Clinical trial NCT04538066
Conditions: Alzheimer Disease
Sponsor: Neurotrope Bioscience, Inc.
Start date: 2020-08-30; Completion date: 2022-11-16
Enrollment: 122 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

Arms: arm 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. arm 2: 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.
Interventions: intervention 1: Bryostatin 1 intervention 2: Placebo
Intervention descriptions: intervention 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. intervention 2: 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.

Protocol documents:
Prot_000.pdf: 
Protocol #: NTRP-101-204 
CONFIDENTIAL 
Version 6.0 
September 7, 2022 
Page 1 of 82 
STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the Safety, 
Tolerability and Long-term Efficacy of Bryostatin in the Treatment of Moderately Severe 
Alzheimer’s Disease Subjects Not Receiving Memantine Treatment 
Protocol Number: 
NTRP-101-204 
Date: 
September 7, 2022 
Study Drug: 
Bryostatin 1; matching Placebo 
Investigational new Drug 
Application (IND) Number: 
71,276 
Version: 
6.0 
Planned FPI to LPLV 
Aug 2020 to Dec 2022 
Study Sponsor: 
Synaptogenix, Inc. (formerly Neurotrope) 
Regulatory Statement 
This study will be performed in compliance with the protocol and in accordance with Good Clinical Practice (GCP) 
(International Conference on Harmonization [ICH], Guidance E6, 1996), principles of human subject protection, and 
applicable country-specific regulatory requirements. 
Confidentiality Statement 
The information in this document contains trade secrets and commercial information that are privileged or 
confidential and may not be disclosed unless such disclosure is required by applicable laws and regulations. In any 
event, persons for whom this information is disclosed must be informed that the information is privileged or 
confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all 
future information supplied to you that is indicated as privileged or confidential 




 
 
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PRINCIPAL INVESTIGATOR’S (PI) SIGNATURE PAGE 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the 
Safety, Tolerability and Long-term Efficacy of Bryostatin in the Treatment of Moderately 
Severe Alzheimer’s Disease Subjects Not Receiving Memantine Treatment 
Protocol Number: NTRP-101-204 
Protocol Version and Date:  Version 6.0   September 7, 2022 
Investigational Medicinal Product: Bryostatin 1  
PI’S STATEMENT OF APPROVAL 
Confidentiality of all information received or developed in connection with this protocol will be 
maintained by me, as well as all other personnel involved in the study who are employed by me. 
By signing this protocol, I confirm that I have read and agree to conduct the study as outlined in 
the protocol and in compliance with Good Clinical Practice, the Declaration of Helsinki as 
amended and all other applicable regulatory requirements. 
 
 
Printed name of PI:  
 
 
 
 
 
 
 
Signature 
 
Date  
 
 
 
 
 
 


 
 
Protocol #: NTRP-101-204 
 
 
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STUDY CONTACT INFORMATION 
 
Sponsor : 
Synaptogenix, Inc. 
1185 Avenue of the Americas. 
3rd Floor 
New York, NY 10036 
Phone : (973)242-0005 
Fax :     (973)242-0009 
 
Alan J. Tuchman, MD 
Chief Medical Officer 
Synaptogenix, Inc.  
Mobile: (917)882-0449 
Email    atuchman@synaptogen.com 
 
 
 
 
 
Elaine Grenier 
Executive Director, Clinical Operations 
Synaptogenix, Inc. 
Mobile:  (415) 548-0368 
Email:    egrenier@synaptogen.com 
 
 
 


 
 
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Study Administrative Structure 
Clinical Research Organization 
 
Worldwide Clinical Trials 
Operational Headquarters 
480 E. Swedesford Road, Suite 200 
Wayne, PA 19087  
Tel:  610 964 2000 
Corporate Headquarters 
401 N Maple Drive 
Beverly Hills, CA 90210 
Tel: (310) 786-9100 
Study Medical Monitor/Emergency Contact 
Information 
 
 
 
Idil Cavus, MD, PhD 
Worldwide Clinical Trials 
Tel: +1-203-623-2622     
Email: Idil.Cavus@worldwide.com 
 
 
Central Laboratory 
 
 
ACM Global Laboratory 
160 Elmgrove Park 
Rochester, NY 14624 
Tel: 1 585-429-2362 
 
 
Central ECG 
Clario (formerly ERT)  
1818 Market Street, Suite 1000 
Philadelphia, PA 19103-3638 
Tel: (215) 282-5303 ERT 
 
 
 
 
 
 


 
 
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PROTOCOL SYNOPSIS 
Name of Company:  
Synaptogenix, Inc. 
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
Title of Study: 
  
A Randomized, Double-Blind, Placebo-Controlled, Confirmatory Phase 2 Study Assessing 
the Safety, Tolerability and Long-term Efficacy of Bryostatin in the Treatment of Moderately 
Severe Alzheimer’s Disease Subjects Not Receiving Memantine Treatment 
Study center(s): Approximately 20 sites in United States (US) 
 
Protocol Number: NTRP-101-204 
 
Study Duration: Approximately 2 years  
Study Phase: 2 
 
Objective:  
 
Primary objective:  
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). 
Study Drug:   Bryostatin 1 or matching Placebo 
Route of Administration: Intravenous by continuous infusion over 45±5 minutes 
Number of Subjects: Approximately 100 subjects (approximately 220 subjects screened) 
Study Design  
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 30 days 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.  
Randomization and Treatment 
Eligible subjects will be stratified based on baseline SIB total scores and will be randomized 
1:1 to one of two treatment arms: 20µg bryostatin or placebo for twelve weeks, the first 
treatment period. 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. The second course of treatment will be identical to the first, beginning 30 days after 


 
 
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Name of Company:  
Synaptogenix, Inc. 
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
completion of the first course. Drug is administered IV by continuous infusion over 45(±5) 
minutes. Subjects are scheduled to receive seven doses over 12 weeks during the first 
treatment period and seven doses over 12 weeks during the second treatment period.  The 
same treatment assigned at randomization will be administered during the second treatment 
period.  
 
Cognitive Assessments 
 
• Severe Impairment Battery (SIB)  
• Mini Mental State Examination, 2nd edition (MMSE-2) 
• Alzheimer’s Disease Cooperative Study – Activities of Daily Living - Severe 
Impairment Version (ADCL-ADL-Sev)  
• Neuropsychiatric Inventory (NPI) metrics. 
 
Safety Assessments 
 
• Treatment emergent adverse events (AEs) and Serious Adverse Events (SAEs) 
• Vital signs, physical examination including body weight 
• ECG parameters  
• Columbia Suicide Severity Rating Scale (C-SSRS), and  
• Clinical laboratory assessments (hematology, blood chemistry) 
 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the change from the pre-treatment baseline in the Severe 
Impairment Battery (SIB) total score at Week 28, after two 12-week courses of treatment.  
 
Secondary Efficacy Endpoints   
 
• SIB total score at the end of the Week 42 follow-up visit, for subjects who completed 
week 42 
• SIB total score from baseline at Week 13 
• SIB total scores from baseline at Weeks 9, 20, 24 and 30 
• SIB total scores from baseline at Weeks 9, 20, 24 and 30 for subjects with baseline 
MMSE-2 scores of 10-14 and 15-18 
• SIB trends over time; individual-specific slopes of total SIB scores will be obtained for 
all patients. 
 


