A Study to Evaluate Safety and Tolerability of Different Doses and Efficacy of PQ912 in Subjects With MCI and Mild AD (VIVIAD)

A Phase 2b Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel Group Dose Finding, Safety, Tolerability and Efficacy Study of PQ912 in Subjects With MCI and Mild Dementia Due to Alzheimer's Disease.

This is a phase 2B multicenter, randomized, double-blind, placebo-controlled, parallel group dose finding study to evaluate the safety, tolerability and efficacy of PQ912, an inhibitor of the glutaminyl cyclase enzyme, in 250 subjects with mild cognitive impairment and mild dementia due to Alzheimer 's Disease.

Study Overview

• Status: Completed
• Conditions: Early Alzheimers Disease; Mild Cognitive Impairment Due to AD
• Intervention / Treatment: Drug: Placebo; Drug: PQ912

Detailed Description

In the parallel group dose finding part of the study the first 90 subjects will be randomized 1:1:1 between PQ912 300 mg BID, 600 mg BID, and placebo. When the 90th patient has completed the week 24 treatment visit, the DSMB will decide on the dose of PQ912 to be continued. The decision is based on safety findings only, no efficacy data will be considered. After the DSMB has reached a decision on the dose to be continued, all subjects randomized to receive PQ912 will be reallocated to this dose (1:1). The duration of Subjects participation in the study is either 48, 60, 72, 84 or 96 weeks of treatment (depending on time of randomization). Subjects recruited early into the study will be kept on treatment for 96 weeks or until the regular, scheduled study visit which is closest to the scheduled week 48 visit of the last subject recruited in the study, whichever comes first.

• Study Type: Interventional
• Enrollment (Actual): 259
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Ganderup, Denmark
    • Sanos Clinics
  • Herlev, Denmark
    • Sanos Clinics
  • Vejle, Denmark
    • Sanos Clinics
• Germany
  • Berlin, Germany, 10450
    • Charité - Universitätsmedizin Berlin
  • Kiel, Germany, 24105
    • Universitätsklinikum Schleswig-Holstein (UKSH), Klinik für Neurologie
  • Magdeburg, Germany, 39120
    • Universitätsklinikum Magdeburg / Institut für Kognitive Neurologie und Demenzforschung
  • Mannheim, Germany, 68165
    • Institut für Studien zur Psychischen Gesundheit (ISPG)
  • München, Germany, 81675
    • Klinikum rechts der Isar der TU München / Klinik für Psychiatrie und Psychotherapie
  • Münster, Germany, 48149
    • Universitätsklinikum Münster / Klinik für Allgemeine Neurologie
  • Ulm, Germany, 89081
    • Klinik für Neurologie Universitätsklinikum Ulm
• Netherlands
  • Amsterdam, Netherlands
    • Brain Research Center
  • Den Bosch, Netherlands
    • Brain Research Center
  • Zwolle, Netherlands, 8025
    • Brain Research Center Zwolle
• Poland
  • Białystok, Poland, 15-756
    • Podlaskie Centrum
  • Warsaw, Poland, 01-737
    • SOMED CR
  • Łódź, Poland, 90-368
    • SOMED CR
  • Łódź, Poland, 92-216
    • Klinika Psychiatrii Wieku Podeszłego i Zaburzeń Psychotycznych Uniwersytetu Medycznego w Łodzi
• Spain
  • Barcelona, Spain, 08028
    • Fundacio ACE
  • Barcelona, Spain, 08025
    • Neurology (Memory Unit) - Hospital de la Santa Creu i Sant Pau
  • Getxo, Spain, 48993
    • CAE Oroitu
  • Seville, Spain, 41009
    • Unidad de Neurociencias. Hospital Victoria Eugenia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

• Positive CSF AD biomarker signature according to the AA-NIA criteria
• Clinical syndrome of MCI or mild dementia according to the AA-NIA Research Framework
• A cognitive impairment in the WAIS IV Coding Test of at least 0.5 standard deviation below the normative data
• Adequate visual and auditory abilities to perform the cognitive and functional assessments in the opinion of the investigator
• Meeting the completion and performance criteria for the CogState NTB
• Outpatient with study partner capable of accompanying the subject on all applicable clinic visits

Main Exclusion Criteria:

• Significant neurological or psychiatric disorders, other than AD, that may affect cognition.
• Atypical clinical presentations of MCI due to AD or mild dementia due to AD, such as the visual variant of AD (including posterior cortical atrophy), frontal variant or the language variant (including logopenic aphasia).
• Moderate and severe dementia with a Mini-Mental State Examination score (MMSE) below 20.
• Current presence of a clinically important major psychiatric disorder (e.g. major depressive disorder) as defined by DSM-5 criteria, or symptom(s) (e.g. hallucinations) that could affect the subject's ability to complete the study.
• History of clinically evident stroke.
• History of seizures within the last two years prior to the screening visit.
• Myocardial infarction within the last six months prior to screening.
• History of uncontrolled hypertension (in the opinion of the investigator) within six months prior to screening.
• Contraindication to lumbar puncture and MRI

