A Study of Bryostatin in Moderately Severe to Severe Alzheimer's Disease Subjects Not On Memantine
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Intervention: Bryostatin; Placebo
Intervention description: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.; The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the experimental drug
Intervention MeSH terms: Bryostatin 1
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
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).
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 108.0
Sex: All
Minimum age: 55 Years
Maximum age: 85 Years
Healthy volunteers: No

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.
    

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