Alzheimer Disease
Conditions
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).
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.
Interventions
DRUGBryostatin 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.
OTHERPlacebo
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.
Sponsors
National Institutes of Health (NIH)
National Institute on Aging (NIA)
Neurotrope Bioscience, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Sponsor, investigators and staff, and the clinical research organization are all blinded to study treatment assignment.
Intervention model description
Study subjects will be randomized 1:1 to receive either the active treatment, bryostatin-1, or placebo.
Eligibility
Sex/Gender
ALL
Age
55 Years to 85 Years
Healthy volunteers
No
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 -
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Severe Impairment Battery Total Score Assessment Obtained After Completion of the Second Couse of Treatment (Week 28) | Primary efficacy 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. |
| Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | Prior to version 6 of the protocol, final assessments were performed at Week 42, 12 weeks after the last study treatment. The final study visit took place at Week 30 for subjects remaining in the study after the protocol amendment. | Treatment emergent adverse events and serious adverse events will be analyzed by treatment group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The SIB Total Score From Baseline at Week 13 | Week 13 followed the first 12-week course of study treatment. | The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment. |
| SIB Trends Over Time | Slopes will be estimated by using SIB data at Week 0, 5, 9, 13, 15, 20, 24, and 28 | Individual-specific slopes of total Severe Impairment Battery (SIB) scores will be obtained for all patients. Scores range from 0-100, lower scores indicate greater impairment. |
| SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Weeks 9, 20, 24 and 30 | 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. Analyses were done comparing all subjects treated with either bryostatin or placebo, and additionally, comparing subjects grouped by MMSE-2 scores of 10-14 and 15-18 treated with either bryostatin or placebo. |
| The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Weeks 9, 20 and 24 occur during the treatment phase of the study. Week 30 occurred 4 weeks after end of treatment. | The Severe Impaorment Battery (SIB) assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment. |
| Severe Impairment Battery (SIB) Total Score at the End of the Week 42 Follow-up Visit | Week 42 was the final follow-up for study subjects, occurring 16 weeks after the last dose of study drug. Subjects who remained in the study at the time version 6 of the protocol was implemented did not have Week 42 visit. | The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment. |
Countries
United States
Participant flow
Recruitment details
Twenty-nine medical clinics in the US were selected to recruit study subjects.
Participants by arm
| Arm | Count |
|---|---|
| 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.
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. | 59 |
| 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.
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. | 58 |
| Total | 117 |
Baseline characteristics
| Characteristic | Bryostatin 1 | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 52 Participants | 48 Participants | 100 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 10 Participants | 17 Participants |
| Age, Continuous | 74.6 years STANDARD_DEVIATION 7.64 | 73.1 years STANDARD_DEVIATION 7.69 | 73.9 years STANDARD_DEVIATION 7.67 |
| Body Mass Index | 26.53 kg/m2 STANDARD_DEVIATION 4.691 | 26.89 kg/m2 STANDARD_DEVIATION 4.119 | 26.71 kg/m2 STANDARD_DEVIATION 4.401 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 13 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 44 Participants | 45 Participants | 89 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 5 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 52 Participants | 53 Participants | 105 Participants |
| Region of Enrollment United States | 59 participants | 58 participants | 117 participants |
| Sex: Female, Male Female | 27 Participants | 28 Participants | 55 Participants |
| Sex: Female, Male Male | 32 Participants | 30 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 59 | 0 / 58 |
| other Total, other adverse events | 35 / 59 | 30 / 58 |
| serious Total, serious adverse events | 3 / 59 | 3 / 58 |
Outcome results
Primary
Efficacy: Severe Impairment Battery Total Score Assessment Obtained After Completion of the Second Couse of Treatment (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.
Time frame: Primary efficacy analysis at Week 28
Population: All subjects who completed Week 28 were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bryostatin 1 | Efficacy: Severe Impairment Battery Total Score Assessment Obtained After Completion of the Second Couse of Treatment (Week 28) | 1.7 score on a scale | Standard Error 1.44 |
| Placebo | Efficacy: Severe Impairment Battery Total Score Assessment Obtained After Completion of the Second Couse of Treatment (Week 28) | 0.2 score on a scale | Standard Error 1.46 |
Primary
Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication
Treatment emergent adverse events and serious adverse events will be analyzed by treatment group.
Time frame: Prior to version 6 of the protocol, final assessments were performed at Week 42, 12 weeks after the last study treatment. The final study visit took place at Week 30 for subjects remaining in the study after the protocol amendment.
Population: All subjected who received any dose of study drug were included in the safety analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bryostatin 1 | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | Treatment related treatment emergent adverse event (TEAE) | 15 number of events |
| Bryostatin 1 | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | Serious TEAE | 4 number of events |
| Bryostatin 1 | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | TEAE leading to early discontinuation of study treatment | 6 number of events |
| Bryostatin 1 | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | TEAE leading to study termination | 3 number of events |
| Placebo | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | TEAE leading to study termination | 3 number of events |
| Placebo | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | Treatment related treatment emergent adverse event (TEAE) | 13 number of events |
| Placebo | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | TEAE leading to early discontinuation of study treatment | 6 number of events |
| Placebo | Safety: Treatment-emergent Adverse Events and Serious Adverse Events for All Randomized Subjects Who Received Any Study Medication | Serious TEAE | 4 number of events |
Secondary
Severe Impairment Battery (SIB) Total Score at the End of the Week 42 Follow-up Visit
The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
Time frame: Week 42 was the final follow-up for study subjects, occurring 16 weeks after the last dose of study drug. Subjects who remained in the study at the time version 6 of the protocol was implemented did not have Week 42 visit.