 
 
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Name of Company:  
Synaptogenix, Inc. 
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
Exploratory Efficacy Endpoints 
• Change from baseline in ADCS-ADL-Sev total score at Week 13 and Week 42, for 
subjects who completed week 42 
• Change from baseline in MMSE-2 total score at Week 13 and Week 42, for subjects 
who completed week 42 
• Change from baseline in NPI total score at Week 13 and Week 42, for subjects who 
completed week 42 
•  
Statistical Considerations: 
 
The primary objective for efficacy is to evaluate whether bryostatin is better than the control 
with respect to the primary and secondary SIB endpoints. 
Efficacy analyses will be conducted for the full analysis set (FAS), consistent with the 
modified intention-to-treat principle, defined as all randomized subjects who received at least 
one dose of randomized study medication and who had at least one post-baseline efficacy 
assessment.  
The per protocol analysis set (PP) is defined as all patients completing the study without 
major protocol deviations.  To be included, subjects must have received at least 11 of the14 
doses (80%).  The completer analysis set (CAS) will be defined as all randomized subjects 
who completed two 12-week courses of treatment, and who have a Week 28 SIB assessment.  
Efficacy analyses will also be conducted for the PP and CAS sets. 
 
Adverse event and other safety data will be analyzed descriptively in all subjects who 
received any dose of study drug (including partial infusions).  These data will be summarized 
by treatment group and by time in study. 


 
 
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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.1  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: 
a. 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 
b.  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 


 
 
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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 more than 2,600 mg/day of acetaminophen for more than 3 consecutive days 
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 


 
 
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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 Edition2, 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]3  
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 
 McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Phelps CH. 2011. 
The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National 


 
 
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Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's 
disease. Alzheimer’s & Dementia : The Journal of the Alzheimer's Association, 7:263–9. 
 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition: DSM-5  – May 27, 2013. American Psychiatric Association. Washington, D.C. 
 http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jspList of References


 
 
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Table of Contents 
SPONSOR’S SIGNATURE PAGE ..............................................................................................2 
STUDY CONTACT INFORMATION ........................................................................................4 
STUDY ADMINISTRATIVE STRUCTURE .............................................................................5 
PROTOCOL SYNOPSIS ..............................................................................................................6 
1 
INTRODUCTION............................................................................................................19 
1.0 
Alzheimer’s disease ...........................................................................................................19 
1.1 
Rationale for the use of bryostatin in the treatment of AD ................................................20 
1.2 
Pharmacokinetics, Toxicology and Drug Metabolism in Animals ....................................20 
1.3 
Genotoxicity .......................................................................................................................21 
2 
CLINICAL TRIAL DATA..............................................................................................21 
2.0 
Oncology Data ...................................................................................................................21 
2.1 
Alzheimer’s Disease Data ..................................................................................................22 
2.1.1 
Study NTRP101-203 ....................................................................................................22 
2.1.2 
Study NTRP101-202 ....................................................................................................24 
2.1.3 
Study NTRP101-201 ....................................................................................................29 
3 
STUDY OBJECTIVES AND HYPOTHESIS ...............................................................31 
3.0 
Primary Objective ..............................................................................................................31 
3.1 
Hypothesis..........................................................................................................................31 
4 
INVESTIGATIONAL PLAN .........................................................................................31 
4.0 
Overview of Study Design .................................................................................................31 
4.1 
Dose Rationale ...................................................................................................................32 
4.2 
Risk/Benefit .......................................................................................................................32 
4.3 
Study Endpoints .................................................................................................................33 
4.3.1 
Safety Assessments ......................................................................................................33 
4.3.2 
Primary Efficacy Endpoint ..........................................................................................33 
4.3.3 
Secondary Efficacy Endpoints .....................................................................................33 
4.3.4 
Exploratory Endpoints..................................................................................................34 
4.4 
Study Population ................................................................................................................34 
4.4.1 
Inclusion Criteria .........................................................................................................34 
4.4.2 
Exclusion Criteria ........................................................................................................35 
5 
PRODUCTS USED IN THIS STUDY ...........................................................................37 
5.0 
Bryostatin ...........................................................................................................................37 
5.1 
Placebo ...............................................................................................................................37 
5.2 
Packaging and Labeling of Study Drug Kits .....................................................................37 
5.3 
Storage and Preparation of Study Drug .............................................................................39 
5.4 
Study Drug Accountability and Disposal ..........................................................................39 
5.5 
Randomization ...................................................................................................................40 
5.6 
 Blinding.............................................................................................................................40 
5.7 
Study Drug Administration ................................................................................................41 
6 
STUDY PROCEDURES AND ASSESSMENTS ..........................................................41 
Table 1 - Schedule of Activities .....................................................................................................42 
6.0 
Assessments .......................................................................................................................43 


 
 
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6.0.1 
Safety ...........................................................................................................................43 
6.0.2 
Efficacy / Psychometric Assessments ..........................................................................45 
6.1 
Visit Procedures .................................................................................................................46 
6.1.1 
Screening and Randomization (Days -28 to -2) ...........................................................46 
6.1.2 
Week 0 (Day 0 Dose 1) ................................................................................................47 
6.1.3 
Week 1 (Day 7 ±2 days Dose 2) ..................................................................................48 
6.1.4 
Week 2 (Day 14 ±2 days/ No dose) .............................................................................48 
6.1.5 
Week 3 (Day 21 ±2 days/ Dose 3) ...............................................................................48 
6.1.6 
Week 5 (Day 35 ±2 days/ Dose 4) ...............................................................................48 
6.1.7 
Week 7 (Day 49 ±2 days/ Dose 5) ...............................................................................49 
6.1.8 
Week 9 (Day 63 ±2 days/ Dose 6) ...............................................................................49 
6.1.9 
Week 11 (Day 77±2 days/ Dose 7) ..............................................................................49 
6.1.10 
Week 13 (Day 91 ±2 days) ..........................................................................................49 
6.1.11 
Week 15 ( Day 105 ±2 days Dose 8) ...........................................................................50 
6.1.12 
Week 16 ( Day 112 ±2 days Dose 9) ...........................................................................50 
6.1.13 
Week 18 (Day 126 ±2 days Dose 10) ..........................................................................50 
6.1.14 
Week 20 (Day 140 ±2 days Dose 11) ..........................................................................51 
6.1.15 
Week 22 (Day 154 ±2 days Dose 12) ..........................................................................51 
6.1.16 
Week 24 (Day 168 ±2 days Dose 13) ..........................................................................51 
6.1.17 
Week 26 (Day 182 ±2 days Dose 14) ..........................................................................52 
6.1.18 
Week 28 (Day 196 ±2 days) ........................................................................................52 
6.1.19 
Week 30 (Day 210 ±2 days) ........................................................................................52 
6.1.20 
Early Termination ........................................................................................................53 
6.1.21 
Follow-up Visits...........................................................................................................53 
6.1.22 
Early Treatment Discontinuation and Follow-up ........................................................53 
6.2 
Concomitant Medications ..................................................................................................54 
6.2.1 
Medications for AD .....................................................................................................54 
6.2.2 
Concomitant Medications for Management of Myalgia ..............................................54 
6.2.3 
Prohibited Medications ................................................................................................54 
7 
ADVERSE EVENTS AND OTHER SAFETY EVALUATIONS ...............................55 
7.0 
Definition of Adverse Events.............................................................................................55 
7.1 
Adverse Event of Special Interest - Myalgia .....................................................................55 
7.2 
Definition of Serious Adverse Event .................................................................................56 
7.3 
Assessment of Intensity .....................................................................................................56 
7.4 
Relationship to Study Drug ................................................................................................57 
7.5 
Table 2 Relationship of AE to Study Drug or Trial-Related Procedures ..........................57 
7.5.1 
Unexpected Adverse Event ..........................................................................................57 
7.6 
Reporting Adverse Events .................................................................................................58 
7.6.1 
SAE reports ..................................................................................................................58 
7.6.2 
Reporting to Regulatory Authorities ............................................................................59 
7.7 
Criteria for Withdrawal of Subjects ...................................................................................59 
7.8 
Criteria for Permanent Discontinuation of Study Drug .....................................................60 
7.9 
Study Discontinuation ........................................................................................................60 
8 
SAFETY MONITORING ...............................................................................................60 
9 
DATA ANALYSIS / STATISTICAL METHODS .......................................................61 
9.0 
Sample Size Determination................................................................................................61 


