of PQ912 at Week 24

The pharmacokinetics (PK) endpoints in Phase 2A are the derived median values of PQ912 levels in plasma and the corresponding calculated target occupancy (TO) in CSF, following at least 8 weeks of treatment at the dose level being tested. Blood samples were obtained and PQ912 plasma concentrations were determined using a validated high-pressure liquid chromatography hyphenated with tandem mass spectrometry (LC-MS/MS) method.

Time frame: Week 24, pre-dose (trough level) and 2-3h post-dose

Arm	Measure	Group	Value (MEDIAN)
PQ912	Phase 2A: Median Plasma Concentrations of PQ912 at Week 24	Week 24 (Visit 7) - pre-dose	208.0 ng/mL
PQ912	Phase 2A: Median Plasma Concentrations of PQ912 at Week 24	Week 24 (Visit 7) - 2-3h post-dose	2790.0 ng/mL

Primary

Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)

The proportion of participants, who experience any AESI during the safety evaluation period, which is from first dose to completion of 8 weeks at the full originally assigned dose. Per protocol, if the first cohort (Cohort A) does not meet the pre-specified Pocock safety stopping boundary within the active arm, that dose will be selected as safe. The dose selected as safe will be the dose carried forward for all participants in the active arm for the remainder of the study. The Pocock boundary is only valid until dose selection. If a higher dose is selected as safe, assignment to lower doses will stop, and all current participants on a lower dose will be titrated up to the selected dose according to uptitration schedule. If Cohort A does not meet the Pocock boundary only evaluation of Cohort A is required for this endpoint.

Time frame: From first dose to completion of 8 weeks on the full dose (Week 16)

Population: All participants started at 150 mg BID and were up-titrated to 600 mg BID. As pre-specified, this endpoint presents data from first 60 participants (Cohort A) after completion of 8 weeks on full dose, 600 mg BID, because Pocock safety stopping boundary applies only until dose selection.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
PQ912	Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)	1 Participants
Placebo	Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)	2 Participants

Primary

Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score

The within-participant change from baseline in CDR-SB scores. The CDR-SB is a composite rating of cognition and everyday function which incorporates both informant input and direct assessment of performance. It assesses through semi-structured interview three cognitive domains (memory, orientation, and judgement/problem solving) and three everyday functional domains (community affairs, home and hobbies, and personal care). Level of impairment in each of the six domains is rated from none (score=0) to severe (score=3). The six domain scores are then summed to create the CDR-SB. Range: 0-18; higher scores indicate greater impairment.

Time frame: 72 weeks

Arm	Measure	Value (LEAST_SQUARES_MEAN)	Dispersion
PQ912	Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score	1.63 Box scores (0-18)	Standard Error 0.36
Placebo	Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score	1.68 Box scores (0-18)	Standard Error 0.34

Comparison: Null hypothesis is that there was no difference in the change of CDR-SB scores between the PQ912 and the Placebo arms. The primary analysis used a mixed model for repeated measures (MMRM) with within-participant change in CDR-SB score as the outcome. The study planned with 207 participants (including 25% drop-out) per group to have 80% power to detect an effect size of 0.7 points in CDR-SB score. Power calculation was based on a 2-sided t-test with significance level of 0.05.p-value: 0.913595% CI: [-1.03, 0.92]Mixed Models Analysis

Secondary

Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Drug Discontinuation Rates

Longer-term safety and tolerability of PQ912 compared between the active and placebo arm as measured by rates of drug discontinuation due to treatment-emergent adverse events (TEAEs), presented as numbers of participants with a TEAE leading to drug discontinuation and percentages.

Time frame: 72 weeks