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

• Sponsor: Neurotrope Bioscience, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03560245
• Collaborator: Worldwide Clinical Trials (Other)
• Enrollment: 108
• Locations: 28
• Arms: 2
• Actual Duration (Months): 13.1
• Patients Per Site: 3.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: Bryostatin; Other: Placebo	Phase 2

Detailed 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. The first two doses of study drug will be a loading dose 20% higher (i.e., 24µg) than the assigned dose and will be administered one week apart. Thereafter, the assigned dose of 20µg will commence with the third dose and be administered every other week. Drug is administered IV by continuous infusion over 45(±5) minutes. Subjects are scheduled to receive seven doses over 12 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 108 participants
• 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).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)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the Safety, Tolerability and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer's Disease Subjects Not Receiving Memantine Treatment
• Actual Study Start Date: Jun 20, 2018
• Actual Primary Completion Date: Jul 25, 2019
• Actual Study Completion Date: Jul 25, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Bryostatin 20µg 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.	Drug: Bryostatin; The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution.
Placebo Comparator: Placebo 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.	Other: Placebo; The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the experimental drug

Outcome Measures

Primary Outcome Measures

1. Safety: Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline through 30 days post end of treatment (up to Day 107)]

   Incidence of adverse events (AEs), serious adverse events (SAEs), Adverse event of special interest - myalgia

2. 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 [The change in the SIB Total Score from baseline to Week 13 (Day 91)]

   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.

Secondary Outcome Measures

1. The Changes From Baseline at Weeks 5, 9 and 15 in the Severe Impairment Battery (SIB) Total Score in the Full Analysis Set. [Weeks 5, 9 and 15 (up to Day 107)]

   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.

2. 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 [Weeks 5, 9, 13 and 15 (up to Day 107)]

   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.

3. 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 [Weeks 5, 9, 13 and 15 (up tp Day 107)]

   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.

4. Individual Patient's Slope Over Time in SIB Total Score Evaluated Via Weeks 0, 5, 9, and 13 [Baseline through Week 13 (Day 91)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts 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 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:

13. 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

14. 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

15. 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

16. 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Neuro Pain Medical Center	Fresno	California	United States	93710
2	Nader Pharmacology Research Institute	Los Alamitos	California	United States	90720
3	Syrentis Clinical Research	Santa Ana	California	United States	92705
4	Southern California Research, LLC	Simi Valley	California	United States	93065
5	JEM Research	Atlantis	Florida	United States	33462
6	Brain Matters Research	Delray Beach	Florida	United States	33445
7	MD Clinical	Hallandale Beach	Florida	United States	33009
8	Alzheimer's Research and Treatment Center	Lake Worth	Florida	United States	33449
9	Miami Jewish Health / Stein Gerontological Institute	Miami	Florida	United States	33137
10	Phoenix Medical Research	Miami	Florida	United States	33165
11	Miami Dade Medical Research Institute, LLC	Miami	Florida	United States	33176
12	Medical Research Group of Central Florida	Orange City	Florida	United States	32763
13	Bioclinica Research	Orlando	Florida	United States	32806
14	Anchor Neuroscience	Pensacola	Florida	United States	32502
15	Stedman Clinical Trials	Tampa	Florida	United States	33613
16	Bioclinica Research	The Villages	Florida	United States	32162
17	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30331
18	Medical Research & Health Education Foundation	Columbus	Georgia	United States	31909
19	Alexian Brothers Neuroscience Institute	Elk Grove Village	Illinois	United States	60007
20	Lake Charles Clinical Trials	Lake Charles	Louisiana	United States	70629
21	Alzheimer's Disease Center	Quincy	Massachusetts	United States	02169
22	Millennium Psychiatric Associates	Creve Coeur	Missouri	United States	63141
23	The Cognitive and Research Center of New Jersey	Springfield	New Jersey	United States	07801
24	Neurological Associates of Albany, PC	Albany	New York	United States	12208
25	Burke Rehabilitation Hospital	White Plains	New York	United States	10605
26	Alzheimer's Memory Center	Charlotte	North Carolina	United States	28270
27	Insight Clinical Trials, LLC	Shaker Heights	Ohio	United States	44122
28	Memory Health Center at Summit Research Network	Portland	Oregon	United States	97210

Sponsors and Collaborators

• Neurotrope Bioscience, Inc.
• Worldwide Clinical Trials

Investigators

• Study Director: Alan Tuchman, MD, Neurotropebioscience, Inc

Study Documents (Full-Text)

• Study Protocol - May 9, 2019
• Statistical Analysis Plan - May 9, 2019

More Information

Publications

None provided.

• Responsible Party: Neurotrope Bioscience, Inc.
• ClinicalTrials.gov Identifier: NCT03560245
• Other Study ID Numbers: NTRP101-203
• First Posted: Jun 18, 2018
• Last Update Posted: Oct 1, 2020
• Last Verified: Jun 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• 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; Bryostatin 1

Study Results

Participant Flow

Recruitment Details	111 subjects were randomized, but 3 subjects withdrew prior to receiving treatment. 108 subjects received treatment.

Arm/Group Title	Bryostatin 20µg	Placebo
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

Baseline Characteristics

Arm/Group Title	Bryostatin 20µg	Placebo	Total
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	Total of all reporting groups
Overall Participants	53	55	108
Age (Count of Participants)
<=18 years	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 (Count of Participants)
Female	29 54.7%	32 58.2%	61 56.5%
Male	24 45.3%	23 41.8%	47 43.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 17%	8 14.5%	17 15.7%
Not Hispanic or Latino	44 83%	47 85.5%	91 84.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	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%
Black or African American	10 18.9%	4 7.3%	14 13%
White	42 79.2%	49 89.1%	91 84.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	53 100%	55 100%	108 100%
Safety Analysis Set (Count of Participants)
Count of Participants [Participants]	53 100%	55 100%	108 100%

Outcome Measures

1. Primary Outcome

Title	Safety: Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
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)

Outcome Measure Data

Analysis Population Description

All participant who received at least one dose of study drug.

Arm/Group Title	Bryostatin 20µg	Placebo
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
Measure Participants	53	55
Count of Participants [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
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)

Outcome Measure Data

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
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.
Measure Participants	52	54
Mean (Standard Deviation) [score on a scale]	1.3 (8.42)	2.1 (9.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bryostatin 20µg, Placebo
	Comments
	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
	Method	t-test, 2 sided
	Comments

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.
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)

Outcome Measure Data

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
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
Measure Participants	52	54
Week 5	-0.1 (7.94)	0.7 (11.0)
Week 9	2.7 (7.18)	1.4 (8.23)
Week 15 or early termination	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
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)

Outcome Measure Data

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
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
Measure Participants	18	18
Week 5	-3.1 (9.55)	1.4 (11.1)
Week 9	1.1 (8.98)	1.1 (13.3)
Week 13	-3.6 (7.42)	1.9 (15.3)
Week 15/ Early Termination	-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
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)

Outcome Measure Data

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
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
Measure Participants	34	36
Week 5	1.4 (6.57)	0.3 (11.1)
Week 9	3.5 (6.13)	1.5 (4.61)
Week 13	3.9 (7.80)	2.2 (4.78)
Week 15/Early Termination	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
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)

Outcome Measure Data

Analysis Population Description

Full Analysis Set

Arm/Group Title	Bryostatin 20µg	Placebo
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
Measure Participants	52	54
Slope > 0	29 54.7%	29 52.7%
Slope < 0	23 43.4%	23 41.8%
Slope = 0	0 0%	2 3.6%

Adverse Events

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.
Arm/Group Title	Bryostatin 20µg		Placebo
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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/53 (0%)		1/55 (1.8%)
Serious Adverse Events
	Bryostatin 20µg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/53 (9.4%)		6/55 (10.9%)
Gastrointestinal disorders
Rectal haemorrhage	1/53 (1.9%)	1	0/55 (0%)	0
General disorders
Death	0/53 (0%)	0	1/55 (1.8%)	1
Infections and infestations
BRONCHITIS	0/53 (0%)	0	1/55 (1.8%)	1
Urinary tract infection	0/53 (0%)	0	1/55 (1.8%)	1
Diverticulitis	1/53 (1.9%)	1	0/55 (0%)	0
Injury, poisoning and procedural complications
Right Distal Femur Fracture	1/53 (1.9%)	1	0/55 (0%)	0
Fall	1/53 (1.9%)	1	1/55 (1.8%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Well-diferentiated invasive colorectal adenocarcino	0/53 (0%)	0	1/55 (1.8%)	1
Nervous system disorders
Syncope	1/53 (1.9%)	1	0/55 (0%)	0
Psychiatric disorders
Agitation	0/53 (0%)	0	1/55 (1.8%)	1
Suicidal ideation	0/53 (0%)	0	1/55 (1.8%)	1
Homicidal ideation	0/53 (0%)	0	1/55 (1.8%)	1
Renal and urinary disorders
Renal failure	1/53 (1.9%)	1	0/55 (0%)	0
Other (Not Including Serious) Adverse Events
	Bryostatin 20µg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/53 (30.2%)		4/55 (7.3%)
Infections and infestations
Urinary tract infection	3/53 (5.7%)	3	2/55 (3.6%)	2
Injury, poisoning and procedural complications
Fall	4/53 (7.5%)	5	1/55 (1.8%)	2
Skin abrasion	3/53 (5.7%)	3	0/55 (0%)	0
Psychiatric disorders
Agitation	6/53 (11.3%)	6	1/55 (1.8%)	1

Limitations/Caveats

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.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.