 
 
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9.1 
Statistical Methods .............................................................................................................61 
9.2 
Exploratory Analysis .........................................................................................................62 
9.3 
Safety Analysis ..................................................................................................................62 
9.4 
Analysis of Primary Efficacy Endpoint .............................................................................63 
9.5 
Secondary Efficacy Endpoints ...........................................................................................63 
9.5.1 
SIB total score from baseline at the Week 42 follow-up visit .....................................63 
9.5.2 
SIB total score from baseline at Week 13 ....................................................................63 
9.5.3 
SIB total scores from baseline at Weeks 9, 20, 24 and 30 ...........................................64 
9.5.4 
SIB total scores from baseline at Weeks 5, 9, 15, 20, and 24 for subjects with 
baseline MMSE-2 scores of 10-14 and 15-18 ..............................................................64 
9.5.5 
Individual patient’s SIB trends over time ....................................................................64 
9.6 
Analysis of Exploratory Endpoints ....................................................................................64 
9.7 
Safety Assessments ............................................................................................................64 
9.8 
Analysis of Safety Data .....................................................................................................65 
9.8.1 
Adverse Events ............................................................................................................65 
9.8.2 
Clinical Laboratory Evaluations ..................................................................................65 
9.8.3 
Physical Examination...................................................................................................66 
9.8.4 
Vital Signs ....................................................................................................................66 
9.8.5 
ECG..............................................................................................................................66 
9.8.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ....................................................66 
10 
DATA MONITORING ....................................................................................................66 
10.0 
Source Documentation .......................................................................................................66 
10.1 
Study Documentation and Record Retention .....................................................................67 
10.2 
Site Monitoring ..................................................................................................................67 
10.3 
Quality Assurance and Quality Control .............................................................................68 
10.4 
Audits and Inspections .......................................................................................................68 
11 
ETHICS ............................................................................................................................69 
11.0 
Institutional Review Board ................................................................................................69 
11.1 
Ethical Conduct of the Study .............................................................................................69 
11.2 
Written Informed Consent .................................................................................................69 
12 
STUDY MANAGEMENT ...............................................................................................70 
12.0 
Data Collection and Management ......................................................................................70 
12.1 
Data Quality Control ..........................................................................................................70 
12.2 
Data Management and Data Storage ..................................................................................70 
12.3 
Inspection of Records ........................................................................................................71 
12.4 
Retention of Records..........................................................................................................71 
12.5 
Confidentiality ...................................................................................................................71 
12.6 
Protocol Amendments ........................................................................................................71 
12.7 
Protocol Deviations ............................................................................................................72 
12.8 
Data Corrections ................................................................................................................72 
12.9 
Insurance ............................................................................................................................72 
13 
PUBLICATION AND DISCLOSURE POLICY ..........................................................72 
14 
APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS ........................73 
15 
APPENDIX 2  LIST OF REFERENCES ......................................................................78 
16  
APPENDIX 3  SUMMARY OF CHANGES  
 
 
 
 
 
 
 
 
 
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LIST OFABREVIATIONS  
 
Abbreviation 
Definition 
 
Aβ 
Beta-amyloid  
AD 
Alzheimer’s Disease  
ADCS-ADL-Sev 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living - 
Severe Impairment Version 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Amino Transferase 
APP 
Amyloid Precursor Protein 
AST 
Aspartate Amino Transferase 
Aβ1-42 
Beta-Amyloid 1-42 
ARIA 
Amyloid Related Imaging Abnormalities 
βAPP 
Beta-amyloid Precursor Protein  
β-hCG  
Human chorionic gonadotropin 
BDNF 
Brain-derived Neurotrophic Factor  
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count 
C-CASA 
Columbia-Classification Algorithm of Suicide Assessment 
CAS 
Completer Analysis Set 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression – Improvement 
CL 
Clearance  
CNS 
Central Nervous System 
CPK 
Creatine phosphokinase  
CRC 
Cancer Research Campaign  
CSF 
Cerebrospinal Fluid  
CT 
Computerized tomography 
C-SSRS 
Columbia Suicide Severity Rating Scale  
DSMB 
Data Safety Monitoring Board 
DSC 
Digit Symbol Coding  
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture  
EMG 
Electromyography 


 
 
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Abbreviation 
Definition 
 
ERB 
Ethical Review Board  
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration 
FLAIR 
Fluid Attenuated Inversion Recovery  
GCP 
Good Clinical Practice 
GEE 
General Estimating Equations 
GGT 
Gamma Glutamyl Transferase  
GI 
Gastrointestinal  
GMP 
Good Manufacturing Practice  
GRE  
Gradient Refocused Echo 
IAP 
Interim Analysis Plan   
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ITT 
Intention-To-Treat  
IU 
International Unit 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase  
LSM 
Least-Squares Means  
MAP 
ΔMI-SIB 
Mitogen Activated Protein 
Maximal Improvement in the Total SIB Score from the Baseline 
MMRM 
Mixed Model for Repeated Measures  
MMSE-2 
Mini Mental State Examination 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose  
NCI 
National Cancer Institute 
NYHA 
New York Heart Association  
NMDA 
N-Methyl-D-Aspartate 
NOAEL 
No Adverse Effect Level  
NPI 
Neuropsychiatric Inventory  


 
 
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Abbreviation 
Definition 
 
PAP 
Pharmacokinetic Analysis Plan  
PBMCs 
Peripheral Blood Mononuclear Cells 
PET 
Tween 80 (polysorbate 80)  
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PKC 
Protein Kinase C 
PKCɛ 
Protein Kinase C Epsilon 
PP 
Per Protocol Analysis Set  
PT,  
 Prothrombin Time  
PTT, 
Partial  Prothrombin Time  
PVC 
Polyvinylchloride  
QTcB 
QTcF  
RBANS 
Corrected QTC – Bazett’s formula 
Corrected QTC – Fridericia’s formula 
Repeatable Battery of Assessments for Neuropsychological Status 
SA 
Safety Analysis Set  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan   
SD 
Standard Deviation 
SIB 
Severe Impairment Battery 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
ULN 
Upper limit of normal 
USP 
United States Pharmacopeia  
US 
United States  
WHO-DRL 
World Health Organization Drug Reference List  
 
 
 


 
 
