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

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ClinicalTrials.gov Identifier: NCT03560245
Recruitment Status : Completed
First Posted : June 18, 2018
Results First Posted : October 1, 2020
Last Update Posted : October 1, 2020
Sponsor:
Collaborator:
Worldwide Clinical Trials
Information provided by (Responsible Party):
Neurotrope Bioscience, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Alzheimer Disease
Interventions Drug: Bryostatin
Other: Placebo
Enrollment 108
Recruitment Details 111 subjects were randomized, but 3 subjects withdrew prior to receiving treatment. 108 subjects received treatment.
Pre-assignment Details  
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description

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.

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

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.

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

Period Title: Overall Study
Started 53 55
Completed 48 48
Not Completed 5 7
Reason Not Completed
Withdrawal by Subject             3             2
Adverse Event             1             1
Protocol Violation             1             0
Death             0             1
Lost to Follow-up             0             1
Physician Decision             0             1
Other             0             1
Arm/Group Title Bryostatin 20µg Placebo Total
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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.

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

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.

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

Total of all reporting groups
Overall Number of Baseline Participants 53 55 108
Hide Baseline Analysis Population Description
There were 108 subjects who received at least one dose of study drug.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 55 participants 108 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
13
  24.5%
10
  18.2%
23
  21.3%
>=65 years
40
  75.5%
45
  81.8%
85
  78.7%
Sex: Female, Male   [1] [2] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 55 participants 108 participants
Female
29
  54.7%
32
  58.2%
61
  56.5%
Male
24
  45.3%
23
  41.8%
47
  43.5%
[1]
Measure Description: There were 111 randomized subjects, however 3 subjects never received study drug.
[2]
Measure Analysis Population Description: The Safety Analysis Set (SAS) was defined as all randomized subjects who received any study medication (either partial or completed infusions of bryostatin or placebo).
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 55 participants 108 participants
Hispanic or Latino
9
  17.0%
8
  14.5%
17
  15.7%
Not Hispanic or Latino
44
  83.0%
47
  85.5%
91
  84.3%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 55 participants 108 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   1.9%
2
   3.6%
3
   2.8%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
10
  18.9%
4
   7.3%
14
  13.0%
White
42
  79.2%
49
  89.1%
91
  84.3%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 53 participants 55 participants 108 participants
53
 100.0%
55
 100.0%
108
 100.0%
Safety Analysis Set   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 53 participants 55 participants 108 participants
53
 100.0%
55
 100.0%
108
 100.0%
[1]
Measure Description: Safety Analysis Set = subjects who received any dose of study drug (either partial or completed infusions of bryostatin or placebo).
1.Primary Outcome
Title Safety: Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Hide Description Incidence of adverse events (AEs), serious adverse events (SAEs), Adverse event of special interest - myalgia
Time Frame Baseline through 30 days post end of treatment (up to Day 107)
Hide Outcome Measure Data
Hide Analysis Population Description
All participant who received at least one dose of study drug.
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description:

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.

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

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.

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

Overall Number of Participants Analyzed 53 55
Measure Type: Count of Participants
Unit of Measure: Participants
21
  39.6%
10
  18.2%
2.Primary Outcome
Title Efficacy: The Primary Efficacy Endpoint is Defined as the Change From Baseline to Week 13 in the Severe Impairment Battery (SIB) Total Score in the Full Analysis Set
Hide Description The Severe Impairment Battery (SIB) assesses cognition in subjects with moderate and severe Alzheimer's disease(AD). Test questions measure 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 total point score range of 0-100. Lower scores indicate greater cognitive impairment.
Time Frame The change in the SIB Total Score from baseline to Week 13 (Day 91)
Hide Outcome Measure Data
Hide Analysis Population Description
The Full Analysis Set (FAS) used for efficacy analyses was defined as all randomized subjects who received at least one dose of study medication and who have at least one post-baseline efficacy assessment.
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description:
Subjects were scheduled to receive seven doses over 12 weeks. The first two doses of study drug were to be a loading dose 20% higher (i.e., 24µg) than the assigned dose and were to be administered one week apart. Thereafter, the assigned dose of 20µg was to commence with the third dose and be administered every other week. The study drug was administered intravenously (IV) by continuous infusion over 45(±5) minutes.
Subjects were scheduled to receive seven doses over 12 weeks. The study drug was administered intravenously (IV) by continuous infusion over 45(±5) minutes.
Overall Number of Participants Analyzed 52 54
Mean (Standard Deviation)
Unit of Measure: score on a scale
1.3  (8.42) 2.1  (9.22)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Bryostatin 20µg, Placebo
Comments [Not Specified]
Type of Statistical Test Equivalence
Comments

The change from baseline to Week 13 in the SIB total score was summarized descriptively and compared using Analysis of Covariance (ANCOVA) adjusted for baseline SIB total score.

If the normality assumption was not met, a non-parametric method or a rank-ANCOVA analysis (i.e., an ANCOVA analysis on rank-transformed data) was to be used.

Statistical Test of Hypothesis P-Value 0.3730
Comments [Not Specified]
Method t-test, 2 sided
Comments [Not Specified]
3.Secondary Outcome
Title The Changes From Baseline at Weeks 5, 9 and 15 in the Severe Impairment Battery (SIB) Total Score in the Full Analysis Set.
Hide Description The Severe Impairment Battery (SIB) assesses cognition in subjects with Alzheimer's disease. SIB scores at Weeks 5, 9 and the Week 15 follow-up visit will be assessed. Test questions measure 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 total point score range of 0-100. Lower scores indicate greater cognitive impairment.
Time Frame Weeks 5, 9 and 15 (up to Day 107)
Hide Outcome Measure Data
Hide Analysis Population Description
At each timepoint, the number of participants whose data was obtained could vary from the number of subjects enrolled. There were occasions when subjects missed a visit or dropped out of the study, resulting in fewer data captured at that timepoint.
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description:

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.

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

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.

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

Overall Number of Participants Analyzed 52 54
Mean (Standard Deviation)
Unit of Measure: score on a scale
Week 5 Number Analyzed 52 participants 51 participants
-0.1  (7.94) 0.7  (11.0)
Week 9 Number Analyzed 49 participants 51 participants
2.7  (7.18) 1.4  (8.23)
Week 15 or early termination Number Analyzed 48 participants 51 participants
1.6  (9.07) 2.1  (9.66)
4.Secondary Outcome
Title The Changes From Baseline at Weeks 5, 9, 13 and 15 in the Severe Impairment Battery (SIB) Total Score for Subjects in the Mini Mental State Exam Version 2 (MMSE-2) 4-9 Stratification Group
Hide Description The SIB is used to assess cognition in subjects with moderate and severe AD and is a useful outcome measure in advanced stages of disease. 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 Weeks 5, 9, 13 and 15 (up to Day 107)
Hide Outcome Measure Data
Hide Analysis Population Description
The MMSE-2 4-9 stratification group represents Severe Alzheimer's disease. The analysis population at each time point varies because of missed visits and dropouts.
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description:

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.

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

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.

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

Overall Number of Participants Analyzed 18 18
Mean (Standard Deviation)
Unit of Measure: score on a scale
Week 5 Number Analyzed 18 participants 17 participants
-3.1  (9.55) 1.4  (11.1)
Week 9 Number Analyzed 16 participants 16 participants
1.1  (8.98) 1.1  (13.3)
Week 13 Number Analyzed 17 participants 15 participants
-3.6  (7.42) 1.9  (15.3)
Week 15/ Early Termination Number Analyzed 16 participants 15 participants
-2.6  (9.81) 0.3  (16.5)
5.Secondary Outcome
Title The Changes From Baseline at Weeks 5, 9, 13 and 15 in the Severe Impairment Battery (SIB) Total Score for Subjects in the Mini Mental State Exam Version 2 (MMSE-2) 10-15 Stratification Group
Hide Description Mini Mental State Exam version 2 (MMSE-2) scores between 10 and 15 are representative of moderately severe Alzheimer's disease. The SIB is used to assess cognition in subjects with moderate and severe AD and is a useful outcome measure in advanced stages of disease. 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 Weeks 5, 9, 13 and 15 (up tp Day 107)
Hide Outcome Measure Data
Hide Analysis Population Description
Mini Mental State Exam version 2 (MMSE-2) scores between 10 and 15 are representative of moderately severe Alzheimer's disease. The number of participants at each time point varies because of missed visits and dropouts.
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description:

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.

