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

Phase 2TerminatedNCT03919162

Vivoryon Therapeutics N.V.112 enrolled

Overview

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.

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).

Conditions

Alzheimer Disease

Interventions

PQ912DRUG

PQ912 150 mg tablets

PlaceboOTHER

Placebo tablets to mimic PQ912 150 mg tablets

Eligibility

Sex: ALLMin age: 50 YearsMax age: 89 Years

Medical Language ↔ Plain English

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.

Locations (22)

Barrow Neurological Institute

Phoenix, Arizona, United States

Outcomes

Primary Outcomes

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)

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

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

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.

Data from ClinicalTrials.gov

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Secondary Outcomes

Phase 2B: Key Secondary Efficacy: Change From Baseline in Cognitive Functional Composite-2 (CFC2) Score, a Cognitive Functional Composite

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.

Time frame: 72 weeks

Phase 2B: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC, 9-item) Score

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.

Time frame: 72 weeks

Phase 2B: 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: 72 weeks

Phase 2B: Change From Baseline in Functional Activities Questionnaire (FAQ)

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.

Time frame: 72 weeks

Phase 2B: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13)

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.

Time frame: 72 weeks

Phase 2B: Change From Baseline in Neuropsychiatric Inventory (NPI)

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.

Time frame: 72 weeks

Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Rates of All Treatment-emergent Serious Adverse Events (SAEs)

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

Time frame: 76 weeks

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)

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.

Time frame: Up to 72 weeks

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

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.

Time frame: 76 weeks

Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Rates of All Treatment-emergent Adverse Events (TEAEs)

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

Time frame: 76 weeks

Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Rates of All Adverse Events of Special Interest (AESIs)

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 .

Time frame: 76 weeks

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