A Double-Blind, Placebo-Controlled Proof-of-Concept Study of a Selective p38 MAP Kinase Alpha Inhibitor, Neflamapimod, Administered for 24 Weeks in Subjects With Mild Alzheimer's Disease
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 161
- 试验地点
- 38
- 主要终点
- Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)
研究概览
简要总结
This is a phase 2b, double-blind, placebo controlled proof-of-concept study of a an oral small molecule selective inhibitor of p38 alpha kinase, neflamapimod, administered for 24 weeks in subjects with mild Alzheimer's disease. The primary objective is to demonstrate significant improvement relative to placebo-treatment in episodic memory function, as assessed by the Hopkins Verbal Learning Test. Secondary endpoints include Clinical Dementia Rating scale (CDR), Wechsler Memory Scale (WMS), Mini-Mental-Status-Examination (MMSE) and Cerebrospinal fluid (CSF) biomarkers of AD disease activity and progression.
详细描述
Details provided elsewhere.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 55 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Men and women age 55 to 85 years, inclusive.
- •Willing and able to provide informed consent.
- •Must have mild cognitive impairment (MCI) or mild AD with evidence of progression ("Mild-AD"), as defined by the following:
- •CDR-Global Score of 0.5 or 1.0, with CDR memory subscore of at least 0.
- •MMSE score ranging from 20 to 28, inclusive.
- •Positive biomarker for AD, as defined by a CSF Aβ1-42R below the threshold and phospho-tau above the threshold for the assay utilized in the study and assessed by the central laboratory.
- •Computed tomography (CT) or magnetic resonance imaging (MRI) findings within 2 years of Screening that are compatible with AD and no other pathologic processes that might potentially account for the subject's cognitive impairment.
- •If the subject is taking a single drug for AD (e.g., donepezil or other cholinesterase inhibitors or memantine; dual therapy is excluded), he/she has been on a stable dose for at least 2 months prior to baseline, and the dose must remain unchanged during the study unless required for management of adverse events (AEs).
- •Adequate visual and auditory abilities to perform all aspects of the cognitive and functional assessments.
- •Must have reliable informant or caregiver.
排除标准
- •Evidence that the primary basis for cognitive impairment is neurodegenerative disease other than AD, including, but not limited to, vascular dementia, dementia with Lewy bodies, and Parkinson's disease.
- •Suicidality, defined as active suicidal thoughts within 6 months before Screening or at Baseline, defined as answering yes to items 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS), or history of suicide attempt in previous 2 years, or, in the Investigator's opinion, at serious risk of suicide.
- •History of major and active psychiatric disorder, moderate to severe depressive symptoms, and or other concurrent medical condition that, EIP-VX17-745-304, Version 1.0, 17 November, 2017 Page 7 of 46 EIP Pharma, LLC Confidential in the opinion of the Investigator, might compromise safety and/or compliance with study requirements.
- •Diagnosis of alcohol or drug abuse within the previous 2 years.
- •History of cancer within the last 5 years, except basal cell carcinoma, squamous skin carcinoma, prostate cancer or carcinoma in situ with no significant progression over the past 2 years.
- •Poorly controlled clinically significant medical illness.
- •History of serum B12 abnormality, anemia with hemoglobin ≤10 g/dL, thyroid function abnormality, electrolyte abnormality, or positive syphilis serology that have not been corrected and/or otherwise addressed.
- •History of epilepsy or unexplained seizure within the past 5 years.
- •Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper limit of normal (ULN), total bilirubin >2 × ULN, and/or International Normalized Ratio (INR) >1.5
- •Known human immunodeficiency virus, hepatitis B, or active hepatitis C virus infection.
- •Subject participated in a study of an investigational drug less than 3 months or 5 half-lives of the investigation drug, whichever is longer, before enrollment in this study.
研究组 & 干预措施
neflamapimod
40 mg hard gelatin capsules, taken twice daily with food.
干预措施: neflamapimod (Drug)
placebo
hard gelatin capsules containing excipients only, weight- and size-matched; taken twice daily with food.
干预措施: placebo (Other)
结局指标
主要结局
Total and Delayed Recall on the Hopkins Verbal Learning Test - Revised (HVLT-R)
时间窗: Baseline and 24 weeks
Combined change from baseline in z-scores of total and delayed recall on the Hopkins Verbal Learning Test - Revised (HVLT-R) in neflamapimod-treated subjects compared to placebo. The primary endpoint was analyzed using Mixed Model for Repeated Measures (MMRM) with fixed effects for treatment, background AD-specific therapy, CDR-Global Score of 0.5 versus 1.0, scheduled visit (nominal) and scheduled visit by treatment interaction, random effect for subject and baseline Z-score as a covariate. For baseline total and delayed recall, a z-score for each subject is defined by z=(x-m)/s where x is the subject's recall at baseline, and m and s are the overall mean and overall standard deviation of recall at baseline across all subjects. A composite baseline z-score for each subject is calculated using equal weighting in the following way: Z=0.5\*z-score for total recall at baseline + 0.5\*z-score for delayed recall at baseline. For HVLT-R, higher score indicates improvement.
次要结局
- Cerebrospinal Fluid Neurofilament Light Chain(Baseline and 24 weeks)
- Cerebrospinal Fluid Total Tau(Baseline and 24 weeks)
- Cerebrospinal Fluid Phospho-tau(Baseline and 24 weeks)
- Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB)(Baseline and 24 weeks)
- Cerebrospinal Fluid Amyloid Beta 1-42(Baseline and 24 weeks)
- Cerebrospinal Fluid Neurogranin(Baseline and 24 weeks)
- Wechsler Memory Scale (WMS) Immediate and Delayed Recall(Baseline and 24 weeks)
- Cerebrospinal Fluid Amyloid Beta 1-40(Baseline and 24 weeks)
- Mini-Mental State Examination (MMSE)(Baseline and 26 Weeks (Follow-up visit, 2 weeks from end of dosing))
- Cerebrospinal Fluid P-tau/AB1-42 Ratio(Baseline and 24 weeks)