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

NCT ID: NCT03919162

Last Updated: 2025-12-12

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 112 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-11-15
• Study Completion Date: 2024-08-12

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).

Conditions

Alzheimer Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

PQ912

All participants started at 150 mg BID and were up-titrated to 600 mg BID

Group Type: EXPERIMENTAL

PQ912

Intervention Type: DRUG

PQ912 150 mg tablets

Placebo

Matching placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo tablets to mimic PQ912 150 mg tablets

Interventions

PQ912

PQ912 150 mg tablets

Intervention Type: DRUG

Placebo

Placebo tablets to mimic PQ912 150 mg tablets

Intervention Type: OTHER

Other Intervention Names

Varoglutamstat

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 89 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Alzheimer's Disease Cooperative Study (ADCS)

OTHER

Sponsor Role: collaborator

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Vivoryon Therapeutics N.V.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Howard Feldman

Role: PRINCIPAL_INVESTIGATOR

Alzheimer's Disease Cooperative Study (ADCS)

Locations

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 D.C., District of Columbia, United States

USF Health Byrd Alzheimer's Center and Research Institute

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

Northwestern University Feinberg School of Medicine

Chicago, Illinois, United States

The University of Iowa Carver College of Medicine

Iowa City, Iowa, United States

The University of Kentucky Sanders-Brown Center on Aging

Lexington, Kentucky, United States

Northern Light Acadia Hospital

Bangor, Maine, United States

NYU Langone Health Tisch Hospital

New York, New York, United States

SUNY Upstate Medical University

Syracuse, New York, United States

Ohio State University

Columbus, Ohio, United States

OHSU Neurology Clinic

Portland, Oregon, United States

Abington Neurological Associates

Abington, Pennsylvania, United States

Rhode Island Hospital

Providence, Rhode Island, United States

Lowcountry Center for Veterans Research (LCVR)

Charleston, South Carolina, United States

UT Health San Antonio

San Antonio, Texas, United States

Countries

United States

References

Feldman HH, Messer K, Qiu Y, Sabbagh M, Galasko D, Turner RS, Lopez O, Smith A, Durant J, Lupo JL, Revta C, Balasubramanian A, Kuehn-Wache K, Wassmann T, Schell-Mader S, Jacobs DM, Salmon DP, Leger G, DeMarco ML, Weber F; ADCS VIVA-MIND Study Group. Varoglutamstat: Inhibiting Glutaminyl Cyclase as a Novel Target of Therapy in Early Alzheimer's Disease. J Alzheimers Dis. 2024;101(s1):S79-S93. doi: 10.3233/JAD-231126.

Reference Type: BACKGROUND

PMID: 39422941 (View on PubMed)

Messer K, Jacobs DM, Salmon DP, Qiu Y, Revta C, Weber F, Kuhn-Wache K, Leger GC, Feldman HH. (2022), A novel, efficient and seamless Phase 2A-2B design to test varoglutamstat in early AD: the VIVAMIND study. Alzheimer's Dement., 18(S10): e065197.

Reference Type: BACKGROUND

Lues I, Weber F, Meyer A, Buhring U, Hoffmann T, Kuhn-Wache K, Manhart S, Heiser U, Pokorny R, Chiesa J, Glund K. A phase 1 study to evaluate the safety and pharmacokinetics of PQ912, a glutaminyl cyclase inhibitor, in healthy subjects. Alzheimers Dement (N Y). 2015 Oct 3;1(3):182-195. doi: 10.1016/j.trci.2015.08.002. eCollection 2015 Nov.

Reference Type: BACKGROUND

PMID: 29854937 (View on PubMed)

Scheltens P, Hallikainen M, Grimmer T, Duning T, Gouw AA, Teunissen CE, Wink AM, Maruff P, Harrison J, van Baal CM, Bruins S, Lues I, Prins ND. Safety, tolerability and efficacy of the glutaminyl cyclase inhibitor PQ912 in Alzheimer's disease: results of a randomized, double-blind, placebo-controlled phase 2a study. Alzheimers Res Ther. 2018 Oct 12;10(1):107. doi: 10.1186/s13195-018-0431-6.

Reference Type: BACKGROUND

PMID: 30309389 (View on PubMed)

Feldman HH, Messer K, Zhang J, Quach NE, Léger GC, Jacobs DM, Edland SD, Duehring J, MacKelfresh A, Pol A, Revta C, Lupo JL, Balasubramanian A, Lama N, Wassmann T, Schaeffer M, Hoffmann T, Meyer A, Schell-Mader S, Wenzkowski C, Weber F, for the ADCS VIVA-MIND Study Group. The VIVA-MIND study: Topline Results from Phase 2 RCT of Varoglutamstat in Early AD. In press, abstract at 2025 AAIC, Alzheimer's and Dementia

Reference Type: RESULT

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1R01AG061146-01

Identifier Type: NIH

Identifier Source: secondary_id

View Link

PBD-01187

Identifier Type: -

Identifier Source: org_study_id