Population: All subjects who completed Week 42 were analyzed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bryostatin 1 | Severe Impairment Battery (SIB) Total Score at the End of the Week 42 Follow-up Visit | 88.4 score on a scale | Standard Error 1.81 |
| Placebo | Severe Impairment Battery (SIB) Total Score at the End of the Week 42 Follow-up Visit | 84.3 score on a scale | Standard Error 1.59 |
Secondary
SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18
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. Analyses were done comparing all subjects treated with either bryostatin or placebo, and additionally, comparing subjects grouped by MMSE-2 scores of 10-14 and 15-18 treated with either bryostatin or placebo.
Time frame: Weeks 9, 20, 24 and 30
Population: The decline in number of participants analyzed reflects attrition in number of subjects remaining in the trial at each successive timepoint.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Bryostatin 1 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 9 | 0.8 scores on a scale | Standard Error 1.37 |
| Bryostatin 1 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 20 | 0.1 scores on a scale | Standard Error 1.87 |
| Bryostatin 1 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 24 | -0.1 scores on a scale | Standard Error 2.18 |
| Bryostatin 1 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 30 | -0.4 scores on a scale | Standard Error 2.7 |
| Placebo | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 30 | -8.3 scores on a scale | Standard Error 2.62 |
| Placebo | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 24 | -6.7 scores on a scale | Standard Error 2.11 |
| Placebo | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 20 | -5.6 scores on a scale | Standard Error 1.81 |
| Placebo | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 9 | -2.6 scores on a scale | Standard Error 1.32 |
| Bryostatin Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 30 | 4.4 scores on a scale | Standard Error 0.79 |
| Bryostatin Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 20 | 3.9 scores on a scale | Standard Error 0.6 |
| Bryostatin Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 24 | 4.1 scores on a scale | Standard Error 0.66 |
| Bryostatin Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 9 | 3.3 scores on a scale | Standard Error 0.61 |
| Placebo Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 30 | 6.3 scores on a scale | Standard Error 0.78 |
| Placebo Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 20 | 5.5 scores on a scale | Standard Error 0.62 |
| Placebo Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 9 | 4.5 scores on a scale | Standard Error 0.66 |
| Placebo Baseline MMSE-2 Score 15-18 | SIB Total Scores From Baseline at Weeks 9, 20, 24 and 30 for Subjects With Baseline Mini Mental State Exam Version 2 (MMSE-2) Scores of 10-14 and 15-18 | Week 24 | 5.8 scores on a scale | Standard Error 0.67 |
Secondary
SIB Trends Over Time
Individual-specific slopes of total Severe Impairment Battery (SIB) scores will be obtained for all patients. Scores range from 0-100, lower scores indicate greater impairment.
Time frame: Slopes will be estimated by using SIB data at Week 0, 5, 9, 13, 15, 20, 24, and 28
Population: All subjects who received any dose of study drug were included in the full analysis set (FAS), 117 subjects.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Bryostatin 1 | SIB Trends Over Time | -1.2863 scores on a scale / week, averaged for e |
| Placebo | SIB Trends Over Time | -1.3205 scores on a scale / week, averaged for e |
Secondary
The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30
The Severe Impaorment Battery (SIB) assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
Time frame: Weeks 9, 20 and 24 occur during the treatment phase of the study. Week 30 occurred 4 weeks after end of treatment.
Population: All subjects who completed Week 9 were analyzed.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Bryostatin 1 | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 9 | 1.9 score on a scale | Standard Error 0.77 |
| Bryostatin 1 | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 20 | 1.8 score on a scale | Standard Error 1.09 |
| Bryostatin 1 | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 24 | 1.7 score on a scale | Standard Error 1.26 |
| Bryostatin 1 | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 30 | 1.7 score on a scale | Standard Error 1.54 |
| Placebo | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 30 | 0.1 score on a scale | Standard Error 1.55 |
| Placebo | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 9 | 1.3 score on a scale | Standard Error 0.8 |
| Placebo | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 24 | 0.4 score on a scale | Standard Error 1.27 |
| Placebo | The Changes From Baseline in SIB Total Scores at Weeks 9, 20, 24, and 30 | Week 20 | 0.7 score on a scale | Standard Error 1.11 |
Secondary
The SIB Total Score From Baseline at Week 13
The SIB assesses cognition. Score range 0-100. Lower scores indicate greater cognitive impairment.
Time frame: Week 13 followed the first 12-week course of study treatment.
Population: All subjects who completed Week 13 were included in the analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Bryostatin 1 | The SIB Total Score From Baseline at Week 13 | 2.4 score on a scale | Standard Error 0.87 |
| Placebo | The SIB Total Score From Baseline at Week 13 | 1.7 score on a scale | Standard Error 0.87 |