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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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.

Conditions
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Early Alzheimers Disease, Mild Cognitive Impairment Due to AD

Intervention / Treatment
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* Drug: PQ912
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo tablets to mimic PQ912 50 mg and 150 mg tablets<br>|
| Experimental: 300 mg<br>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<br>* PQ912 50 mg tablets and 150 mg tablets<br>* Other names: varoglutamstat;|
| Experimental: 600 mg<br>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<br>* PQ912 50 mg tablets and 150 mg tablets<br>* Other names: varoglutamstat;|

What is the study measuring?
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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) |