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1 INTRODUCTION  
1.0 
Alzheimer’s disease 
Alzheimer’s disease is the most common cause of dementia, affecting approximately 5.3 
million people in the United States (US) and 30 million people worldwide.  There is a 
disproportionate representation of women with nearly 2/3 of the affected individuals being 
female.  Of the 5.3 million affected Americans, 5.1 million are older than 65 (Alzheimer’s 
Association website www.alz.org, 2015).  Since aging is the single most important risk factor 
for development of dementia and medical advances are prolonging survival, the incidence of 
AD will increase.  The US Census Bureau data suggest that the number of individuals living 
until age 100 between the years 2000 and 2020 will increase by more than 200% and the 
number of individuals living until age 90-95 will double.4   By 2050 the number of 
individuals with Alzheimer’s disease will almost triple to a projected 13.8 million.  In 2013, 
15.5 million family and friends provided 17.7 billion hours of unpaid care to those with 
Alzheimer’s and other dementias – care valued at $220.2 billion (Alzheimer’s Association 
website www.alz.org, 2015). 
The currently approved treatments for AD provide modest symptomatic benefit and do not 
alter the disease progression.  These therapies primarily consist of cholinesterase inhibitors 
[tacrine (Cognex), donepezil (Aricept), rivastigmine (Exelon), and galantamine 
(galanthamine, Reminyl)] and the N-methyl-D-aspartate (NMDA) antagonist, memantine 
(Namenda).  The development of a medication that produces a significant improvement in 
clinical symptoms and/or slows the progression of the disease would be a significant advance 
in the therapeutics of AD. 
The protein kinase C (PKC) signaling pathways have been shown to play an integral role in 
learning and memory. Several animal models have demonstrated that PKC is involved in the 
learning process.5, 6  In addition, PKC activity regulates phosphorylation of Tau and cleavage 
of Aβ amyloid through its effects on alpha secretase and GSK3β.13  The single most 
important risk factor for the sporadic form of AD, increased age, has also been linked to 
impaired PKC-mediated α-secretase activation.7  Aged animal models, for example, have 
shown age-specific changes of PKC isozyme distribution in the brain,8, 9 impaired PKC 
translocation, reduced levels of the PKC anchoring protein, RACK1,10 alterations in mitogen 
activated protein (MAP) kinase Erk1/2,11 and reduced levels of the α-secretase cleaved 
Amyloid Precursor Protein (APP), soluble amyloid precursor protein alpha (sAPPα), in the 
cerebrospinal fluid (CSF).12  Aging of normal human fibroblasts also reduced secretion of 
sAPPα.   
The demonstration of reduced levels of PKC in the brain of Alzheimer’s subjects suggests a 
potential target to improve cognition in AD is the activation of PKC which in turn activates a 
series of downstream pathways that enhance synaptic function and promote synaptogenesis. 
Bryostatin is a potent stimulator of PKCε and is non-tumorigenic. Hongpaisan et.al 13 have 
recently demonstrated the cognitive benefits and the effect on synaptogenesis in two strains 
of transgenic AD mice.  Their work was recently reproduced by Schrott, et.al.14 Activation of 
PKCε by bryostatin was associated with reduced levels of β amyloid, increased levels of the 


 
 
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Brain Derived Neurotropic Factor (BDNF), prevention of synapse loss, reduced plaque 
formation and restored memory and learning even in the presence of plaques.  
1.1 
Rationale for the use of bryostatin in the treatment of AD 
The pharmacological basis for the use of bryostatin for the treatment of AD is based on the 
hypothesis that low dose, intermittent administration of bryostatin will activate PKC 
isozymes α and ε. Activation of PKC is associated with:  
• Enhanced associative learning and recent memory via PKC-mediated phosphorylation 
of downstream substrates 
• Increased synthesis of proteins such as MAP kinase Erk1/2, and synaptogenic 
proteins such as BDNF required for long-term memory 
• Activation of α-secretases, thereby increasing non-toxic fragments of the beta-
amyloid precursor protein (βAPP) and reducing the neurotoxic fragment of βAPP, 
Aβ1-42, and the associated neuropathology 
• Activation of Aβ1-42 – degrading enzymes 
• Phosphorylation of GSK-3 beta, inhibiting production of Tau and the associated 
neuropathology 
• Improved memory and learning in 3 different strains of transgenic mice with single or 
multiple Alzheimer’s gene mutations even in the presence of amyloid plaque 13-15  
 
Thus, activation of PKC can enhance existing synaptic function, reduce the toxic effects of 
amyloid and promote synaptogenesis, all potential targets to improve cognitive function in 
AD.  
1.2 
Pharmacokinetics, Toxicology and Drug Metabolism in Animals  
Single dose toxicity of bryostatin has been characterized in four non-GLP studies conducted 
under National Cancer Institute’s (NCI) IND, including three IV toxicity studies in mice and 
one IV toxicity study in rats.  Bryostatin was evaluated in a single GLP–repeated dose 21-day 
IV toxicity study in rats.  The single dose toxicity studies were conducted using two different 
dosing formulations: bryostatin in ethanol/saline or bryostatin in polyethylene glycol, 
ethanol, and Tween 80 (PET) diluent.  LD50 ranged from a low of 38µg/kg to 75µg/kg.  The 
21-day repeat-dose toxic study performed in rats at doses of 0, 10, 15 and 25µg/m2 with the 
ethanol/saline formulation resulted in no relevant toxicology findings.  The maximum 
tolerated dose (MTD) and no adverse effect level (NOAEL) were noted to be 25µg/m2 the 
highest dose studied.  However, since there were no toxicologically relevant findings, the 
report suggested that the MTD and NOAEL are greater than 25µg/m2. 
Two preliminary dose range finding IV toxicology studies were performed in the rat and dog 
to characterize the toxicity of bryostatin and to estimate the maximum tolerable dose (MTD) 
when administered by bolus injection and continuous infusion.  In the Sprague-Dawley rat 
bryostatin was tolerated up to 10µg/kg (infusion) and 15ug/kg (bolus) with no significant 
differences in toxicity noted between the two routes of administration.  In the beagle dog 
bryostatin was tolerated at doses up to 15µg/kg (infusion and bolus).  There were no 


 
 
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significant differences in toxicity between the two routes of administration.  A more detailed 
results summary can be found in the Investigator’s Brochure. 
Limited pharmacokinetics (PK) data are available in animals.  The pharmacokinetics of 
bryostatin was analyzed in female CD1/F2 mice by using [C26-3H]-labeled bryostatin 
following IV and IP administration (Zhang et al 1996).  Following IV administration of 
40µg/kg (120mg/m2), the plasma disappearance curve for bryostatin could be described by a 
2-compartment model, with a distribution t½ of 1.05 hours and an elimination t½ of 22.96 
hours.  In contrast, following IP administration, the plasma disappearance curve was better 
described by a first-order absorption one-compartment model, with an absorption t½ of 0.81 
hours and an elimination t½ of 28.76 hours. 
Urinary excretion represented the major pathway of elimination in the first 12 hours after IV 
administration, with 23.0 ± 1.9% (mean ± standard deviation) of the administered dose 
excreted. Approximately equal amounts of radioactivity (40%) were excreted in feces 
compared with urine within 72 hours after IV administration.  A greater area under the curve, 
longer mean resident time, and lower clearance were observed with IP administration 
compared with IV administration.  Bryostatin was widely distributed to various tissues 
following both IV and IP administration.  However, accumulation was observed in the lung, 
liver, gastrointestinal (GI) tract, and fatty tissue. 
1.3 
Genotoxicity  
Bryostatin 1 was evaluated using the bacterial reverse mutation assay (i.e., the Ames test) 
with no positive responses observed.  Bryostatin 1 was evaluated as negative 
(nonclastogenic) in the micronucleus assay; it was also evaluated as negative (non-DNA 
damaging) in the Comet Assay.  Overall, based on the results of the Ames test and the 
combined micronucleus/comet assay, bryostatin 1 is not considered to be genotoxic. 
2 CLINICAL TRIAL DATA 
2.0 
Oncology Data  
Safety data are available from published clinical studies of bryostatin for the treatment of 
cancer.  Altogether, over 1400 oncology subjects received bryostatin, mainly under NCI’s 
IND # 42,780, with exposures to bryostatin in both single and combination agent studies.  
About 584 subjects received bryostatin as monotherapy, with dose levels ranging from 
5μg/m2 to >180μg/m2.  Most subjects in both the monotherapy and combination therapy 
studies received bryostatin at doses >25μg/m2, most often as 1-hour infusions administered at 
various time intervals from weekly infusion to continuous infusions for 72 hours.  Most 
studies were repeated dose studies where subjects received treatment for several weeks (See 
Investigators Brochure).  
Adverse events occurring in the single agent studies that resulted in discontinuation from the 
studies were myalgia (28 subjects), acute transient reaction (dyspnea, flushing, hypotension, 
and bradycardia; 4 subjects each), phlebitis (attributed to ethanol in the formulations, 6 
subjects), fatigue (3 subjects), and 1 subject each with bacteremia, chest pain, dehydration, 


