Alzheimer's Disease
Conditions
Keywords
Alzheimer's, bryostatin, PKC epsilon
Brief summary
This study is being done to evaluate the safety, tolerability and potential effectiveness of a new investigational drug, bryostatin 1, in patients with Alzheimer's disease (AD).
Detailed description
This study is a single center, randomized, double-blind, placebo-controlled, parallel groups trial in patients with AD. Each subject enrolled in the trial will be randomized to receive a single IV dose of 0 (placebo) or 25 μg/m2 bryostatin. A total of 15 subjects (5 in the placebo arm and 10 in the treatment arm) will be enrolled in the study. The study consists of screening evaluations and on study evaluations divided into two segments, an inpatient segment and an outpatient segment. The four-day inpatient segment will consist of baseline evaluations and a 1-hour IV infusion of study drug followed by evaluations at multiple evaluations over the first 72 hrs post dose. During the outpatient segment, patients will be followed for AEs and have a final evaluation at 2 weeks post dose and a 4-week telephone safety follow up. Evaluations will include safety, efficacy, pharmacokinetics, and pharmacodynamics as assessed by PKC activity
Interventions
DRUGBryostatin 1
25 μg/m2 bryostatin 1, single dose via intravenous infusion over 1 hour.
DRUGPlacebo
Placebo, single dose via intravenous infusion over 1 hour.
Sponsors
Blanchette Rockefeller Neurosciences Insitute
Neurotrope Bioscience, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, age 50 - 85 yrs. Females are non-childbearing potential * Patient must have a cognitive deficit present for at least 1 year and meet diagnostic criteria for probable Alzheimer's Disease Dementia by NIA-AA criteria or prodromal Alzheimer's Disease * Mini Mental State Exam score of 16-26 * Ability to walk, at least with an assistive device * Vision and hearing sufficient to comply with testing * Normal cognitive and social functioning prior to onset of dementia, with evidence of progressive symptoms from patient or informant * Consistent caregiver to accompany patient to visits * Sufficient basic education to be able to complete the cognitive assessments * Living outside an institution
Exclusion criteria
* Dementia due to any condition other than AD, including vascular dementia * Significant neuroimaging abnormalities, previously known or discovered on screening MRI scan, * Evidence of clinically significant unstable cardiovascular, renal, hepatic, gastrointestinal, neurological, or metabolic disease within the past 6 months * Use of any drug within 14 days prior to randomization unless the dose of the drug and the condition being treated have been stable for at least 30 days and are expected to remain stable during the study * Use of tobacco products or nicotine-containing products within 3 months before Day 1 * Use of high dose vitamin E, or valproic acid * Any medical or psychiatric condition that may require medication or surgical treatment during the study * Life expectancy less than 6 months * Use of an investigational drug within 2 months prior to the screening visit * Clinically significant neurological disease other than AD * Major depression, alcohol or drug dependence or suicidality * Psychotic episodes requiring hospitalization or antipsychotic therapy for more than 2 weeks within the past 10 years, not linked to AD * Agitation sufficient to preclude participation in this trial * Epilepsy or anti-epileptic drug therapy * Abnormal laboratory tests that might point to another etiology for dementia; * Acute or poorly controlled medical illness * Likelihood, according to clinical judgment, of being transferred to a nursing home within 6 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Within 2 weeks of study drug dosing | Evaluate the safety and tolerability of bryostatin 1 (hereinafter referred to as bryostatin) in patients with Alzheimer's Disease (AD) following a single intravenous (IV) dose. |
| Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | 48 hours post start of study drug infusion | Hopkins Verbal Learning Test - Revised (HVLT-R) delayed recall; change from baseline. HVLT consists of a 12-item word list drawn from 3 semantic categories, presented in 3 learning trials. Score range = 0-12. The lower the number, the more impaired. Repeatable Battery of Assessments for Neuropsychological Status (RBANS) figure recall; change from baseline. Total Score Range: 0-20. Each portion of the drawing is scored 1 point for correctness and completeness and 1 point for being placed properly in relation to the rest of the drawing. Drawing and placement scores are summed for the item total. To obtain subtest total score, the drawing and placement scores are summed for each item. The lower the number, the more impaired. