A Study of Bryostatin in Moderately Severe to Severe Alzheimer's Disease Subjects Not On Memantine

Study Overview
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Brief Summary
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This is a randomized double-blind Placebo-controlled, Phase 2 study comparing bryostatin to placebo for the treatment of moderately severe to severe Alzheimer's disease in subjects not receiving memantine treatment. The study is 15 weeks in duration, including a safety and efficacy evaluation 30 days after the last dose of study drug. Subjects will receive 7 doses of study drug during the study. The primary efficacy endpoint is defined as the change from baseline to Week 13 in the Severe Impairment Battery (SIB) total score.

Detailed Description
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Eligible subjects will be stratified based on Mini Mental State Exam (MMSE-2) scores 4-9 vs. 10-15 and will be randomized 1:1 to one of two treatment arms: 20µg bryostatin or placebo for twelve weeks. The first two doses of study drug will be a loading dose 20% higher (i.e., 24µg) than the assigned dose and will be administered one week apart. Thereafter, the assigned dose of 20µg will commence with the third dose and be administered every other week. Drug is administered IV by continuous infusion over 45(±5) minutes. Subjects are scheduled to receive seven doses over 12 weeks.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the Safety, Tolerability and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease Subjects Not Receiving Memantine Treatment

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Bryostatin
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from caregiver and subject (if possible) or legally acceptable representative if different from caregiver Male and female subjects 55-85 years of age inclusive Cognitive deficit present for at least 2 years that meet the diagnostic criteria for probable Alzheimer's dementia. The diagnosis must be confirmed at the time of the screening visit MMSE-2 score of 4-15 inclusive (applies to Screening Visit only) Patients must be able to perform at least one item on the SIB and may not have a SIB score >93 at screening Neuroimaging computerized tomography (CT) or Magnetic Resonance Imaging (MRI) within the last 24 months consistent with a diagnosis of probable AD without any other clinically significant co-morbid pathologies. If there has been a significant change in the subject's clinical status since the last imaging study that is not consistent with progression of the subject's AD, an imaging study should be performed to confirm eligibility Reliable caregiver(s) or informant(s) who attends the subject at least an average of 3 hours or more per day for 3 or more days per week and who will agree to accompany the subject to the clinic visits and reliably complete the caregiver questions Adequate vision and motor function to comply with testing If taking an approved cholinesterase inhibitor for treatment of Alzheimer's disease, must be on a stable dose for at least 3 months prior to entry into study and the dose must not change during the study unless a change is required due to an adverse effect of the prescribed medication or a clinically significant change in the patient's status Subjects who are memantine naïve or have been off memantine for at least 30 days prior to initial treatment with study drug Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks (dose adjustments will be permitted) Females participating in the study must meet one the following criteria: Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal ligation) for at least 6 months or postmenopausal (postmenopausal females must have no menstrual bleeding for at least 1 year) or If not postmenopausal, agree to use a double method of contraception, one of which is a barrier method (e.g., intrauterine device plus condom, spermicidal gel plus condom) 30 days prior to dosing until 30 days after last dose and have negative human chorionic gonadotropin (β-hCG) test for pregnancy at screening Males who have not had a vasectomy must use appropriate contraception methods (barrier or abstinence) from 30 days prior to dosing until 30 days after last dose In the opinion of the PI subjects should be in reasonably good health over the last 6 months and any chronic disease should be stable - Exclusion Criteria: Dementia due to any condition other than AD, including vascular dementia (Rosen-Modified Hachinski Ischemic score ≥ 5) Evidence of significant central nervous system (CNS) vascular disease on previous neuroimaging including but not limited to: cortical stroke, multiple infarcts, localized single infarcts in the thalamus, angular gyrus, multiple lacunar infarcts or extensive white matter injury Clinically significant neurologic disease or condition other than AD, such as cerebral tumor, chronic subdural fluid collections, Huntington's Disease, Parkinson's Disease, normal pressure hydrocephalus, or any other diagnosis that could interfere with assessment of safety and efficacy Evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, neurologic, or metabolic disease within the 6 months prior to enrollment. . If there is a history of cancer the subject should be clear of cancer for at least 2 years prior to screening. More recent history of basal cell or squamous cell carcinoma and melanoma in situ (Stage 0) may be acceptable after review by the Medical Monitor. Creatinine clearance (CL) of <45ml/min Poorly controlled diabetes, at the discretion of the Principal Investigator Concomitant treatment with NMDA receptor antagonists such as but not limited to memantine or drug combinations containing memantine, dextromethorphan (a cough suppressant), ketamine, phencyclidine (PCP), methoxetamine (MXE), nitrous oxide (N2O) and the following synthetic opioids: penthidine, levorphanol, methadone, dextropropoxyphene, tramadol, and ketobemidone. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to screening Use of valproic acid within 14 days prior to screening Use of an active Alzheimer's vaccine within 2 years prior to screening Use of a monoclonal antibody for treatment of AD within 1 year prior to screening Any medical or psychiatric condition that is likely to require initiation of additional medication or surgical intervention during the course of the study Any screening laboratory values outside the reference ranges that are deemed clinically significant by the PI Use of an investigational drug within 30 days prior to screening Suicidality defined as active suicidal thoughts during the 6 months prior to screening or at Baseline [Type 4 or 5 on C-SSRS], or history of suicide attempt in previous 2 years, or at serious suicide risk in PI's judgment Major psychiatric illness such as current major depression according to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition , current or past diagnosis of bipolar disorder, schizophrenia, or any other psychiatric disorder that might interfere with the assessments of safety or efficacy at the discretion of the PI Diagnosis of alcohol or drug abuse within the last 2 years Abnormal laboratory tests that suggest an alternate etiology for dementia. If the patient has prior history of serum B12 abnormality, anemia with hemoglobin ≤10g /dl, thyroid function abnormality, electrolyte abnormality, or positive syphilis serology the patient should be revaluated to determine if these potential causes of dementia have been addressed. Only if these causes have been ruled out as the cause of the dementia can the patient be enrolled. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per central reader) Acute or poorly controlled medical illness: blood pressure > 180 mmHg systolic or 100 mmHg diastolic; myocardial infarction within 6 months; uncompensated congestive heart failure [New York Heart Association (NYHA) Class III or IV] Known to be seropositive for human immunodeficiency virus (HIV) Known to be seropositive for Hepatitis B or C, unless successful curative treatment for Hepatitis C (e.g., Harvoni) has been received and there is documentation that there is no Hep B/C virus detected 3 months after completion of treatment AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or International Normalized Ratio (INR) >1.5 Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug Any other concurrent medical condition, which in the opinion of the PI makes the subject unsuitable for the clinical study