 
 
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dysphagia, hematuria, nausea, skin rash, subclavian vein thrombosis, thrombocytopenia, and 
vomiting.  The following AEs were associated with death in the single agent trials: cardiac 
arrest (2), hypotensive with evidence of renal and hepatic failure (1), perforated gastric ulcer 
(1), renal function decline with cardiac arrest and perforated gastric ulcer (1; PIs considered 
not related to bryostatin), and sudden death (1; PIs considered likely to be cardiovascular 
event).  Relatedness to bryostatin treatment was not assessed except where noted.  
Other severe (Grade 3 or higher) AEs reported in the single agent clinical studies in cancer 
subjects included: alkaline phosphatase (ALP) (elevated; subject had pre-existing liver 
metastases), allergic reaction, anemia, anorexia, arthralgia, ataxia, cardiac arrhythmias, 
cardiovascular, coagulation, community-acquired pneumonia, congestive heart failure, 
constipation, dermatitis, dermatologic, diarrhea, dyspnea, edema/weight gain, fever, 
gastrointestinal, genitourinary, granulocytopenia, headache, hepatic, hyperbilirubinemia, 
hyperglycemia, hypokalemia, hyponatremia, infection, leg weakness, lymphedema, 
lymphocytopenia, myocardial infarction, neurotoxicity, neutropenia, pain (abdominal, back, 
eye, site not specified), pulmonary, pulmonary embolus from inferior vena cava tumor 
thrombus, sepsis and pneumonia without neutropenia, syncope, and urinary frequency. 
The absence of a Placebo-control group in bryostatin oncology studies makes it difficult to 
determine the extent to which underlying disease or concomitant medications may have 
contributed to this safety profile.   
2.1 Alzheimer’s Disease Data 
2.1.1 Study NTRP101-203 
NTRP 101-203 was a randomized, double-blind, placebo-controlled, phase 2 trial assessing 
the safety, tolerability (primary objective) and efficacy (secondary objective) of bryostatin in 
the treatment of moderately severe to severe Alzheimer’s disease subjects.  This study was 
intended to confirm the results of study NTRP101-202 both in safety and efficacy for 
subjects not receiving concurrent memantine treatment at time points through Week 15. 
2.1.1.1 Methodology 
 
The study was designed to have an initial telephonic prescreening, followed by an actual 
screening period where the eligible subjects were selected and stratified based on MMSE-2 
scores: 4-9 vs. 10-15 and randomized 1:1 to either 20μg bryostatin or placebo treatment arm, 
and then treated for 12 weeks. 
The study drug was administered via continuous intravenous (IV) infusion over 45(±5) 
minutes. The first two doses of study drug administered were a loading dose 20% higher (i.e., 
24μg) than the assigned treatment given one week apart. Subsequently, the assigned doses of 
20μg were commenced as the third dose and were delivered every other week. 
 
The primary endpoint for this study was the change from baseline to Week 13 in the Severe 
Impairment Battery (SIB) total score. The changes from baseline at Weeks 5, 9, and 15 in the 
SIB total score, and the changes from baseline at each tested time point for subjects in each 


 
 
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stratification group were assessed as secondary outcome measures. Individual patient’s slope 
over time in SIB total score were evaluated via Weeks 0, 5, 9 and 13. 
Exploratory outcome measures were: change from baseline in Alzheimer’s Disease 
Cooperative Study - Activities of Daily Living – Severe Impairment Version (ADCS-ADL-
Sev) total score, change from baseline in Mini Mental State Examination, 2nd edition 
(MMSE-2) total score, change from baseline in the 10-point Neuropsychiatric Inventory 
(NPI) total score, and Clinical Global Impression of Improvement Scale (CGI-I) score. 
 
2.1.1.2 Demographics 
A sum total of 217 subjects signed the informed consent forms. Of these subjects, 106 
subjects were screen failed. The most common cause of screen failures was subject’s lacking 
to fulfill the inclusion /exclusion criteria for eligibility of the study. A total of 111 subjects 
were randomized to bryostatin (55 subjects) and placebo (56) treatment arms. Of the subjects 
randomized to bryostatin, 96.4% (96.4%, 53/55) received treatment. The study was completed 
by 87.3% subjects (87.3%, 48/55) and the remaining seven subjects (12.7%,7/55) did not 
complete the study primarily due to withdrawal by subject (9.1%, 5/55) followed by protocol 
deviation and adverse event (1.8%, 1/55 each). Of 56 subjects assigned to placebo treatment, 
98.2% (98.2%, 55/56) received placebo. Of these, 85.7% (85.7, 48/56) completed the study 
and 14.3% (14.3%, 8/56) terminated due to either subject withdrawal (5.4%,3/56), adverse 
event, lost to follow up, physician’s decision, death or other reasons (1.8%, 1/56 each). 
Approximately 56% of subjects (56.5%, 61/108) in the Safety Analysis Set were females. The 
majority of the subjects were white (84.3%, 91/108) and not of Hispanic or Latino 
background. The mean (SD) age of the subjects in the Safety Analysis Set was 72 years. 
 
No disparities between the study treatment groups were noted in majority of the baseline 
characteristics; however, there is a 5 unit difference in the baseline total score of Severe 
Impairment Battery (SIB), indicating subjects with a greater impairment were randomized to 
the bryostatin group. The mean baseline SIB score of the two randomized populations were 
73.7 in bryostatin group and 78.6 for the placebo group.  
 
2.1.1.3 Safety 
 
A total of 116 treatment emergent adverse events (TEAEs) were reported for 47 subjects in the 
study (43.5%,47/108). In bryostatin group, 57 AEs were reported by 23 subjects (43.4%, 23/53). 
In the placebo group, 59 AEs were reported by 24 (43.6%, 24/55) subjects. The majority of AEs 
were either mild or moderate. A total of 16 related AEs were reported in 11 subjects (10.2%, 
11/108). There were 7 related AEs reported for 5 subjects (9.4%, 5/53) in the bryostatin group, 
and 9 related AEs for 6 subjects (10.9%; 6/55) in placebo group. A total of 15 serious adverse 
events (SAE) were reported for 11 subjects (10.2%, 11/108) in bryostatin and placebo groups 
combined. One reported AE in placebo group resulted in death. A total of four AEs led to drug 
withdrawal in one subject (0.9%, 1/108). A sum total of 12 AEs led to interruption in drug 
scheduling regimen (4.6%, 5/108). 11 subjects reported 15 SAEs together in bryostatin and 
placebo groups. However, all of the 15 observed SAEs were considered to be ‘unlikely related’ 


 
 
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to the study treatment. There was one death reported in this study. The subject was randomized 
to the placebo group and the cause of death is unknown. Details regarding adverse events can be 
found on ClinicalTrials.gov, study identifier: NCT03560245. 
 
