Clinical trial NCT03560245: A Study of Bryostatin in Moderately Severe to Severe Alzheimer's Disease Subjects Not On Memantine
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alzheimer Disease
Lead sponsor: Neurotrope Bioscience, Inc.
Sponsor class: INDUSTRY
Collaborators: name: Worldwide Clinical Trials
First posted: 2018-06-18
Enrollment: 108
Sex: ALL
Minimum age (years): 55
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Written informed consent from caregiver and subject (if possible) or legally acceptable representative if different from caregiver
2. Male and female subjects 55-85 years of age inclusive
3. 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
4. MMSE-2 score of 4-15 inclusive (applies to Screening Visit only)
5. Patients must be able to perform at least one item on the SIB and may not have a SIB score \>93 at screening
6. 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
7. 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
8. Adequate vision and motor function to comply with testing
9. 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
10. Subjects who are memantine naïve or have been off memantine for at least 30 days prior to initial treatment with study drug
11. Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks (dose adjustments will be permitted)
12. Females participating in the study must meet one the following criteria:

    1. 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
    2. 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
13. 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
14. 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:

1. Dementia due to any condition other than AD, including vascular dementia (Rosen-Modified Hachinski Ischemic score ≥ 5)
2. 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
3. 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
4. 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.
5. Creatinine clearance (CL) of \<45ml/min
6. Poorly controlled diabetes, at the discretion of the Principal Investigator
7. 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.
8. Use of vitamin E \> 400 International Units (IU) per day within 14 days prior to screening
9. Use of valproic acid within 14 days prior to screening
10. Use of an active Alzheimer's vaccine within 2 years prior to screening
11. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening
12. Any medical or psychiatric condition that is likely to require initiation of additional medication or surgical intervention during the course of the study
13. Any screening laboratory values outside the reference ranges that are deemed clinically significant by the PI
14. Use of an investigational drug within 30 days prior to screening
15. 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
16. 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
17. Diagnosis of alcohol or drug abuse within the last 2 years
18. 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.
19. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF \>499 per central reader)
20. Acute or poorly controlled medical illness: blood pressure \> 180 mmHg systolic or 100 mmHg diastolic; myocardial infarction within 6 months; uncompensated congestive heart failure \[New York Heart Association (NYHA) Class III or IV\]
21. Known to be seropositive for human immunodeficiency virus (HIV)
22. 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
23. AST or ALT \>3x upper limit of normal (ULN) and total bilirubin \>2x ULN or International Normalized Ratio (INR) \>1.5
24. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug
25. Any other concurrent medical condition, which in the opinion of the PI makes the subject unsuitable for the clinical study

Primary outcomes:
measure: Safety: Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline through 30 days post end of treatment (up to Day 107)
measure: 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
timeFrame: The change in the SIB Total Score from baseline to Week 13 (Day 91)
Secondary outcomes:
measure: The Changes From Baseline at Weeks 5, 9 and 15 in the Severe Impairment Battery (SIB) Total Score in the Full Analysis Set.
timeFrame: Weeks 5, 9 and 15 (up to Day 107)
measure: 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
timeFrame: Weeks 5, 9, 13 and 15 (up to Day 107)
measure: 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
timeFrame: Weeks 5, 9, 13 and 15 (up tp Day 107)
measure: Individual Patient's Slope Over Time in SIB Total Score Evaluated Via Weeks 0, 5, 9, and 13
timeFrame: Baseline through Week 13 (Day 91)
Other outcomes:
Locations:
city: Fresno
country: United States
facility: Neuro Pain Medical Center
state: California
city: Los Alamitos
country: United States
facility: Nader Pharmacology Research Institute
state: California
city: Santa Ana
country: United States
facility: Syrentis Clinical Research
state: California
city: Simi Valley
country: United States
facility: Southern California Research, LLC
state: California
city: Atlantis
country: United States
facility: JEM Research
state: Florida
city: Delray Beach
country: United States
facility: Brain Matters Research
state: Florida
city: Hallandale Beach
country: United States
facility: MD Clinical
state: Florida
city: Lake Worth
country: United States
facility: Alzheimer's Research and Treatment Center
state: Florida
city: Miami
country: United States
facility: Miami Jewish Health / Stein Gerontological Institute
state: Florida
city: Miami
country: United States
facility: Phoenix Medical Research
state: Florida
city: Miami
country: United States
facility: Miami Dade Medical Research Institute, LLC
state: Florida
city: Orange City
country: United States
facility: Medical Research Group of Central Florida
state: Florida
city: Orlando
country: United States
facility: Bioclinica Research
state: Florida
city: Pensacola
country: United States
facility: Anchor Neuroscience
state: Florida
city: Tampa
country: United States
facility: Stedman Clinical Trials
state: Florida
city: The Villages
country: United States
facility: Bioclinica Research
state: Florida
city: Atlanta
country: United States
facility: Atlanta Center for Medical Research
state: Georgia
city: Columbus
country: United States
facility: Medical Research & Health Education Foundation
state: Georgia
city: Elk Grove Village
country: United States
facility: Alexian Brothers Neuroscience Institute
state: Illinois
city: Lake Charles
country: United States
facility: Lake Charles Clinical Trials
state: Louisiana
city: Quincy
country: United States
facility: Alzheimer's Disease Center
state: Massachusetts
city: Creve Coeur
country: United States
facility: Millennium Psychiatric Associates
state: Missouri
city: Springfield
country: United States
facility: The Cognitive and Research Center of New Jersey
state: New Jersey
city: Albany
country: United States
facility: Neurological Associates of Albany, PC
state: New York
city: White Plains
country: United States
facility: Burke Rehabilitation Hospital
state: New York
city: Charlotte
country: United States
facility: Alzheimer's Memory Center
state: North Carolina
city: Shaker Heights
country: United States
facility: Insight Clinical Trials, LLC
state: Ohio
city: Portland
country: United States
facility: Memory Health Center at Summit Research Network
state: Oregon
Study officials:
affiliation: Neurotropebioscience, Inc
name: Alan Tuchman, MD
role: STUDY_DIRECTOR
References: