Clinical trial NCT03919162: A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Alzheimer Disease
Keywords: Alzheimer's Disease
Mild Cognitive Impairment
Mild Alzheimer's Disease
Early Alzheimer's disease
MCI
Lead sponsor: Vivoryon Therapeutics N.V.
Sponsor class: INDUSTRY
Collaborators: name: Alzheimer's Disease Cooperative Study (ADCS)
name: National Institute on Aging (NIA)
First posted: 2019-04-18
Enrollment: 112
Sex: ALL
Minimum age (years): 50
Maximum age (years): 89
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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.

Primary outcomes:
measure: 2A Primary safety: proportion of participants who experience any adverse event of interest (AE-I).
timeFrame: 24 weeks
measure: 2A Primary PK: derived mean values of varoglutamstat levels and corresponding calculated target occupancy (TO)
timeFrame: 24 weeks
measure: 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.
timeFrame: 24 weeks
measure: 2A Primary efficacy:The within-participant change from baseline to week 24 in quantitative EEG (global relative theta wave power)
timeFrame: 24 weeks
measure: 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.
timeFrame: 72 weeks
Secondary outcomes:
measure: Key secondary efficacy: CFC2, a cognitive-functional composite
timeFrame: 72 weeks
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Chula Vista
country: United States
facility: The Neuron Clinic
state: California
city: Irvine
country: United States
facility: University of California
state: California
city: La Jolla
country: United States
facility: UCSD Alzheimer's Disease Research Center
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Center
state: California
city: Poway
country: United States
facility: PCND Neurology
state: California
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Tampa
country: United States
facility: USF Health Byrd Alzheimer's Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Feinberg School of Medicine
state: Illinois
city: Iowa City
country: United States
facility: The University of Iowa Carver College of Medicine
state: Iowa
city: Lexington
country: United States
facility: The University of Kentucky Sanders-Brown Center on Aging
state: Kentucky
city: Bangor
country: United States
facility: Northern Light Acadia Hospital
state: Maine
city: New York
country: United States
facility: NYU Langone Health Tisch Hospital
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: OHSU Neurology Clinic
state: Oregon
city: Abington
country: United States
facility: Abington Neurological Associates
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Charleston
country: United States
facility: Lowcountry Center for Veterans Research (LCVR)
state: South Carolina
city: San Antonio
country: United States
facility: UT Health San Antonio
state: Texas
Study officials:
affiliation: Alzheimer's Disease Cooperative Study (ADCS)
name: Howard Feldman
role: PRINCIPAL_INVESTIGATOR
References: