Alzheimer DiseasePhase 2VIVA-MINDNCT03919162
A Trial to Evaluate the Efficacy and Safety of PQ912 in Patients With Early AD
A Phase 2 study testing PQ912 in people with Alzheimer Disease, run by Vivoryon Therapeutics N.V. at 22 sites in United States.
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… Read more about this study
- Who is it for?
- Ages 50 to 89 years
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- PQ912
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 112 participants
- Where
- 22 sitesUnited States
- Study dates
- 15 Nov 2021to 12 Aug 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 50 to 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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
Show all 12Show fewer
- 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.
Trial locations and contacts
22 sites in 1 country.
22 sites in 1 country
United States22 sites
Abington Neurological Associates
Abington, Pennsylvania, 19001
Emory University
Atlanta, Georgia, 30329
Northern Light Acadia Hospital
Bangor, Maine, 04401
Lowcountry Center for Veterans Research (LCVR)
Charleston, South Carolina, 29403
Northwestern University Feinberg School of Medicine
Chicago, Illinois, 60611
The Neuron Clinic
Chula Vista, California, 91910
Ohio State University
Columbus, Ohio, 43210
The University of Iowa Carver College of Medicine
Iowa City, Iowa, 52242
University of California
Irvine, California, 92868
UCSD Alzheimer's Disease Research Center
La Jolla, California, 92037
The University of Kentucky Sanders-Brown Center on Aging
Lexington, Kentucky, 40504
Cedars-Sinai Center
Los Angeles, California, 90048
NYU Langone Health Tisch Hospital
New York, New York, 10016
Barrow Neurological Institute
Phoenix, Arizona, 85013
OHSU Neurology Clinic
Portland, Oregon, 97239
PCND Neurology
Poway, California, 92064
Rhode Island Hospital
Providence, Rhode Island, 02903
UT Health San Antonio
San Antonio, Texas, 78229
Banner Sun Health Research Institute
Sun City, Arizona, 85351
SUNY Upstate Medical University
Syracuse, New York, 13210
USF Health Byrd Alzheimer's Center and Research Institute
Tampa, Florida, 33613
Georgetown University Medical Center
Washington D.C., District of Columbia, 20057
About this study
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)
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.
Read the 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
- Being tested
- PQ912, Placebo
- Keywords
- Alzheimer's Disease, Mild Cognitive Impairment, Mild Alzheimer's Disease, Early Alzheimer's disease, MCI
- Medical subject headings
- Alzheimer Disease, Cognitive Dysfunction
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PQ912Drug
Also called Varoglutamstat
PQ912 150 mg tablets
PlaceboOther
Placebo tablets to mimic PQ912 150 mg tablets
| Study group | Role | What they receive |
|---|---|---|
| PQ912 | Experimental | All participants started at 150 mg BID and were up-titrated to 600 mg BID Receives: Drug: PQ912 |
| Placebo | Placebo comparator | Matching placebo Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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
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. TO in CSF was estimated from plasma PQ912 concentrations.
Measured: 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.
Measured: 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.
Measured: 24 weeks
Phase 2A: 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.
Measured: 24 weeks
Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score
The within-participant change from baseline in CDR-SB scores. 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, and 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.
Measured: 72 weeks
Secondary outcomes (12)
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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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.
Measured: 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.
Measured: 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
Measured: 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 .
Measured: 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.
Measured: 72 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Apr 2019
- Study start15 Nov 2021
- Primary completion12 Jul 2024
- Study completion12 Aug 2024
Why it stopped: It has been made the strategic decision to terminate the study. This decision to terminate the study early is not being made for safety reasons.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 112 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vivoryon Therapeutics N.V.
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Alzheimer's Disease Cooperative Study (ADCS), National Institute on Aging (NIA)
- Responsible party
- Sponsor
- Investigators
- Howard Feldman, Principal investigator, Alzheimer's Disease Cooperative Study (ADCS)
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03919162
- Sponsor's protocol ID
- PBD-01187
- Other IDs
- 1R01AG061146-01
- Acronym
- VIVA-MIND
- Status last verified
- Dec 2025
- First submitted
- 15 Apr 2019
- Last updated
- 12 Dec 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data sharing is integral to the ADCS's (Alzheimer's Disease Cooperative Study) mission to develop and execute innovative clinical trials focused on interventions that may prevent, delay, or treat the expression of Alzheimer's disease and related dementias. The ADCS is committed to sharing resources and tools, including data, biospecimens, trial designs, outcome and analysis measures following NIH guidelines. DATA SHARING: The ADCS Data and Sample Sharing Committee (DSSC) grants access to de-identified data to individuals who complete the request process and agree to the conditions in an ADCS/UCSD Data Use Agreement (DUA). After approval and receipt of the fully executed DUA, applicants are authorized to acquire data. Non-compliance with the DUA, including the requirement to provide requested updates will jeopardize further access to data.