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo tablets to mimic PQ912 50 mg and 150 mg tablets
Experimental: 300 mg; Dose in weeks 1 and 2: 50 mg once daily (evening) Dose in weeks 3 and 4: 50 mg BID Dose in weeks 5-8: 150 mg BID Dose in weeks 9-24: 300 mg BID	Drug: PQ912; PQ912 50 mg tablets and 150 mg tablets; Other Names: varoglutamstat
Experimental: 600 mg; Dose in weeks 1 and 2: 50 mg once daily (evening) Dose in weeks 3 and 4: 50 mg BID Dose in weeks 5-8: 150 mg BID Dose in weeks 9-12: 300 mg BID Dose in weeks 12-24: 600 mg BID	Drug: PQ912; PQ912 50 mg tablets and 150 mg tablets; Other Names: varoglutamstat

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Primary safety: The proportion of participants who experience any Adverse Event (AE), Serious Adverse Event (SAE), Adverse Event of Interest (AE-I)	The safety analysis will include the number of subjects with, and the number of any AE, any SAE (both overall and related), AEs leading to discontinuation of treatment, AEs leading to temporary treatment interruption, treatment compliance, the number of subjects with AEs of interest as defined above, the severity, duration and outcome of AEs	48 weeks
Primary efficacy: within-participant linear change with time of the combinded z-score for cognition compared between active arm and placebo.	The within-participant change over time in cognition measured by the combined z-score of the Detection test, Identification test and the 'One Back' test (attention and working memory domains) of the Neurological Test Battery	48 weeks and EoT (96 weeks at maximum)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Secondary efficacy: The within-participant linear change from baseline to week 48 in quantitative EEG (global relative theta wave power), compared between active and placebo.	Using a quantitative EEG the within-participant change from baseline to week 48 of the global relative theta wave power (4-8 Hz) will serve as a primary efficacy outcome.	48 weeks at minimum or until EoT (96 weeks at maximum)
Secondary efficacy: The within-participant linear change with time in overall cognition as measured by the CogState Brief Battery (CBB) Z-score compared between active arm and placebo	he within-participant linear change with time in overall cognition as measured by the CBB (CogState Detection, Identification, One Card Learning and One Back test) -Z-score	48 weeks and EoT (96 weeks at maximum)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory efficacy - The within-participants change from baseline in a set of representative functional network topology EEG measures compared between active arms and placebo.	Evaluation of brain functional network activity and connectivity will be performed using quantitative EEG measurements, as described by (Briels et al. 2020; Poil et al. 2013; Scheltens et al. 2018) Global relative power in the delta (0.5 - 4 Hz), alpha (8 -13 Hz) and beta (13 - 30Hz) frequency bands; Global posterior dominant peak frequency; Amplitude Envelope Correlation (AEC) in the 4- 13 Hz band Functional network topology measures such as centrality, modularity, minimum spanning tree.	48 weeks

Collaborators and Investigators

• Sponsor: Vivoryon Therapeutics N.V.
• Collaborators: Amsterdam UMC, location VUmc; Nordic Bioscience A/S
• Investigators: Study Chair: Everard Vijverberg, Dr, VUmc Alzheimer Centre

Publications and helpful links

General Publications

• Vijverberg EGB, Axelsen TM, Bihlet AR, Henriksen K, Weber F, Fuchs K, Harrison JE, Kuhn-Wache K, Alexandersen P, Prins ND, Scheltens P. Rationale and study design of a randomized, placebo-controlled, double-blind phase 2b trial to evaluate efficacy, safety, and tolerability of an oral glutaminyl cyclase inhibitor varoglutamstat (PQ912) in study participants with MCI and mild AD-VIVIAD. Alzheimers Res Ther. 2021 Aug 23;13(1):142. doi: 10.1186/s13195-021-00882-9.

Study record dates

Study Major Dates

• Study Start (Actual): July 6, 2020
• Primary Completion (Actual): December 18, 2023
• Study Completion (Actual): January 12, 2024

Study Registration Dates

• First Submitted: July 21, 2020
• First Submitted That Met QC Criteria: August 3, 2020
• First Posted (Actual): August 4, 2020

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Cognition Disorders; Alzheimer Disease; Cognitive Dysfunction
• Other Study ID Numbers: PBD-01180; 2019-003532-23 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No