 
2.1.1.4 Efficacy 
The primary efficacy endpoint was defined as the change in the SIB total score from baseline 
to Week 13. Severe Impairment Battery (SIB) scoring is used to assess cognition in subjects 
with moderate and severe AD and is a useful outcome measure in advanced stages of disease. 
Forty questions are included with a point score range of 0-100. Lower scores indicate greater 
cognitive impairment. The mean baseline SIB score of the two randomized populations were 
73.7 in bryostatin group and 78.6 for the placebo group. At week 13, the mean SIB score for 
bryostatin and placebo reached 76.0 and 80.9, respectively. An average increase of 1.3 point 
and 2.1 points was observed for the bryostatin and placebo groups, respectively at Week 13 
and the difference between the treatment groups was not statistically significant. 
 
2.1.1.5 Summary 
The bryostatin treatment group showed minimal differences from the placebo treatment 
group in safety assessments, with an imbalance of 4.6 units in the baseline SIB scores 
between the bryostatin treatment group and the placebo group. The majority of AEs were 
either mild or moderate.  There were no statistically significant bryostatin/placebo 
differences in efficacy assessments.  
 
2.1.2 Study NTRP101-202  
NTRP 101-202 was a randomized, double-blind, placebo-controlled, phase 2 trial assessing 
the safety and tolerability (primary objective) and efficacy (secondary objective) of bryostatin 
in the treatment of moderately severe to severe Alzheimer’s disease subjects. Exploratory 
objectives characterize the pharmacokinetics (PK) and pharmacodynamics of bryostatin in 
this subject population. Seven doses of study drug were administered by a 45-minute 
continuous intravenous (IV) infusion over 12 weeks.  
2.1.2.1 Methodology 
Eligible subjects with moderately severe to severe AD were stratified based on Mini Mental 
State Exam (MMSE-2) scores 4-9 vs. 10-15 and randomized 1:1:1 to one of three treatment 
arms: 20μg, 40μg, or placebo for twelve weeks. Trial drug was administered IV by 
continuous infusion. The first two doses (24μg, 48μg) of each of the two active treatment 
arms were a loading dose, 20% higher than the assigned dose (20μg, 40μg), and were 
administered one week apart. Thereafter, the assigned dose commenced with the third dose 
and was administered every other week. Subjects were scheduled to receive seven doses over 
12 weeks, with the primary efficacy measure being at Week 13, and a follow-up visit 
scheduled 30 days from the last dose of trial drug administration.  


 
 
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2.1.2.2 Demographics 
A total of 264 subjects were screened in the trial. Of these, 147 subjects were randomized on 
a 1:1:1 basis to a treatment group. There were 50 subjects randomized to the placebo 
treatment group, 49 randomized to the 20μg bryostatin treatment group, and 48 randomized 
to the 40μg bryostatin treatment group. A total of 141 of the randomized subjects were 
treated with investigational product (IP) and were included in the Safety Analysis Set (SAS). 
A total of 135 subjects provided a post-baseline efficacy assessment and were analyzed as the 
Full Analysis Set (FAS). A total of 113 subjects out of 147 randomized (76.9%) performed a 
Week 13 evaluation of the SIB and were analyzed as the Completer Analysis Set (CAS). A 
total of 106 subjects in the SAS completed the trial (75.2%). A total of 35 subjects in the 
SAS and 29 subjects in the FAS withdrew early from the trial. The most common reason for 
early withdrawal was withdrawal of consent (18 subjects), followed by AE (11 subjects). 
2.1.2.3 Safety 
Overall, the 20μg bryostatin treatment group showed minimal differences from the placebo 
treatment group in safety assessments. The 40μg bryostatin treatment group had significantly 
greater AEs than the other treatment groups. There was also no clear difference in Serious 
Adverse events (SAEs) between the 20μg bryostatin group and placebo treatment groups, and 
again the 40μg bryostatin treatment group had significantly greater SAEs than the other 
treatment group.  
Similarly, the placebo and 20μg group had similar numbers of TEAEs (28 events vs 
30 events, respectively). The TEAEs observed more often in the 20μg treatment group vs 
placebo were infusion site reaction (8 events vs 3 events in placebo) and diarrhea (5 events vs 
1 event in placebo). The 40μg treatment group was associated with more TEAEs than either 
the 20μg or placebo treatment groups across multiple system organ classes (SOC).  
The most common treatment related TEAEs were grouped infusion reactions, diarrhea, 
headache, fatigue, and myalgia. Myalgia was seen in 5 subjects; 4 of those subjects were 
given the higher dose of bryostatin. Myalgia observed was mostly mild and managed with 
analgesics. There were also more treatment related TEAEs of diarrhea, headache, and fatigue 
in the higher dose bryostatin group. Both bryostatin treatment groups reported higher rates of 
infusion site TEAEs, and in particular the 40μg bryostatin treatment group reported 4 events 
of infusion site cellulitis. Although IV infusion-related reactions were also reported more 
often in the higher dose bryostatin group, none were reported following WebEx-based 
training on IV infusion and universal precautions, suggesting that this AE can be prevented.  
The higher dose bryostatin group also reported more TEAEs of seizure and fall compared to 
the lower dose bryostatin and placebo groups.  
A total of 97 (68.8%) subjects in all treatment groups reported 287 separate TEAEs. Of these, 
49 (34.8%) subjects reported 107 separate treatment-related TEAEs. There were 8 (16.7%) 
subjects with 20 treatment-related TEAEs in the placebo treatment group, 17 (37.0%) 
subjects with 30 events in the 20μg bryostatin treatment group, and 24 (51.1%) subjects with 
57 events in the 40μg bryostatin treatment group. Six subjects had a TEAE that lead to trial 
drug discontinuation, 2 in the placebo treatment group, 1 in the 20μg bryostatin treatment 
group, and 3 in the 40μg bryostatin treatment group.  Overall, 43 (30.5%) subjects had a 
TEAE that was mild in intensity, 46 (32.6%) subjects had a TEAE that was moderate in 
intensity, and 8 (5.7%) subjects had a TEAE that was severe in intensity. 


