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)
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 112
- 试验地点
- 22
- 主要终点
- Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 50 Years 至 89 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •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.
研究组 & 干预措施
Placebo
Matching placebo
干预措施: Placebo (Other)
PQ912
All participants started at 150 mg BID and were up-titrated to 600 mg BID
干预措施: PQ912 (Drug)
结局指标
主要结局
Phase 2A: Number of Participants With Any Adverse Event of Special Interest (AESI)
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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)
时间窗: 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
时间窗: 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.
次要结局
- Phase 2B: Key Secondary Efficacy: Change From Baseline in Cognitive Functional Composite-2 (CFC2) Score, a Cognitive Functional Composite(72 weeks)
- Phase 2B: Change From Baseline in Alzheimer's Disease Neuroimaging Initiative (ADNI) Battery Composite (ABC, 9-item) Score(72 weeks)
- Phase 2B: Change From Baseline in Quantitative Electroencephalogram (qEEG)(72 weeks)
- Phase 2B: Change From Baseline in Functional Activities Questionnaire (FAQ)(72 weeks)
- Phase 2B: Change From Baseline in Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog-13)(72 weeks)
- Phase 2B: Change From Baseline in Neuropsychiatric Inventory (NPI)(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)(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)(Up to 72 weeks)
- Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Mortality Rates(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)(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)(76 weeks)
- Phase 2B: Assessment of the Longer-term Safety and Tolerability of PQ912 as Measured by Drug Discontinuation Rates(72 weeks)