Clinical trial NCT04498650: A Study to Evaluate Safety and Tolerability of Different Doses and Efficacy of PQ912 in Subjects With MCI and Mild AD
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Early Alzheimers Disease
Mild Cognitive Impairment Due to AD
Lead sponsor: Vivoryon Therapeutics N.V.
Sponsor class: INDUSTRY
Collaborators: name: Nordic Bioscience A/S
name: Amsterdam UMC, location VUmc
First posted: 2020-08-04
Enrollment: 259
Sex: ALL
Minimum age (years): 50
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Primary safety: The proportion of participants who experience any Adverse Event (AE), Serious Adverse Event (SAE), Adverse Event of Interest (AE-I)
timeFrame: 48 weeks
measure: Primary efficacy: within-participant linear change with time of the combinded z-score for cognition compared between active arm and placebo.
timeFrame: 48 weeks and EoT (96 weeks at maximum)
Secondary outcomes:
measure: 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.
timeFrame: 48 weeks at minimum or until EoT (96 weeks at maximum)
measure: 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
timeFrame: 48 weeks and EoT (96 weeks at maximum)
Other outcomes:
measure: Exploratory efficacy - The within-participants change from baseline in a set of representative functional network topology EEG measures compared between active arms and placebo.
timeFrame: 48 weeks
Locations:
city: Ganderup
country: Denmark
facility: Sanos Clinics
city: Herlev
country: Denmark
facility: Sanos Clinics
city: Vejle
country: Denmark
facility: Sanos Clinics
city: Berlin
country: Germany
facility: Charité - Universitätsmedizin Berlin
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein (UKSH), Klinik für Neurologie
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg / Institut für Kognitive Neurologie und Demenzforschung
city: Mannheim
country: Germany
facility: Institut für Studien zur Psychischen Gesundheit (ISPG)
city: München
country: Germany
facility: Klinikum rechts der Isar der TU München / Klinik für Psychiatrie und Psychotherapie
city: Münster
country: Germany
facility: Universitätsklinikum Münster / Klinik für Allgemeine Neurologie
city: Ulm
country: Germany
facility: Klinik für Neurologie Universitätsklinikum Ulm
city: Amsterdam
country: Netherlands
facility: Brain Research Center
city: Den Bosch
country: Netherlands
facility: Brain Research Center
city: Zwolle
country: Netherlands
facility: Brain Research Center Zwolle
city: Białystok
country: Poland
facility: Podlaskie Centrum
city: Warsaw
country: Poland
facility: SOMED CR
city: Łódź
country: Poland
facility: SOMED CR
city: Łódź
country: Poland
facility: Klinika Psychiatrii Wieku Podeszłego i Zaburzeń Psychotycznych Uniwersytetu Medycznego w Łodzi
city: Barcelona
country: Spain
facility: Neurology (Memory Unit) - Hospital de la Santa Creu i Sant Pau
city: Barcelona
country: Spain
facility: Fundació ACE
city: Getxo
country: Spain
facility: Cae Oroitu
city: Seville
country: Spain
facility: Unidad de Neurociencias. Hospital Victoria Eugenia
Study officials:
affiliation: VUmc Alzheimer Centre
name: Everard Vijverberg, Dr
role: STUDY_CHAIR
References:
citation: 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.