Ages Eligible for Study
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Minimum Age: 55 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: Parallel Assignment
Interventional Model Description: Eligible subjects will be stratified based on Mini Mental State Exam (MMSE-2) scores 4-9 vs. 10-15 and will be randomized 1:1 to one of two treatment arms: 20µg bryostatin or placebo for twelve weeks (7 doses).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bryostatin 20µg<br>20µg Bryostatin administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. | Drug: Bryostatin<br>* The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.<br>|
| Placebo Comparator: Placebo<br>Placebo administered IV over 45 minutes every other weekafter 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks. The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the active drug, intended for IV infusion upon reconstitution and dilution. | Other: Placebo<br>* The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the experimental drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety: Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Incidence of adverse events (AEs), serious adverse events (SAEs), Adverse event of special interest - myalgia | Baseline through 30 days post end of treatment (up to Day 107) | 
| Efficacy: The Primary Efficacy Endpoint is Defined as the Change From Baseline to Week 13 in the Severe Impairment Battery (SIB) Total Score in the Full Analysis Set | The Severe Impairment Battery (SIB) assesses cognition in subjects with moderate and severe Alzheimer's disease(AD). Test questions measure attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses are allowed, thus decreasing the need for language output. Forty questions are included with a total point score range of 0-100. Lower scores indicate greater cognitive impairment. | The change in the SIB Total Score from baseline to Week 13 (Day 91) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Changes From Baseline at Weeks 5, 9 and 15 in the Severe Impairment Battery (SIB) Total Score in the Full Analysis Set. | The Severe Impairment Battery (SIB) assesses cognition in subjects with Alzheimer's disease. SIB scores at Weeks 5, 9 and the Week 15 follow-up visit will be assessed. Test questions measure attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses are allowed, thus decreasing the need for language output. Forty questions are included with a total point score range of 0-100. Lower scores indicate greater cognitive impairment. | Weeks 5, 9 and 15 (up to Day 107) | 
| The Changes From Baseline at Weeks 5, 9, 13 and 15 in the Severe Impairment Battery (SIB) Total Score for Subjects in the Mini Mental State Exam Version 2 (MMSE-2) 4-9 Stratification Group | The SIB is used to assess cognition in subjects with moderate and severe AD and is a useful outcome measure in advanced stages of disease. It is divided into nine subscales that include attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses are allowed, thus decreasing the need for language output. Forty questions are included with a point score range of 0-100. Lower scores indicate greater cognitive impairment. | Weeks 5, 9, 13 and 15 (up to Day 107) | 
| The Changes From Baseline at Weeks 5, 9, 13 and 15 in the Severe Impairment Battery (SIB) Total Score for Subjects in the Mini Mental State Exam Version 2 (MMSE-2) 10-15 Stratification Group | Mini Mental State Exam version 2 (MMSE-2) scores between 10 and 15 are representative of moderately severe Alzheimer's disease. The SIB is used to assess cognition in subjects with moderate and severe AD and is a useful outcome measure in advanced stages of disease. It is divided into nine subscales that include attention, language, orientation, memory, praxis, visuospatial ability, construction, social skills, orienting head to name. Non-verbal responses are allowed, thus decreasing the need for language output. Forty questions are included with a point score range of 0-100. Lower scores indicate greater cognitive impairment. | Weeks 5, 9, 13 and 15 (up tp Day 107) | 
| Individual Patient's Slope Over Time in SIB Total Score Evaluated Via Weeks 0, 5, 9, and 13 | Severe Impairment Battery (SIB) trend analyses will be assessed for individual patients. SIB scores were evaluated in subjects at various time points during the study. Individual-specific SIB slopes were estimated for all patients over each person's available SIB outcome measures. | Baseline through Week 13 (Day 91) |