 
 
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There was 1 death in the trial, a subject in the 40μg bryostatin treatment group who suffered 
a severe TEAE of worsening of AD that was unrelated to the IP.  
There were 12 (8.5%) subjects who had 14 treatment emergent non-fatal SAEs during the 
trial; 4 subjects with 4 events in the placebo treatment group, 2 subjects with 2 events in the 
20μg bryostatin treatment group, and 6 subjects with 8 SAEs in the 40µg bryostatin treatment 
group. A total of 4 subjects in the 40μg bryostatin treatment group had 4 events that were 
judged as possibly or probably related to the IP: 3 events of cellulitis, and 1 event of seizure. 
There were no apparent differences between treatment groups in laboratory assessments over 
time.  
No differences were apparent between treatment groups when examining most vital signs, 
PEs, and ECG. However, there was a decline in weight in the bryostatin groups, which was 
more prominent in the higher dose group: 20μg bryostatin treatment group (mean loss of -
1.65±2.77kg) and the 40μg bryostatin treatment group (-2.98±2.10kg), while there was a 
slight weight gain in the placebo treatment group (0.442±2.52kg). Further, 5 subjects in the 
40μg bryostatin treatment group had 5 TEAEs of weight decreased, 3 of which were judged 
to be related to the IP. No weight related TEAEs were observed in the 20μg bryostatin dose 
group.  
There were no differences between treatment groups on the C-SSRS as most subjects did not 
have suicidal thoughts during the trial, and there were no attempts at suicide by any subject 
during the trial. 
Details regarding adverse events can be found on ClinicalTrials.gov, study identifier: 
NCT02431468. 
2.1.2.4 Efficacy 
Consistent with the initial hypothesis for bryostatin effects on PKCε and cognition, treatment 
with 20μg of bryostatin is effective in the treatment of Alzheimer’s disease in a FAS and 
CAS. The overall weight of data shows that subjects treated with 20μg bryostatin displayed 
significant improvement on the SIB, ADCS-ADL-Sev, and other secondary and exploratory 
endpoints (one-sided at α=0.10), as outlined below. 
Baseline scores on the SIB for the FAS were similar across all treatment groups. In the FAS, 
the treatment difference between the placebo treatment group and the 20μg bryostatin 
treatment group was statistically significant only at Week 5 (treatment difference 3.0[0.6, 
5.3]80%CI P=0.056). There were no statistically significant differences between the placebo 
treatment group and either the 20μg bryostatin treatment group or 40μg bryostatin treatment 
group at Week 9 or Week 13. Combining the bryostatin treatment groups and comparing 
with the placebo treatment group also did not produce a statistically significant difference at 
any time point.  
For the CAS, pre-specified along with FAS to assess primary and secondary endpoints, mean 
scores on the SIB followed the same pattern seen in the FAS. Baseline scores were similar 
across all treatment groups. There was a statistically significant difference, however, between 
the placebo treatment group and the 20μg bryostatin treatment group at Week 5 (P=0.016), 
and the treatment difference at Week 13 was also statistically significant (P=0.070). Further, 
when both bryostatin treatment groups were pooled, there was a statistically significant 
difference between the placebo treatment group and pooled group at Week 5 (P=0.039) and a 
statistically significant treatment difference at Week 13 (P=0.094). There were no 


 
 
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statistically significant differences between the placebo treatment group and the 
40μg bryostatin treatment group at any time point. 
In the CAS there were significant differences in the ADCS-ADL-Sev at Week 13 between 
the placebo treatment group and the 20μg bryostatin treatment group (P=0.082), and between 
the placebo treatment group and pooled bryostatin treatment group (P=0.087). There were no 
statistically significant differences between treatment groups for the ADCS-ADL-Sev, 
MMSE-2, NPI, or CGI-I assays for any time point in the FAS. 
In multiple exploratory analyses adjusting for covariates for the primary endpoint, there were 
additional significant differences between the placebo treatment group and bryostatin 
treatment groups. In an MMRM analysis of change from baseline in SIB total score, 
excluding all subjects from sites that recruited 2 or fewer subjects during the trial, there was a 
significant difference between the placebo treatment group and the 20μg bryostatin treatment 
group at Week 5 (P=0.068). There was a significant difference between the placebo treatment 
group and the 20μg bryostatin treatment group (P=0.031), and between the placebo treatment 
group and the pooled bryostatin treatment group in an MMRM analysis of change from 
baseline in SIB total score at the 30-day follow up visit (P=0.041). When an ANCOVA was 
performed to assess site effect on SIB, there was a significant difference between the placebo 
treatment group and 20μg bryostatin treatment group (P=0.032), and between the placebo 
treatment group and pooled bryostatin treatment groups (P=0.049) at Week 5. In an 
ANCOVA of change from baseline in SIB total score, with use of AChEI or memantine at 
baseline as an additional covariate, at Week 5 the 20μg bryostatin treatment group and 
pooled bryostatin treatment groups had statistically significant treatment differences from the 
placebo treatment group (P=0.024 and P=0.027, respectively).  
In multiple exploratory analyses adjusting for covariates for secondary endpoints, there were 
statistically significant differences between the placebo treatment group and the 20μg 
bryostatin treatment group at Week 5 (P=0.062), and the placebo treatment group and pooled 
bryostatin treatment group at Week 5 (P=0.041) when performing an ANVOCA of change 
from baseline in ADCS-ADL-Sev total score for subjects with > median baseline ADCS-
ADL-Sev total score. There was a statistically significant difference between the placebo and 
40μg bryostatin treatment groups at Week 5 (P=0.099) in an ANCOVA of change from 
baseline in NPI Total score to assess site affects. When performing an ANVOCA of change 
from baseline in NPI total score for subjects with > median baseline NPI total score, there 
were statistically significant differences between the placebo treatment group and the 40μg 
bryostatin treatment group at Week 9 (P=0.054) and Week 13 (P-0.096).  
No clear differences were apparent between treatment groups for Caregiver distress on the 
NPI, each NPI subscore at baseline, or on the NPI 10-item score. 
The results for SIB score from the MSSE-2 Stratum 1 analysis show the 20μg bryostatin 
treatment group had a more positive response than any treatment group at Week 5 and Week 
9 and the 40μg bryostatin treatment group had a slightly better response at Week 13. Results 
for SIB score in the MSSE-2 Stratum 2 analysis show the positive response varied across 
time point and treatment group. The placebo treatment group showed greater improvement in 
ADCS-ADL-Sev total score at Weeks 5 and 9 than either bryostatin treatment group in 
Stratum 1 or 2, and also at Week 13 in Stratum 2. At Week 13 in Stratum 1, the 
20μg bryostatin treatment group showed the best response compared to placebo or the 
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There was a significant difference in the FAS between the placebo treatment group and the 
20μg bryostatin treatment group (P=0.031), and between the placebo treatment group and the 
pooled bryostatin treatment group (P=0.041) in an MMRM analysis of change from baseline 
in SIB total score at the 30-day follow up visit. 
Additional post-hoc analyses were performed on the TEAE by MMSE-2 baseline strata, SIB 
by BSA-adjusted Dose, ADCS-ADL-Sev by BSA-adjusted Dose, TEAE by BSA-adjusted 
Dose, SIB by memantine use, ADCS-ADL-Sev by memantine use, the NPI 10-item total 
score by memantine use, and administration site-specific TEAE. The SIB and ADCS-ADL-
Sev scores also appeared to be affected by BSA-adjusted dose, as the lowest tertile of 
bryostatin dose in general had a better response to treatment than higher tertiles or placebo 
(these data were also not analyzed statistically). Subjects treated with bryostatin who did not 
take memantine at baseline had significantly better improvement in SIB score compared to 
the placebo group in an MMRM analyses of SIB total score in both the CAS and FAS. Both 
the pooled bryostatin and 20μg bryostatin treatment groups had significantly better scores 
than the placebo treatment group at Weeks 5, 13, and at 30-day Follow-up. Similar results 
(which were not statistically analyzed) were seen in the ADCS-ADL-Sev test and in the NPI 
10-item score. 
 
