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

• ClinicalTrials.gov Identifier: NCT04498650
• Recruitment Status: Recruiting
• First Posted: August 4, 2020
• Last Update Posted: February 2, 2022
• Sponsor: Vivoryon Therapeutics N.V.
• Collaborators: Nordic Bioscience A/S; Amsterdam UMC, location VUmc
• Information provided by (Responsible Party): Vivoryon Therapeutics N.V.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Early Alzheimers Disease; Mild Cognitive Impairment Due to AD	Drug: PQ912; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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.
• Actual Study Start Date: July 6, 2020
• Estimated Primary Completion Date: May 2023
• Estimated Study Completion Date: July 2023

Arms and Interventions

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 Name: 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 Name: varoglutamstat

Outcome Measures

Primary Outcome Measures :

1. Primary safety: The proportion of participants who experience any Adverse Event (AE), Serious Adverse Event (SAE), Adverse Event of Interest (AE-I) [ Time Frame: 48 weeks ]
   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
2. Primary efficacy: within-participant linear change with time of the combinded z-score for cognition compared between active arm and placebo. [ Time Frame: 48 weeks and EoT (96 weeks at maximum) ]
   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

Secondary Outcome Measures :

1. 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. [ Time Frame: 48 weeks at minimum or until EoT (96 weeks at maximum) ]
   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.
2. 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 [ Time Frame: 48 weeks and EoT (96 weeks at maximum) ]
   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

Other Outcome Measures:

1. Exploratory efficacy - The within-participants change from baseline in a set of representative functional network topology EEG measures compared between active arms and placebo. [ Time Frame: 48 weeks ]

   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Contacts

Contact: Katharina Fuchs; +49 5559900; clinics@vivoryon.com

Contact: Kerstin Kuehn-Wache; +49 5559900; clinics@vivoryon.com

Locations

Denmark

Sanos Clinics; Recruiting

Ganderup, Denmark

Contact: Hanne Soerensen

Principal Investigator: Pernille Luehdorf, MD

Sanos Clinics; Recruiting

Herlev, Denmark

Contact: Charlotta Arpi

Principal Investigator: Ulla Schmidt, MD

Sanos Clinics; Recruiting

Vejle, Denmark

Contact: Ellen Frank

Principal Investigator: Peter Alexandersen, MD

Germany

Charité - Universitätsmedizin Berlin; Recruiting

Berlin, Germany, 10450

Contact: Katja Lindner

Principal Investigator: Oliver Peters, MD

Universitätsklinikum Schleswig-Holstein (UKSH), Klinik für Neurologie; Recruiting

Kiel, Germany, 24105

Contact: Katrin Lange

Principal Investigator: Thorsten Bartsch, MD

Universitätsklinikum Magdeburg / Institut für Kognitive Neurologie und Demenzforschung; Recruiting

Magdeburg, Germany, 39120

Contact: Urte Schneider

Principal Investigator: Emrah Duezel, MD

Institut für Studien zur Psychischen Gesundheit (ISPG); Recruiting

Mannheim, Germany, 68165

Contact: Dörthe Hafke

Principal Investigator: Georg Adler, MD

Klinikum rechts der Isar der TU München / Klinik für Psychiatrie und Psychotherapie; Recruiting

München, Germany, 81675

Contact: Karin Liebl

Principal Investigator: Timo Grimmer, MD

Universitätsklinikum Münster / Klinik für Allgemeine Neurologie; Recruiting

Münster, Germany, 48149

Contact: Gloria Lwanga

Principal Investigator: Matthias Pawlowski, MD

Klinik für Neurologie Universitätsklinikum Ulm; Recruiting

Ulm, Germany, 89081

Principal Investigator: Doerte Polivka, MD

Netherlands

Brain Research Center; Recruiting

Amsterdam, Netherlands

Contact: Femke van der Linden

Principal Investigator: Sterre Rutgers, MD

Brain Research Center; Recruiting

Den Bosch, Netherlands

Contact: Hetty Den Burger

Principal Investigator: Paul Dautzenberg, MD

Brain Research Center Zwolle; Recruiting

Zwolle, Netherlands, 8025

Contact: Carlie Dille-Amo

Principal Investigator: Niels Prins, MD

Spain

Neurology (Memory Unit) - Hospital de la Santa Creu i Sant Pau; Recruiting

Barcelona, Spain, 08025

Contact: Andrea Subirana

Principal Investigator: Alberto Lleo, MD

Fundació ACE; Recruiting

Barcelona, Spain, 08028

Contact: Mar Buendia

Principal Investigator: Merce Boada, MD

Unidad de Neurociencias. Hospital Victoria Eugenia; Recruiting

Seville, Spain, 41009

Contact: Angelles Barro

Principal Investigator: Felix Vinuela, MD

Sponsors and Collaborators

Vivoryon Therapeutics N.V.

Nordic Bioscience A/S

Amsterdam UMC, location VUmc

Investigators

• Study Chair: Philip Scheltens; Amsterdam UMC, location VUmc

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vijverberg EGB, Axelsen TM, Bihlet AR, Henriksen K, Weber F, Fuchs K, Harrison JE, Kühn-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.

• Responsible Party: Vivoryon Therapeutics N.V.
• ClinicalTrials.gov Identifier: NCT04498650
• Other Study ID Numbers: PBD-01180; 2019-003532-23 ( EudraCT Number )
• First Posted: August 4, 2020
• Last Update Posted: February 2, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Cognitive Dysfunction; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders