Bryostatin Treatment of Moderately Severe Alzheimer's Disease

• ClinicalTrials.gov Identifier: NCT04538066
• Recruitment Status: Completed
• First Posted: September 3, 2020
• Last Update Posted: November 18, 2023
• Sponsor: Neurotrope Bioscience, Inc.
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA)
• Information provided by (Responsible Party): Neurotrope Bioscience, Inc.

Study Description

Brief Summary:

To evaluate the safety, tolerability, and long-term efficacy of bryostatin 1 (hereafter referred to as bryostatin) for the treatment of moderately severe Alzheimer's disease (AD).

Condition or disease	Intervention/treatment	Phase
Alzheimer Disease	Drug: Bryostatin 1; Other: Placebo	Phase 2

Detailed Description:

This is a randomized double-blind placebo-controlled, Phase 2 study comparing bryostatin-1 to placebo for long-term efficacy in the treatment of moderately severe AD (Mini Mental State Examination, 2nd edition scores of 10-18 at baseline) in the absence of memantine. Eligible subjects will receive 7 doses of bryostatin (i.v., 20μg) or matching placebo during the first 12 weeks. A second course of treatment consisting of 7 doses will begin 30 days after the final dose of the first treatment period. Cognitive tests will be assessed at intervals during the study and 4 months after the final dose of study drug. The primary endpoint is the total SIB score assessment obtained at Week 28, following completion of 2 courses of treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 117 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Study subjects will be randomized 1:1 to receive either the active treatment, bryostatin-1, or placebo.
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Sponsor, investigators and staff, and the clinical research organization are all blinded to study treatment assignment.
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing Safety, Tolerability and Long-term Efficacy of Bryostatin in the Treatment of Moderately Severe Alzheimer's Disease Subjects Not Receiving Memantine Treatment
• Actual Study Start Date: August 30, 2020
• Actual Primary Completion Date: November 16, 2022
• Actual Study Completion Date: November 16, 2022

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Bryostatin 1; 20ug Bryostatin will be administered over 45 minutes IV. The course of treatment will include 7 doses over the first 12 weeks, followed by a second identical treatment period beginning 30 days after completion of the first treatment period.	Drug: Bryostatin 1; Bryostatin 20 micrograms 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, followed by a second identical course of treatment beginning 30 days after completion of the first 7-dose course.
Placebo Comparator: Placebo; Placebo will be administered over 45 minutes IV. The course of treatment will include 7 doses over the first 12 weeks, followed by a second identical treatment period beginning 30 days after completion of the first treatment period.	Other: Placebo; Placebo 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, followed by a second identical course of treatment beginning 30 days after completion of the first 7-dose course.

Outcome Measures

Primary Outcome Measures :

1. Safety: Treatment-emergent adverse events and serious adverse events for all randomized subjects who received any study medication [ Time Frame: Baseline through 30 days post end of treatment ]
   Treatment emergent adverse events and serious adverse events will be analyzed by treatment group.
2. Efficacy: Severe Impairment Battery total score [ Time Frame: Primary analysis at Week 28 ]
   The treatment difference in the primary efficacy endpoint of Severe Impairment Battery (SIB). The SIB is used to assess cognition in subjects with moderate and severe AD. 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.

Secondary Outcome Measures :

1. Severe Impairment Battery (SIB) total score at the end of the Week 42 follow-up visit [ Time Frame: Week 42 is the final follow-up for study subjects, occurring 16 weeks after the last dose of study drug. ]
   The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
2. The SIB total score from baseline at Week 13 [ Time Frame: Week 13 follows the first 12-week course of study treatment. ]
   The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
3. SIB total scores from baseline at Weeks 5, 9,15, 20 and 24 [ Time Frame: Weeks 5, 9,15, 20 and 24 occur during the treatment phase of the study. ]
   The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
4. SIB total scores from baseline at Weeks 5, 9, 15, 20 and 24 for subjects with baseline Mini Mental State Exam version 2 (MMSE-2) scores of 10-14 and 15-18 [ Time Frame: Weeks 5, 9, 15, 20 and 24 ]
   MMSE-2 tests selected aspects of cognition on a scale of 0-30. Subjects with MMSE-2 scores of 10-18 will be enrolled in the study. Scores of 10-14 indicate greater impairment than scores of 15-18.
5. SIB trends over time [ Time Frame: Slopes will be estimated by using SIB data at Week 0, 5, 9, 13, 15, 20, 24, and 28 ]
   Individual-specific slopes of total SIB scores will be obtained for all patients.

