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

Alzheimer Disease Clinical Trial

— VIVA-MIND  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03919162
• Other study ID #: PBD-01187
• Secondary ID: 1R01AG061146-01
• Status: Recruiting
• Phase: Phase 2
• Start date: November 15, 2021
• Est. completion date: September 30, 2024

Study information

• Verified date: April 2024
• Source: Vivoryon Therapeutics N.V.
• Contact: Archana Balasubramanian
• Phone: +1 858-246-1277
• Email: viva-mind[@]health.ucsd.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 414
• Est. completion date: September 30, 2024
• Est. primary completion date: September 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 50 Years to 89 Years

Eligibility

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 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

• 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.

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• PQ912
PQ912 150 mg tablets

Other:
• Placebo
Placebo tablets to mimic PQ912 150 mg tablets

Locations

Country	Name	City	State
United States	Abington Neurological Associates	Abington	Pennsylvania
United States	Emory University	Atlanta	Georgia
United States	Northern Light Acadia Hospital	Bangor	Maine
United States	Lowcountry Center for Veterans Research (LCVR)	Charleston	South Carolina
United States	Northwestern University Feinberg School of Medicine	Chicago	Illinois
United States	The Neuron Clinic	Chula Vista	California
United States	Ohio State University	Columbus	Ohio
United States	The University of Iowa Carver College of Medicine	Iowa City	Iowa
United States	University of California	Irvine	California
United States	UCSD Alzheimer's Disease Research Center	La Jolla	California
United States	The University of Kentucky Sanders-Brown Center on Aging	Lexington	Kentucky
United States	Cedars-Sinai Center	Los Angeles	California
United States	NYU Langone Health Tisch Hospital	New York	New York
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	OHSU Neurology Clinic	Portland	Oregon
United States	PCND Neurology	Poway	California
United States	Rhode Island Hospital	Providence	Rhode Island
United States	UT Health San Antonio	San Antonio	Texas
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	SUNY Upstate Medical University	Syracuse	New York
United States	USF Health Byrd Alzheimer's Center and Research Institute	Tampa	Florida
United States	Georgetown University Medical Center	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
Vivoryon Therapeutics N.V.	Alzheimer's Disease Cooperative Study (ADCS), National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	2A Primary safety: proportion of participants who experience any adverse event of interest (AE-I).	The primary endpoint in phase 2A is the proportion of participants, for each dose, who experience any adverse event of interest (AE-I) during the safety reporting period, from first dose to completion of 8 weeks at the full originally assigned dose.	24 weeks
Primary	2A Primary PK: derived mean values of varoglutamstat levels and corresponding calculated target occupancy (TO)	The pharmacokinetics (PK) endpoints in Phase 2A are the derived mean values of varoglutamstat levels in plasma and the correspondingcalculated TO in CSF, for each dose.	24 weeks
Primary	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.	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.	24 weeks
Primary	2A Primary efficacy:The within-participant change from baseline to week 24 in quantitative EEG (global relative theta wave power)	The within-participant change frombaseline to week 24 of the global relative theta wave power (4-8 Hz) compared between active arm and placebo.	24 weeks
Primary	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.	The CDR-SB evaluates cognition and everyday functioning incorporating both informant input and direct assessment of performance. It is scored on a five-point scale a five point scale with following five possible scores: 0 = Normal 0.5 = Very Mild Dementia; = Mild Dementia; = Moderate Dementia; = Severe Dementia	72 weeks
Secondary	Key secondary efficacy: CFC2, a cognitive-functional composite	The key secondary objective in phase 2B is to evaluate the efficacy of PQ912 as measured by CFC2, a cognitive-functional composite, over a 72-week treatment period.	72 weeks