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

NCT ID: NCT03560245

Last Updated: 2020-10-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 108 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-06-20
• Study Completion Date: 2019-07-25

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.

Conditions

Alzheimer Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Bryostatin 20µg

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.

Group Type: EXPERIMENTAL

Bryostatin

Intervention Type: DRUG

The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Placebo

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the experimental drug

Interventions

Bryostatin

The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.

Intervention Type: DRUG

Placebo

The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the experimental drug

Intervention Type: OTHER

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

• Minimum Eligible Age: 55 Years
• Maximum Eligible Age: 85 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Worldwide Clinical Trials

OTHER

Sponsor Role: collaborator

Neurotrope Bioscience, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alan Tuchman, MD

Role: STUDY_DIRECTOR

Neurotropebioscience, Inc

Locations

Neuro Pain Medical Center

Fresno, California, United States

Nader Pharmacology Research Institute

Los Alamitos, California, United States

Syrentis Clinical Research

Santa Ana, California, United States

Southern California Research, LLC

Simi Valley, California, United States

JEM Research

Atlantis, Florida, United States

Brain Matters Research

Delray Beach, Florida, United States

MD Clinical

Hallandale, Florida, United States

Alzheimer's Research and Treatment Center

Lake Worth, Florida, United States

Miami Jewish Health / Stein Gerontological Institute

Miami, Florida, United States

Phoenix Medical Research

Miami, Florida, United States

Miami Dade Medical Research Institute, LLC

Miami, Florida, United States

Medical Research Group of Central Florida

Orange City, Florida, United States

Bioclinica Research

Orlando, Florida, United States

Anchor Neuroscience

Pensacola, Florida, United States

Stedman Clinical Trials

Tampa, Florida, United States

Bioclinica Research

The Villages, Florida, United States

Atlanta Center for Medical Research

Atlanta, Georgia, United States

Medical Research & Health Education Foundation

Columbus, Georgia, United States

Alexian Brothers Neuroscience Institute

Elk Grove Village, Illinois, United States

Lake Charles Clinical Trials

Lake Charles, Louisiana, United States

Alzheimer's Disease Center

Quincy, Massachusetts, United States

Millennium Psychiatric Associates

Creve Coeur, Missouri, United States

The Cognitive and Research Center of New Jersey

Springfield, New Jersey, United States

Neurological Associates of Albany, PC

Albany, New York, United States

Burke Rehabilitation Hospital

White Plains, New York, United States

Alzheimer's Memory Center

Charlotte, North Carolina, United States

Insight Clinical Trials, LLC

Shaker Heights, Ohio, United States

Memory Health Center at Summit Research Network

Portland, Oregon, United States

Countries

United States

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

NTRP101-203

Identifier Type: -

Identifier Source: org_study_id