Eligibility Criteria

• Ages Eligible for Study: 55 Years to 85 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 10-18 inclusive (applies to Screening Visit only)
5. Patients must have a baseline SIB total score of at least 60 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 90 days prior to initial treatment with study drug
11. Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks at screening (dose adjustments will be permitted if medically necessary at the discretion of the PI)

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:

Eligibility Criteria:

Inclusion

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 10-18 inclusive (applies to Screening Visit only) 5. Patients must have a baseline SIB total score of at least 60 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 90 days prior to initial treatment with study drug 11. Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks at screening (dose adjustments will be permitted if medically necessary at the discretion of the PI) 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

   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, dextrpropoxyphene, tramadol, and ketobemidone.
   8. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to screening
   9. Use of acetaminophen within 14 days prior to screening
   10. Use of gabapentin within 14 days prior to screening
   11. Use of valproic acid within 14 days prior to screening
   12. Use of an active Alzheimer's vaccine within 2 years prior to screening
   13. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening
   14. Any medical or psychiatric condition that is likely to require initiation of additional medication or surgical intervention during the course of the study
   15. Any screening laboratory values outside the reference ranges that are deemed clinically significant by the PI
   16. Use of an investigational drug within 90 days prior to screening
   17. 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
   18. 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
   19. Diagnosis of alcohol or drug abuse within the last 2 years
   20. 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.
   21. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per central reader)
   22. 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]
   23. Known to be seropositive for human immunodeficiency virus (HIV)
   24. 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
   25. AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or International Normalized Ratio (INR) >1.5
   26. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug
   27. Any other concurrent medical condition, which in the opinion of the PI makes the subject unsuitable for the clinical study -

Contacts and Locations

Locations

United States, California

Axiom Research

Colton, California, United States, 92324

Pacific Research Network

San Diego, California, United States, 92103

United States, Florida

JEM Research

Atlantis, Florida, United States, 33462

Galiz Research

Hialeah, Florida, United States, 33016

ClinCloud

Maitland, Florida, United States, 32751

Miami Dade Medical Research Institute

Miami, Florida, United States, 33176

Anchor Neuroscience

Pensacola, Florida, United States, 32502

Progressive Medical Research

Port Orange, Florida, United States, 32127

Alzheimer's Research and Treatment Center

Wellington, Florida, United States, 33414

United States, Georgia

Atlanta Center for Medical Research

Atlanta, Georgia, United States, 30331

Columbus Memory Center

Columbus, Georgia, United States, 31909

iResearch Atlanta

Decatur, Georgia, United States, 30030

iResearch Savannah

Savannah, Georgia, United States, 31405

United States, Indiana

Fort Wayne Neurological Center

Fort Wayne, Indiana, United States, 46804

United States, Missouri

Millenium Psychiatric Associates

Saint Louis, Missouri, United States, 63132

United States, New York

Neurological Associates of Albany, P. C.

Albany, New York, United States, 12208

United States, North Carolina

Alzheimer's Research Center

Matthews, North Carolina, United States, 28105

United States, Oregon

Summitt Research Network (Oregon)

Portland, Oregon, United States, 97210

United States, Washington

Kingfisher Cooperative

Spokane, Washington, United States, 99202

Sponsors and Collaborators

Neurotrope Bioscience, Inc.

National Institutes of Health (NIH)

National Institute on Aging (NIA)

  Study Documents (Full-Text)

Documents provided by Neurotrope Bioscience, Inc.:

Study Protocol  [PDF] September 7, 2022

Statistical Analysis Plan  [PDF] November 15, 2022

More Information

• Responsible Party: Neurotrope Bioscience, Inc.
• ClinicalTrials.gov Identifier: NCT04538066
• Other Study ID Numbers: NTRP101-204; R44AG066366 ( U.S. NIH Grant/Contract )
• First Posted: September 3, 2020
• Last Update Posted: November 18, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Bryostatin 1; Adjuvants, Immunologic; Immunologic Factors; Physiological Effects of Drugs; Antineoplastic Agents