A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD
- Registration Number
- NCT03919162
- Lead Sponsor
- Vivoryon Therapeutics N.V.
- 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). This study will further evaluate whether varoglutamstat's mechanism of action can result in a measurable therapeutic effect on cognition, function and relevant pharmacodynamic and biological markers in early AD.
The study is a phase 2A multi-center, randomized, double-blind, parallel group trial, with a stage gate to phase 2B. Phase 2A will determine the highest dose that is both safe and well tolerated. During this phase, there is an adaptive dosing evaluation, using a well-defined safety stopping boundary, of three dose levels with exposure to varoglutamstat or placebo for a minimum of 24 weeks to help determine which dose will be carried forward in phase 2B. A sequential dose design will be employed in phase 2A where each of three dose cohorts are randomized equally to placebo or varoglutamstat and treated for at least 8 weeks at the originally assigned full dose. Participants will be randomized 1:1 to varoglutamstat or placebo, and stratified between mild AD and MCI, as well as by site.
Phase 2A also includes preliminary evaluation of both cognitive function and pharmacodynamics changes on electroencephalogram (EEG) spectral analysis.
In the event that the stage gate for phase 2B is reached from data in this phase 2A study, then phase 2B will assess the longer-term efficacy and safety of varoglutamstat in a larger study group, using the highest dose selected in 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.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 112
- 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 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
- • 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 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo - 300 mg PQ912 First 4 weeks 150 mg BID, week 5-24 300 mg BID 150 mg PQ912 24 weeks on 150 mg BID 600 mg PQ912 First 4 weeks 150 mg BID, week 5-8 300 mg BID, week 9-24 600 mg BID
- Primary Outcome Measures
Name Time Method 2A Primary safety: proportion of participants who experience any adverse event of special interest (AESI). 16 weeks The primary endpoint in phase 2A is the proportion of participants, for each dose, who experience any adverse event of special interest (AESI) during the safety evaluation period, from first dose to completion of 8 weeks at the full originally assigned dose.
2A Primary PK: derived mean values of varoglutamstat levels and corresponding calculated target occupancy (TO) 24 weeks The pharmacokinetics (PK) endpoints in Phase 2A are the derived mean values of varoglutamstat levels in plasma and the corresponding calculated TO in CSF, for each cohort following at least 8 weeks of treatment at the dose levels being tested
2A Primary efficacy: The within-participant change from baseline to week 24 in the composite sum of standardized scores from the ADNI Battery Composite (ABC, 9-item) compared between active arm and placebo. 24 weeks The ABC is a set of ADNI neuropsychological test measures, including: Category Fluency (Animals and Vegetables), Trail Making A and B, Digit Symbol Substitution, Boston Naming Test, Rey's Auditory and Verbal Learning Test (RAVLT, Immediate and Delayed), Digit Span Forward and Backward.
2A Primary efficacy: The within-participant change from baseline to week 24 in quantitative EEG (global relative theta wave power) 24 weeks The within-participant change from baseline to week 24 of the global relative theta wave power (4-8 Hz) in quantitative EEG compared between active arm and placebo.
2B Primary efficacy: The within-participant change from baseline to week 72 in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) score, compared between active arm and placebo. 72 weeks 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, 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 Outcome Measures
Name Time Method 2B Secondary safety and tolerability: Assessment of the longer-term safety and tolerability of varoglutamstat as measured by mortality rates 76 weeks Number of participants (and percentage) with a fatal Treatment-emergent Serious Adverse Event (SAE)
2B Key secondary efficacy: The within-participant change from baseline to week 72 in the efficacy of varoglutamstat assessed by Cognitive Functional Composite-2 (CFC2), a cognitive-functional composite, compared between active and placebo. 72 weeks The Cognitive Functional Composite-2 (CFC2) is a novel composite outcome measure of cognition and everyday function that has been derived from measures used in ADNI and optimized for detecting change in early AD (doi.org/10.1016/j.jalz.2012.05.2187). CFC2 is comprised of selected subtests from the ADAS-Cog (Word Recall, Delayed Word Recall, and Orientation); CDR Sum of the Cognitive Boxes (Memory, Orientation, Judgement \& Problem Solving); and the 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.
2B Other secondary efficacy: The within-participant change from baseline to week 72 in qEEG (global relative theta wave power) 72 weeks The within-participant change from baseline to week 72 in qEEG (global relative theta wave power), compared between active and placebo.
2B Other secondary efficacy: The within-participant change from baseline to week 72 in the ADNI Battery Composite (ABC, 9-item) compared between active arm and placebo. 72 weeks The within-participant change from baseline to week 72 in the composite sum of standardized scores from a set of ADNI neuropsychological test measures, the ADNI Battery Composite (ABC, 9-item) compared between active arm and placebo.
The ADNI Battery Composite (ABC) score is calculated from the following 9 measures from the ADNI-1 Neuropsychological Test Battery: 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 mITT 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.2B Other secondary efficacy: The within-participant change from baseline to week 72 in Functional Activities Questionnaire (FAQ), compared between active and placebo. 72 weeks 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.
2B Other secondary efficacy: The within-participant change from baseline to week 72 in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog-13), compared between active and placebo. 72 weeks The ADAS-Cog13 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.
2B Other secondary efficacy: The within-participant change from baseline to week 72 in Neuropsychiatric Inventory (NPI), compared between active and placebo. 72 weeks The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD 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.
2B Secondary safety and tolerability: Assessment of the longer-term safety and tolerability of varoglutamstat as measured by rates of all Treatment-emergent Serious Adverse Events (SAEs) 76 weeks Number of participants (and percentage) with at least one Treatment-emergent Serious Adverse Event (SAE)
2B Secondary safety and tolerability: Assessment of the longer-term safety and tolerability of varoglutamstat via Suicidality on the Columbia-Suicide Severity Rating Scale (C-SSRS). 72 weeks 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.
2B Secondary safety and tolerability: Assessment of the longer-term safety and tolerability of varoglutamstat as measured by rates of all Treatment-emergent Adverse Events (TEAEs) 76 weeks Number of participants (and percentage) with at least one Treatment-emergent Adverse Event (TEAEs)
2B Secondary safety and tolerability: Assessment of the longer-term safety and tolerability of varoglutamstat as measured by drug discontinuation rates 72 weeks Number of participants (and percentage) who discontinued the study drug
2B Secondary safety and tolerability: Assessment of the longer-term safety and tolerability of varoglutamstat as measured by rates of all AESIs (Adverse Events of Special Interest) 76 weeks Number of participants (and percentage) with at least one AESI (Adverse Event of Special Interest)
Trial Locations
- Locations (22)
Barrow Neurological Institute
🇺🇸Phoenix, Arizona, United States
Banner Sun Health Research Institute
🇺🇸Sun City, Arizona, United States
The Neuron Clinic
🇺🇸Chula Vista, California, United States
University of California
🇺🇸Irvine, California, United States
UCSD Alzheimer's Disease Research Center
🇺🇸La Jolla, California, United States
Cedars-Sinai Center
🇺🇸Los Angeles, California, United States
PCND Neurology
🇺🇸Poway, California, United States
Georgetown University Medical Center
🇺🇸Washington, District of Columbia, United States
USF Health Byrd Alzheimer's Center and Research Institute
🇺🇸Tampa, Florida, United States
Emory University
🇺🇸Atlanta, Georgia, United States
Scroll for more (12 remaining)Barrow Neurological Institute🇺🇸Phoenix, Arizona, United States