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Specified timepoints within 2 weeks post study drug infusion | HVLT-R (Hopkins Verbal Learning Test-Revised™) delayed recall (change from baseline). A 12-item word list: 3 learning trials. Score range = 0-12. The lower the number, the more impaired. Repeatable Battery of Assessments for Neuropsychological Status (RBANS) figure recall; change from baseline. Score Range: 0-20. The lower the number, the more impaired. Digit Symbol Coding (observed), Score range: 0-125. The lower the number, the more impaired. Clinical Dementia Rating- Sum of Boxes (CDR-SB, observed). Sum of 6 investigated domains (Memory, Orientation, Judgment and Problem Solving, Community Affairs, Home and Hobbies, Personal Care). Each subtest range is 0-3; Sum of all 6 subtest scores gives total CDR-SB score (range= 0-18).The higher the number, the more impaired. Mini Mental State Exam, version 2 (MMSE-2), change from baseline. The MMSE-2 measures aspects of cognitionon a scale of 0-30. Lower scores indicate greater cognitive impairment. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic Parameters of Bryostatin. | Bryostatin plasma concentration pre-dose and at 15 min, 30 min, 1 hr, 1.5 hr, 2hr, 3hr and 6rs post dose. | Preliminary evaluation of pharmacokinetics and pharmacodynamics (Cmax, Tmax, AUClast). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Bryostatin 1 single dose of 25 μg/m2 bryostatin, intravenous infusion over 1 hour
Bryostatin 1: 25 μg/m2 bryostatin 1, single dose via intravenous infusion over 1 hour. | 6 |
| Placebo single dose of placebo, intravenous infusion over 1 hour
Placebo: Placebo, single dose via intravenous infusion over 1 hour. | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Placebo | Bryostatin 1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 5 Participants | 8 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Continuous | 70.7 years STANDARD_DEVIATION 7.23 | 72.5 years STANDARD_DEVIATION 8.04 | 71.9 years STANDARD_DEVIATION 7.37 |
| Region of Enrollment United States | 3 participants | 6 participants | 9 participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 3 / 3 |
| serious Total, serious adverse events | 0 / 6 | 0 / 3 |
Outcome results
Primary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
Evaluate the safety and tolerability of bryostatin 1 (hereinafter referred to as bryostatin) in patients with Alzheimer's Disease (AD) following a single intravenous (IV) dose.
Time frame: Within 2 weeks of study drug dosing
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Bryostatin 1 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Headache | 1 event |
| Bryostatin 1 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Rash Papular | 0 event |
| Bryostatin 1 | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Dizziness | 0 event |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Dizziness | 1 event |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Headache | 1 event |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Rash Papular | 1 event |
Primary
Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD
Hopkins Verbal Learning Test - Revised (HVLT-R) delayed recall; change from baseline. HVLT consists of a 12-item word list drawn from 3 semantic categories, presented in 3 learning trials. Score range = 0-12. The lower the number, the more impaired. Repeatable Battery of Assessments for Neuropsychological Status (RBANS) figure recall; change from baseline. Total Score Range: 0-20. Each portion of the drawing is scored 1 point for correctness and completeness and 1 point for being placed properly in relation to the rest of the drawing. Drawing and placement scores are summed for the item total. To obtain subtest total score, the drawing and placement scores are summed for each item. The lower the number, the more impaired.
Time frame: 48 hours post start of study drug infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R at 48hrs (change from baseline) | 1.3 units on a scale, change from baseline | Standard Deviation 2.16 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | RBANS figure recall at 48hrs (CBL) | 4.5 units on a scale, change from baseline | Standard Deviation 4.14 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R at 48hrs (change from baseline) | 3.7 units on a scale, change from baseline | Standard Deviation 1.15 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | RBANS figure recall at 48hrs (CBL) | 6.7 units on a scale, change from baseline | Standard Deviation 3.06 |
Secondary
Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD
HVLT-R (Hopkins Verbal Learning Test-Revised™) delayed recall (change from baseline). A 12-item word list: 3 learning trials. Score range = 0-12. The lower the number, the more impaired. Repeatable Battery of Assessments for Neuropsychological Status (RBANS) figure recall; change from baseline. Score Range: 0-20. The lower the number, the more impaired. Digit Symbol Coding (observed), Score range: 0-125. The lower the number, the more impaired. Clinical Dementia Rating- Sum of Boxes (CDR-SB, observed). Sum of 6 investigated domains (Memory, Orientation, Judgment and Problem Solving, Community Affairs, Home and Hobbies, Personal Care). Each subtest range is 0-3; Sum of all 6 subtest scores gives total CDR-SB score (range= 0-18).The higher the number, the more impaired. Mini Mental State Exam, version 2 (MMSE-2), change from baseline. The MMSE-2 measures aspects of cognitionon a scale of 0-30. Lower scores indicate greater cognitive impairment.
