Study to Evaluate the Safety, Tolerability and the Effect of BMS-241027 on Cerebrospinal Fluid Biomarkers in Subjects With Mild Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of the study is to evaluate safety and the pharmacodynamic effects of BMS-241027 on cerebrospinal fluid (CSF) Tau, connectivity magnetic resonance imaging (MRI), and computerized cognitive tests in mild Alzheimer's disease (AD) subjects, following 9 weekly intravenous (IV) infusions of BMS-241027

Official Title
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A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability and the Effect of BMS-241027 on Cerebrospinal Fluid Biomarkers in Subjects With Mild Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: BMS-241027
* Drug: BMS-241027
* Drug: BMS-241027
* Drug: Placebo matching BMS-241027


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Mild AD Subjects meeting National Institute of Neurological Disorders and Stroke - Alzheimer's Disease Related Disorders Association(NINCDS-ADRDA) and Diagnostic and Statistical Manual of Mental Disorders-Forth Edition, Text Revision (DSM-IV-TR) criteria Mini-Mental State Exam (MMSE) Score between 20 & 26 (inclusive) CSF consistent with AD pathology Screening brain MRI - normal - commensurate with age or demonstrate atrophy consistent with AD diagnosis (dx); reveal no more than mild white matter disease; up to 2 lacunar infarcts acceptable except in anterior thalamus, genu of internal capsule or basal forebrain; reveal no cortical infarcts; reveal no more than 4 microbleeds; reveal no focal asymmetric lobar atrophy or other findings suggesting primary cause of dementia is attributed to a cause other than AD; reveal no macrohemorrhages (>10 mm) Subjects must have reliable study partners Men and Women of Non Child Bearing Potentia (WONCBP), ages 50-90 years Exclusion Criteria: Subjects with any other medical condition other than mild AD that could explain subjects' memory or cognitive deficits Subjects diagnosed with moderate or severe AD per DSM-IV criteria Subjects with a history (hx) of stroke Subjects with a hx of GI illnesses Subjects with Vitamin B12 or folate deficiency Subjects with any unstable cardiovascular (CV), pulmonary, Gastrointestinal (GI) or hepatic disease within 30 days prior to screening Subjects with active liver dx or history of hepatic intolerance Subjects with a Geriatric Depression Scale score of ≥ 6 at screening Subjects treated for or have had a diagnosis of schizophrenia Subjects treated for or have had a diagnosis of bipolar disease within 3 years prior to screening Subjects with a history of generalized peripheral neuropathy

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 90 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: BMS-241027 (0.003 mg/kg)<br> | Drug: BMS-241027<br>* Intravenous (IV), 0.003 mg/kg, Once Weekly, 9 weeks<br>|
| Experimental: Arm 2: BMS-241027 (0.01 mg/kg)<br> | Drug: BMS-241027<br>* Intravenous (IV), 0.01 mg/kg, Once Weekly, 9 weeks<br>|
| Experimental: Arm 3: BMS-241027 (0.03 mg/kg)<br> | Drug: BMS-241027<br>* Intravenous (IV), 0.03 mg/kg, Once Weekly, 9 weeks<br>|
| Experimental: Arm 4: Placebo matching BMS-241027<br> | Drug: Placebo matching BMS-241027<br>* Intravenous (IV), 0.0 mg/kg, Once Weekly, 9 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessments: based on frequency of Serious Adverse Events (SAEs), frequency of Adverse events (AEs), discontinuation due to AEs and dose reduction |  | Within the first 70 day after first dose | 
| Biomarker Measures: CSF levels of Tau N-terminal domain fragments |  | Within the first 70 day after first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of BMS-241027 on CSF levels of the mid-domain Tau fragment |  | Within the first 70 days after first dose | 
| Effects of BMS-241027 on cognitive performance using computerized cognitive tests |  | Weeks 3, 6 and 9 | 
| Effects of BMS-241027 on connectivity MRI |  | Within the first 70 days after first dose | 
| Maximal observed plasma concentration (Cmax) of BMS-241027 in subjects with mild Alzheimer's disease | Intensive pharmacokinetic parameter Cmax will be derived from subgroups of subjects at Week 7 | Weeks 1, 4, and 9 | 
| Observed plasma concentration at 24 hours post dose (C24) of BMS-241027 in subjects with mild Alzheimer's disease | Intensive pharmacokinetic parameter C24 will be derived from subgroups of subjects at Week 7 | Weeks 1, 4, and 9 | 
| Time of maximal observed plasma concentration (Tmax) of BMS-241027 in subjects with mild Alzheimer's disease | Intensive pharmacokinetic parameter Tmax will be derived from subgroups of subjects at Week 7 | Weeks 1, 4, and 9 | 
| Area under the concentration-time curve in one dosing interval [AUC(TAU)] of BMS-241027 in subjects with mild Alzheimer's disease | Intensive pharmacokinetic parameter AUC(TAU) will be derived from subgroups of subjects at Week 7 | Weeks 1, 4, and 9 | 
| Safety assessments: based on vital sign measurements, ECGs and clinical laboratory tests |  | Within the first 70 day after first dose | 
| Effects of BMS-241027 on CSF levels of neurofilaments |  | Within the first 70 days after first dose |