Publications
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.
PubMed 39422941Messer 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.
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.
PubMed 29854937Scheltens 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.
PubMed 30309389Feldman 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
Study at a glance
From the registry record, last updated by the sponsor on 12 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT03919162
- Acronym / sponsor ID
- VIVA-MIND / PBD-01187
- Conditions
- Alzheimer Disease
- Keywords
- Alzheimer's Disease, Mild Cognitive Impairment, Mild Alzheimer's Disease, Early Alzheimer's disease, MCI
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: It has been made the strategic decision to terminate the study. This decision to terminate the study early is not being made for safety reasons.
- Enrolment
- 112 participants (actual)
- Lead sponsor
- Vivoryon Therapeutics N.V.Industry (pharma, biotech, devices)
- Collaborators
- Alzheimer's Disease Cooperative Study (ADCS), National Institute on Aging (NIA)
- Study start
- 15 Nov 2021 (actual)
- Primary completion
- 12 Jul 2024 (actual)
- Study completion
- 12 Aug 2024 (actual)
- First posted
- 18 Apr 2019 (actual)
- Results
- Posted 12 Dec 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| PQ912 | Experimental | Drug: PQ912All participants started at 150 mg BID and were up-titrated to 600 mg BID |
| Placebo | Placebo comparator | Other: PlaceboMatching placebo |
Who may qualify
- Ages
- 50 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- 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
Key exclusion criteria (12 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PQ912Also: VaroglutamstatPQ912 150 mg tablets | Drug | PQ912 |
| PlaceboPlacebo tablets to mimic PQ912 150 mg tablets | Other | Placebo |
Primary outcome
Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)
Time frame: From first dose to completion of 8 weeks on the full dose (Week 16)
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.
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
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. TO in CSF was estimated from plasma PQ912 concentrations.
Phase 2A: Median Plasma Concentrations of PQ912 at Week 24
Time frame: Week 24, pre-dose (trough level) and 2-3h post-dose
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.
Phase 2A: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC) Score
Time frame: 24 weeks
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.
Phase 2A: Change From Baseline in Quantitative Electroencephalogram (qEEG)
Time frame: 24 weeks
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.
Phase 2B: Change From Baseline in Clinical Dementia Rating - Sum of Boxes (CDR-SB) Score
Time frame: 72 weeks
The within-participant change from baseline in CDR-SB scores. 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, and 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.
12 secondary outcomes
Phase 2B: Key Secondary Efficacy: Change From Baseline in Cognitive Functional Composite-2 (CFC2) Score, a Cognitive Functional Composite
Time frame: 72 weeks
Phase 2B: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC, 9-item) Score
Time frame: 72 weeks
Phase 2B: Change From Baseline in Quantitative Electroencephalogram (qEEG)
Time frame: 72 weeks
Phase 2B: Change From Baseline in Functional Activities Questionnaire (FAQ)
Time frame: 72 weeks
Phase 2B: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13)
Time frame: 72 weeks
Phase 2B: Change From Baseline in Neuropsychiatric Inventory (NPI)
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)
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)
Time frame: Up to 72 weeks
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Mortality Rates
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)
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)
Time frame: 76 weeks
Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Drug Discontinuation Rates
Time frame: 72 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Dec 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 39422941Feldman 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.
- BackgroundMesser 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.
- Background: PubMed 29854937Lues 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.
- Background: PubMed 30309389Scheltens 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.
- Results publicationFeldman 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
- Individual participant dataSharing planned: Yes. Data sharing is integral to the ADCS's (Alzheimer's Disease Cooperative Study) mission to develop and execute innovative clinical trials focused on interventions that may prevent, delay, or treat the expression of Alzheimer's disease and related dementias. The ADCS is committed to sharing resources and tools, including data, biospecimens, trial designs, outcome and analysis measures following NIH guidelines. DATA SHARING: The ADCS Data and Sample Sharing Committee (DSSC) grants access to de-identified data to individuals who complete the request process and agree to the conditions in an ADCS/UCSD Data Use Agreement (DUA). After approval and receipt of the fully executed DUA, applicants are authorized to acquire data. Non-compliance with the DUA, including the requirement to provide requested updates will jeopardize further access to data.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Howard Feldman principal investigator
Alzheimer's Disease Cooperative Study (ADCS)
22 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing PQ912 in people with Alzheimer Disease, run by Vivoryon Therapeutics N.V. at 22 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 12 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 12 Dec 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI) (time frame: From first dose to completion of 8 weeks on the full dose (Week 16)). The study lists 6 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03919162, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Dec 2025.