Time frame: Specified timepoints within 2 weeks post study drug infusion
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R 24hr Delayed Recall (change from baseline) | 0.5 units on a scale | Standard Deviation 3.27 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R 2 Wks Delayed Recall (change from baseline) | 0.3 units on a scale | Standard Deviation 1.63 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | RBANS 24hr Figure Recall (change from baseline) | 4.7 units on a scale | Standard Deviation 4.76 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | RBANS 2 Wks Figure Recall (CBL) | 4.2 units on a scale | Standard Deviation 5.6 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R delayed recall of stimuli at 48hr (CBL) | -1.2 units on a scale | Standard Deviation 1.17 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding baseline (observed) | 32.2 units on a scale | Standard Deviation 9.13 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 24hrs post start of infusion | 36.0 units on a scale | Standard Deviation 10.75 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 48hrs post start of infusion | 37.3 units on a scale | Standard Deviation 11.64 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 2 wks post start of infusion | 38.3 units on a scale | Standard Deviation 7.61 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | CDR, CDR-SB baseline (observed) | 1.3 units on a scale | Standard Deviation 0.98 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | CDR, CDR-SB 2wks (observed) | 1.5 units on a scale | Standard Deviation 1 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | MMSE-2 3hrs post start of inf (change) | 1.8 units on a scale | Standard Deviation 1.72 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding baseline (observed) | 32.2 units on a scale | Standard Deviation 9.13 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 3hrs post start of inf (observ | 32.7 units on a scale | Standard Deviation 6.86 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | MMSE-2 at 72hrs (change from Baseline) | 2.6 units on a scale | Standard Deviation 1.52 |
| Bryostatin 1 | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | MMSE-2 at 2wks (change from Baseline) | 3.3 units on a scale | Standard Deviation 1.86 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | MMSE-2 at 2wks (change from Baseline) | 4.7 units on a scale | Standard Deviation 1.15 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R 24hr Delayed Recall (change from baseline) | 1.3 units on a scale | Standard Deviation 2.52 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 2 wks post start of infusion | 52.7 units on a scale | Standard Deviation 6.66 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R 2 Wks Delayed Recall (change from baseline) | 2.3 units on a scale | Standard Deviation 2.52 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding baseline (observed) | 42.3 units on a scale | Standard Deviation 12.5 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | RBANS 24hr Figure Recall (change from baseline) | 6.0 units on a scale | Standard Deviation 2.65 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | CDR, CDR-SB baseline (observed) | 0.7 units on a scale | Standard Deviation 0.29 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | RBANS 2 Wks Figure Recall (CBL) | 7.3 units on a scale | Standard Deviation 3.06 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | MMSE-2 at 72hrs (change from Baseline) | 3.3 units on a scale | Standard Deviation 2.52 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | HVLT-R delayed recall of stimuli at 48hr (CBL) | 2.7 units on a scale | Standard Deviation 2.08 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | CDR, CDR-SB 2wks (observed) | 0.7 units on a scale | Standard Deviation 0.29 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding baseline (observed) | 42.3 units on a scale | Standard Deviation 12.5 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 3hrs post start of inf (observ | 45.3 units on a scale | Standard Deviation 11.5 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 24hrs post start of infusion | 49.0 units on a scale | Standard Deviation 4.58 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | MMSE-2 3hrs post start of inf (change) | -1.0 units on a scale | Standard Deviation 2.65 |
| Placebo | Preliminary Efficacy of a Single Dose of Bryostatin in the Treatment of Patients With AD | Digit Symbol Coding 48hrs post start of infusion | 53.7 units on a scale | Standard Deviation 4.73 |
Other Pre-specified
Pharmacokinetic Parameters of Bryostatin.
Preliminary evaluation of pharmacokinetics and pharmacodynamics (Cmax, Tmax, AUClast).
Time frame: Bryostatin plasma concentration pre-dose and at 15 min, 30 min, 1 hr, 1.5 hr, 2hr, 3hr and 6rs post dose.
Population: Subjects who received a single dose of 25 μg/m2 bryostatin, intravenous infusion over 1 hour (PK population)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | predose Bryostatin Plasma Concentration (ng/mL) | 0.0 bryostatin plasma concentration (ng/mL) | Standard Deviation 0 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 15 min post (ng/mL) | 0.880 bryostatin plasma concentration (ng/mL) | Standard Deviation 0.133 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 30 min post (ng/mL) | 0.941 bryostatin plasma concentration (ng/mL) | Standard Deviation 0.168 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 1 hr post (ng/mL) | 1.04 bryostatin plasma concentration (ng/mL) | Standard Deviation 0.309 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 1.5 hrs post (ng/mL) | 0.181 bryostatin plasma concentration (ng/mL) | Standard Deviation 0.148 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 2 hrs post (ng/mL) | 0.0702 bryostatin plasma concentration (ng/mL) | Standard Deviation 0.109 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 3 hrs post (ng/mL) | 0.0 bryostatin plasma concentration (ng/mL) | Standard Deviation 0 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Concentration 6 hrs post (ng/mL) | 0.0 bryostatin plasma concentration (ng/mL) | Standard Deviation 0 |
| Bryostatin 1 | Pharmacokinetic Parameters of Bryostatin. | Cmax (ng/mL) | 1.09 bryostatin plasma concentration (ng/mL) | Standard Deviation 0.246 |
Comparison: Bryostatin plasma concentration: mean Tmax (h)
Comparison: Bryostatin plasma concentration AUC0-last (h\*ng/mL)