Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics Study of Bryostatin 1 in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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The main purpose of this study is find out how safe a single dose of bryostatin 1 is in patients with Alzheimer's Disease (AD). This study is also being done 1) to determine how effective a single dose of bryostatin 1 is in the treatment of AD, 2) to find out what happens to bryostatin 1 once it enters the body by measuring the levels of bryostatin 1 in blood, and 3) to measure a substance in the blood (protein kinase C) that may help to better understand how bryostatin 1 works.

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

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Bryostatin for Injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, age 50 yrs or older. Females must be of non-childbearing potential (surgically sterilized or at least 2 yrs post-menopausal) Must have a cognitive deficit present for at least 1 yr & meet DSM-IV-TRTM criteria for AD & meet NINCDS/ADRDA criteria for the presence of probable AD Severity of AD must be mild to moderate, documented with a MMSE score of 12-26 Has a CT scan or MRI scan within the prior 12 months, which is compatible with a diagnosis of probable AD Ability to walk, at least with an assistive device Vision & hearing sufficient to comply with testing Normal cognitive & social functioning prior to onset of dementia Consistent caregiver to accompany patient to assessment visits Sufficient basic education to be able to complete the cognitive assessments Living outside an institution Informed consent signed & dated by patient or legal representative Has provided written authorization for the use & disclosure of protected health information Exclusion Criteria: Dementia due to any condition other than AD, including vascular dementia (modified Hachinski Ischemic Scale ≥ 5; positive NINDS-AIREN criteria) Evidence of clinically significant unstable cardiovascular, renal, hepatic, gastrointestinal, neurological, or metabolic disease within the past 6 months (as determined by medical history, ECG results, chest x-ray, or physical examination) Use of any drug within 14 days prior to randomization unless the dose of the drug & the condition being treated have been stable for at least 30 days & are expected to remain stable during the study & neither the drug nor the condition being treated is expected to interfere with the study endpoints Any medical or psychiatric condition that may require medication or surgical treatment during the study Life expectancy less than 6 months Any other screening laboratory values outside the normal ranges that are deemed clinically significant by the investigator Use of an investigational drug within 30 days prior to the screening visit or during the entire study Significant neurological disease other than AD, including cerebral tumor, Huntington's Disease, Parkinson's Disease, normal pressure hydrocephalus, & other entities Major depression according to DSM-IV Psychotic episodes requiring hospitalization or antipsychotic therapy for more than 2 weeks within the past 10 yrs, not linked to AD Agitation sufficient to preclude participation in this trial Alcohol or drug dependence diagnosed within the past 10 yrs Epilepsy or anti-epileptic drug therapy Abnormal laboratory tests that might point to another etiology for dementia: serum B12, folate, thyroid functions, electrolytes, syphilis serology Musculoskeletal diseases that could interfere with assessment Acute or poorly controlled medical illness: blood pressure> 180 mmHg systolic or 100 mmHg diastolic; myocardial infarction within 6 months; uncompensated congestive heart failure (NYHA Class III or IV), severe renal, hepatic or gastrointestinal disease that could alter drug pharmacokinetics; blood glucose > 180 mg/dl on repeated testing at entry into study or need for insulin therapy Previous randomization in this trial or participation in another investigational trial < 2 months prior to randomization Likelihood, according to clinical judgment, of being transferred to a nursing home within 6 months Change in dosage of any concomitant antidepressant within 30 days prior to randomization Lack of caregiver Pregnant or lactating females Patients who in the judgment of the Investigator may be unreliable or uncooperative with the evaluation procedures outlined in this protocol HIV positive Hepatitis B or C positive Concomitant use of medications other than AD or antidepressant medications for which the dose regimens are stabilized for at least 30 days prior to enrollment in study

Ages Eligible for Study
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Minimum Age: 50 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 |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* A single one-hour intravenous infusion of placebo on Day 1<br>* Other names: PET (60/30/10) diluent plus sodium chloride for injection;|
| Experimental: 10 ug/m2 Bryostatin<br> | Drug: Bryostatin for Injection<br>* A single one-hour intravenous infusion of 10 or 15 ug/m2 Bryostatin for Injection on Day 1<br>* Other names: CAS No. 83314-01-6;|
| Experimental: 15 ug/m2 Bryostatin<br> | Drug: Bryostatin for Injection<br>* A single one-hour intravenous infusion of 10 or 15 ug/m2 Bryostatin for Injection on Day 1<br>* Other names: CAS No. 83314-01-6;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events |  | 4-weeks | 
| Alzheimer's Disease Assessment Scale |  | 4-weeks post dose | 
| Clinician's Interview Based Impression of Change |  | 4-weeks post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alzheimer's Disease Assessment Scale |  | 24, 48, and 72 hrs post dose | 
| Clinician's Interview Based Impression of Change |  | 24, 48, and 72 hrs post dose | 
| Clinical Dementia Rating Battery |  | 24, 48, and 72 hrs post dose and 4-weeks post dose | 
| Alzheimer's Disease Cooperative Study - Activities of Daily Living |  | 24, 48, and 72 hrs post dose and 4-weeks post dose | 
| Severe Impairment Battery |  | 24, 48, and 72 hrs post dose and 4-weeks post dose | 
| Hopkins Verbal Learning Test-Revised |  | 24, 48, and 72 hrs post dose and 4-weeks post dose | 
| Temperature |  | 48 hrs and 4-weeks post dose | 
| Respiratory rate |  | 48 hrs and 4-weeks post dose | 
| Blood pressure |  | 15, 30, and 60 minutes after start of study drug infusion, and at 1, 2, 4, 8, 12, 24, 48, and 72 hrs post infusion and 4-weeks post infusion | 
| Heart rate |  | 15, 30, and 60 minutes after start of study drug infusion, and at 1, 2, 4, 8, 12, 24, 48, and 72 hrs post infusion and 4-weeks post infusion | 
| Electrocardiogram |  | 15, 30, and 60 minutes after start of study drug infusion, and at 1, 2, 4, 8, 12, and 24 hrs post infusion and 4-weeks post infusion | 
| Physical Exam |  | 48 hrs and 4-weeks post dose | 
| Hematology |  | 48 hrs and 4-weeks post dose | 
| Blood chemistry |  | 48 hrs and 4-weeks post dose | 
| Urinalysis |  | 48 hrs and 4-weeks post dose | 
| Pharmacokinetics |  | Blood draws at baseline, during the study drug infusion (15, 30, and 60 minutes after start of infusion), and at 20 minutes, 1 hr, 2 hrs, 6 hrs, 24 hrs, 48 hrs, and 72 hrs post infusion | 
| Protein kinase C activity (pharmacodynamics) |  | Blood draws at baseline, during the study drug infusion (15, 30, and 60 minutes after start of infusion), and at 20 minutes, 1 hr, 2 hrs, 6 hrs, 24 hrs, 48 hrs, and 72 hrs post infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, bryostatin 1, bryostatin, safety, efficacy, pharmacokinetics, pharmacodynamics, protein kinase C