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

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.

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

Overall Number of Participants Analyzed 34 36
Mean (Standard Deviation)
Unit of Measure: score on a scale
Week 5 Number Analyzed 34 participants 34 participants
1.4  (6.57) 0.3  (11.1)
Week 9 Number Analyzed 33 participants 35 participants
3.5  (6.13) 1.5  (4.61)
Week 13 Number Analyzed 32 participants 33 participants
3.9  (7.80) 2.2  (4.78)
Week 15/Early Termination Number Analyzed 32 participants 36 participants
3.7  (8.03) 2.8  (4.74)
6.Secondary Outcome
Title Individual Patient's Slope Over Time in SIB Total Score Evaluated Via Weeks 0, 5, 9, and 13
Hide Description Severe Impairment Battery (SIB) trend analyses will be assessed for individual patients. SIB scores were evaluated in subjects at various time points during the study. Individual-specific SIB slopes were estimated for all patients over each person's available SIB outcome measures.
Time Frame Baseline through Week 13 (Day 91)
Hide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description:

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.

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

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.

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

Overall Number of Participants Analyzed 52 54
Measure Type: Count of Participants
Unit of Measure: Participants
Slope > 0
29
  55.8%
29
  53.7%
Slope < 0
23
  44.2%
23
  42.6%
Slope = 0
0
   0.0%
2
   3.7%
Time Frame Treatment emergent adverse events (TEAEs) were defined as an event with onset on or after the first treatment administration. The time duration was 15 weeks, beginning on the date of the first dose, including a period of 30 days after the last study drug treatment.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Bryostatin 20µg Placebo
Hide Arm/Group Description

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.

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

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.

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

All-Cause Mortality
Bryostatin 20µg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   0/53 (0.00%)      1/55 (1.82%)    
Hide Serious Adverse Events
Bryostatin 20µg Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/53 (9.43%)      6/55 (10.91%)    
Gastrointestinal disorders     
Rectal haemorrhage  1  1/53 (1.89%)  1 0/55 (0.00%)  0
General disorders     
Death  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Infections and infestations     
BRONCHITIS  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Urinary tract infection  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Diverticulitis  1  1/53 (1.89%)  1 0/55 (0.00%)  0
Injury, poisoning and procedural complications     
Right Distal Femur Fracture  1  1/53 (1.89%)  1 0/55 (0.00%)  0
Fall  1  1/53 (1.89%)  1 1/55 (1.82%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Well-diferentiated invasive colorectal adenocarcino  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Nervous system disorders     
Syncope  1  1/53 (1.89%)  1 0/55 (0.00%)  0
Psychiatric disorders     
Agitation  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Suicidal ideation  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Homicidal ideation  1  0/53 (0.00%)  0 1/55 (1.82%)  1
Renal and urinary disorders     
Renal failure  1  1/53 (1.89%)  1 0/55 (0.00%)  0
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Bryostatin 20µg Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   16/53 (30.19%)      4/55 (7.27%)    
Infections and infestations     
Urinary tract infection  1  3/53 (5.66%)  3 2/55 (3.64%)  2
Injury, poisoning and procedural complications     
Fall  1  4/53 (7.55%)  5 1/55 (1.82%)  2
Skin abrasion  1  3/53 (5.66%)  3 0/55 (0.00%)  0
Psychiatric disorders     
Agitation  1  6/53 (11.32%)  6 1/55 (1.82%)  1
1
Term from vocabulary, MedDRA
Indicates events were collected by systematic assessment
An imbalance in the baseline Severe Impairment Battery (primary endpoint) was observed between the bryostatin treatment group and the placebo group, with the placebo group having an average SIB score higher than the treatment group.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Alan J. Tuchman, MD, Acting Chief Medical Officer
Organization: Neurotropebioscience, Inc
Phone: 973-242-0005
EMail: atuchman@neurotrope.com
Layout table for additonal information
Responsible Party: Neurotrope Bioscience, Inc.
ClinicalTrials.gov Identifier: NCT03560245    
Other Study ID Numbers: NTRP101-203
First Submitted: June 6, 2018
First Posted: June 18, 2018
Results First Submitted: June 17, 2020
Results First Posted: October 1, 2020
Last Update Posted: October 1, 2020