Study to Evaluate the Preliminary Safety, Efficacy, PK and PD of Bryostatin 1 in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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This study is being done to evaluate the safety, tolerability and potential effectiveness of a new investigational drug, bryostatin 1, in patients with Alzheimer's disease (AD).

Detailed Description
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This study is a single center, randomized, double-blind, placebo-controlled, parallel groups trial in patients with AD. Each subject enrolled in the trial will be randomized to receive a single IV dose of 0 (placebo) or 25 μg/m2 bryostatin. A total of 15 subjects (5 in the placebo arm and 10 in the treatment arm) will be enrolled in the study. The study consists of screening evaluations and on study evaluations divided into two segments, an inpatient segment and an outpatient segment. The four-day inpatient segment will consist of baseline evaluations and a 1-hour IV infusion of study drug followed by evaluations at multiple evaluations over the first 72 hrs post dose. During the outpatient segment, patients will be followed for AEs and have a final evaluation at 2 weeks post dose and a 4-week telephone safety follow up. Evaluations will include safety, efficacy, pharmacokinetics, and pharmacodynamics as assessed by PKC activity

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate the Preliminary Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Bryostatin 1 in Patients With Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Bryostatin 1
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 50 - 85 yrs. Females are non-childbearing potential Patient must have a cognitive deficit present for at least 1 year and meet diagnostic criteria for probable Alzheimer's Disease Dementia by NIA-AA criteria or prodromal Alzheimer's Disease Mini Mental State Exam score of 16-26 Ability to walk, at least with an assistive device Vision and hearing sufficient to comply with testing Normal cognitive and social functioning prior to onset of dementia, with evidence of progressive symptoms from patient or informant Consistent caregiver to accompany patient to visits Sufficient basic education to be able to complete the cognitive assessments Living outside an institution Exclusion Criteria: Dementia due to any condition other than AD, including vascular dementia Significant neuroimaging abnormalities, previously known or discovered on screening MRI scan, Evidence of clinically significant unstable cardiovascular, renal, hepatic, gastrointestinal, neurological, or metabolic disease within the past 6 months Use of any drug within 14 days prior to randomization unless the dose of the drug and the condition being treated have been stable for at least 30 days and are expected to remain stable during the study Use of tobacco products or nicotine-containing products within 3 months before Day 1 Use of high dose vitamin E, or valproic acid Any medical or psychiatric condition that may require medication or surgical treatment during the study Life expectancy less than 6 months Use of an investigational drug within 2 months prior to the screening visit Clinically significant neurological disease other than AD Major depression, alcohol or drug dependence or suicidality Psychotic episodes requiring hospitalization or antipsychotic therapy for more than 2 weeks within the past 10 years, not linked to AD Agitation sufficient to preclude participation in this trial Epilepsy or anti-epileptic drug therapy Abnormal laboratory tests that might point to another etiology for dementia; Acute or poorly controlled medical illness Likelihood, according to clinical judgment, of being transferred to a nursing home within 6 months

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 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: Single Group Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Bryostatin 1<br>single dose of 25 μg/m2 bryostatin, intravenous infusion over 1 hour | Drug: Bryostatin 1<br>* 25 μg/m2 bryostatin 1, single dose via intravenous infusion over 1 hour.<br>|
| Placebo Comparator: placebo<br>single dose of placebo, intravenous infusion over 1 hour | Drug: Placebo<br>* Placebo, single dose via intravenous infusion over 1 hour.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Evaluate the safety and tolerability of bryostatin 1 (hereinafter referred to as bryostatin) in patients with Alzheimer's Disease (AD) following a single intravenous (IV) dose. | Within 2 weeks of study drug dosing | 
| Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Hopkins Verbal Learning Test - Revised (HVLT-R) delayed recall; change from baseline. HVLT consists of a 12-item word list drawn from 3 semantic categories, presented in 3 learning trials. Score range = 0-12. The lower the number, the more impaired. Repeatable Battery of Assessments for Neuropsychological Status (RBANS) figure recall; change from baseline. Total Score Range: 0-20. Each portion of the drawing is scored 1 point for correctness and completeness and 1 point for being placed properly in relation to the rest of the drawing. Drawing and placement scores are summed for the item total. To obtain subtest total score, the drawing and placement scores are summed for each item. The lower the number, the more impaired. | 48 hours post start of study drug infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R (Hopkins Verbal Learning Test-Revised™) delayed recall (change from baseline). A 12-item word list: 3 learning trials. Score range = 0-12. The lower the number, the more impaired. Repeatable Battery of Assessments for Neuropsychological Status (RBANS) figure recall; change from baseline. Score Range: 0-20. The lower the number, the more impaired. Digit Symbol Coding (observed), Score range: 0-125. The lower the number, the more impaired. Clinical Dementia Rating- Sum of Boxes (CDR-SB, observed). Sum of 6 investigated domains (Memory, Orientation, Judgment and Problem Solving, Community Affairs, Home and Hobbies, Personal Care). Each subtest range is 0-3; Sum of all 6 subtest scores gives total CDR-SB score (range= 0-18).The higher the number, the more impaired. Mini Mental State Exam, version 2 (MMSE-2), change from baseline. The MMSE-2 measures aspects of cognitionon a scale of 0-30. Lower scores indicate greater cognitive impairment. | Specified timepoints within 2 weeks post study drug infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's, bryostatin, PKC epsilon