2.1.2.5 Pharmacokinetics 
Mean plasma bryostatin concentrations increased approximately proportional to dose for an 
increase in dose between 20μg and 40μg, infused IV over 45 minutes. The median Tmax 
occurred at the end of the 45-min infusion. 
Mean Cmax ranged from 0.563 ng/mL to 0.653 ng/mL after 20 μg and from 0.792 ng/mL to 
1.34 ng/mL after 40μg. Mean T1/2 ranged from 1.33 h to 5.37 h.  Mean CL was similar for 
both dose levels and ranged from 24.97 L/h to 28.42 L/h for Weeks 0 and 3. The mean CL on 
Weeks 7 and 11 was slightly lower, ranging from 13.38 L/h to 23.91 L/h. 
Within a given dose level, the ranges of values for Cmax, AUClast, and AUCinf were 
consistent 
across weeks and there was no indication of systemic accumulation of bryostatin during 
administration of bryostatin once every 2 weeks. 
2.1.2.6 Summary 
Bryostatin treatment was in general safe to use and well tolerated.  
The 20μg bryostatin treatment group had similar numbers of TEAEs to the placebo treatment 
group except in injection site reactions and diarrhea. The 40μg treatment group had more 
TEAEs and SAEs than the 20μg or placebo treatment groups across many SOCs.  
The 40μg dose of bryostatin was associated with more TEAEs. With a decrease in systemic 
CL especially noted with 40µg bryostatin dosing, the higher drug exposure may further 
explain the increased number of TEAEs. The most common treatment related TEAEs were 
diarrhea, headache, fatigue, and myalgia, and all were reported in greater frequency with the 
40μg dose of bryostatin. Subjects given the 40μg dose of bryostatin also reported more 
TEAEs of seizure and fall. 


 
 
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The primary efficacy endpoint for the SIB and secondary efficacy endpoint for the ADCS-
ADL-Sev was met in the CAS with the 20μg dose, which was statistically significantly 
different from placebo at Weeks 5 and 13. The 40μg dose was not statistically significant 
from the placebo.  
SIB improvement was significant for the Week 5 FAS measurement (p< .056). No other 
primary or secondary endpoints were met in the FAS. 
Multiple exploratory analyses in the FAS for covariates in the primary and secondary 
endpoints revealed additional significant differences, but these occurred predominantly at the 
Week 5 time point.  
2.1.3 Study NTRP101-201  
This was a randomized, double-blind, Placebo-controlled safety study of a single dose of 
bryostatin in subjects with mild to moderate AD (MMSE: 14-26).  Subjects were randomized 
2:1 to receive bryostatin 25µg/m2 or Placebo.  The primary objective was to evaluate the 
safety and tolerability of bryostatin by the incidence of AEs and SAEs.  Secondary safety 
endpoints included assessment of physical examination, hematology including complete 
blood count (CBC) and platelet count, coagulation parameters, serum chemistries, ECG, 
urinalysis and vital signs. 
The primary efficacy endpoint was a composite end point of change from baseline in the 
Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall and Repeatable Battery of 
Assessments for Neuropsychological Status (RBANS) figure recall at 48 hours post study 
drug infusion. 
The study included single dose PK, and measurement of PKCε in peripheral blood 
mononuclear cells (PBMCs) as a potential biomarker.  
 
2.1.3.1 Demographics 
The study enrolled nine subjects, 4 male and 5 female, with a mean age of 71.8 ±7.4 years 
(range 62 to 82).  The mean MMSE-2 at baseline was 22.5 for the three placebo subjects 
(range 19-24) and 22 (range 16-26) for the six bryostatin treated subjects. 
 
2.1.3.2 Safety 
Bryostatin was well tolerated.  There were no deaths or SAEs reported.  No subjects had an 
AE leading to withdrawal during the study.  There were five treatment emergent adverse 
events occurring in three subjects: headache, dizziness, and papular rash.  There were no 
reported episodes of myalgia, a known side effect of bryostatin.  The only adverse event in 
the bryostatin treated group was headache, which was not considered related to study drug.  
All adverse events were mild and resolved without treatment.  All laboratory assessments, 
including hematology, chemistry, coagulation, renal function and liver function as well as 
cardiac assessments were unremarkable after treatment and there was no clinically significant 
change in any vital signs. 


 
 
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2.1.3.3 Efficacy  
There were no clinically significant differences between the mean or mean change from 
baseline between bryostatin and placebo in the HVLT-R or MMSE-2 assessments or any 
other efficacy assessment to suggest a treatment effect after a single dose of 25μg/m2 
bryostatin. However, the possibility of an early effect on MMSE was identified even at small 
sample size and warranted further investigation in a more adequately powered trial. There 
was no difference in HVLT-R delayed recall or the RBANS delayed figure recall at 48 hours.  
Additional time points of assessment for these measures (day 2, day 4 and day 15) did not 
indicate any difference between groups.  Additional endpoints included the change from 
baseline in Digit Symbol Coding (DSC), and MMSE-2 at various time points.  There was no 
difference in mean values between groups for these endpoints at any time point.  Both the 
treatment and the Placebo group showed an improvement in the MMSE-2 score most likely 
due to practice effects since the MMSE-2 was administered five times in 2 weeks. 
In summary, there was no clinically significant difference between the mean or mean change 
from baseline between bryostatin and placebo in the HVLT-R or MMSE-2 assessments or 
any other efficacy assessments to suggest a treatment effect after a single dose of 25μg/m2 
bryostatin. 
2.1.3.4 
Pharmacokinetics  
The pharmacokinetics of bryostatin were assessed in 6 subjects following 25 µg/m2 
bryostatin administered as a single 1-hour IV infusion.  Individual bryostatin plasma 
concentrations were observed to increase and approach steady-state within the 1 hour 
infusion periods, and then rapidly decrease following the end of the infusion.  The bryostatin 
maximum plasma concentrations occurred at the end of the IV infusions, and had a mean 
(±standard deviation (SD)) value of 1.09 ±0.25 ng/mL.  A terminal elimination rate could not 
be calculated for most subjects due to sampling frequency, the rapid drug elimination, and 
the sensitivity limitations of the assay.  Based on the observed individual bryostatin plasma 
concentration profiles, the elimination t1/2 associated with the observed drug exposure was 
estimated to be less than 30 minutes.  Total drug CL was observed to be high (~ 40 L/h), 
consistent across the individual administered doses, and did not appear to be related to body 
weight, BSA, or sex.  The bryostatin pharmacokinetic parameters were observed to have low 
to moderate intersubject variability. 
2.1.3.5 Pharmacodynamics/ PKCε 
Preliminary assessment of PKCε concentration in PBMCs suggests there is an increase in the 
total amount of PKCε (cytosol plus membrane bound concentration) following treatment 
with bryostatin.  Additional analysis is underway to further characterize the increase and 
pharmacodynamics. 
2.1.3.6 Conclusions 
This was the first double-blind assessment of the safety of bryostatin treatment in subjects 
with Alzheimer’s disease.  The study met its primary endpoint of safety and tolerability.  
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Alzheimer’s disease.  Except for an improvement in MMSE 3 hours after infusion, no 
improvement was detected in cognitive function on the efficacy measurements though the 
study was not powered to detect cognitive benefit.  There was no evidence of an adverse 
effect on cognition following treatment with bryostatin.   
 
3 STUDY OBJECTIVES AND HYPOTHESIS 
3.0 
Primary Objective 
To evaluate the safety, tolerability and long-term efficacy of bryostatin for the treatment of 
moderately severe Alzheimer’s disease in subjects not receiving concurrent memantine 
treatment, including 1) how long the therapeutic effects will last; and 2) whether a second 
treatment would be equally effective if the therapeutic effects of the first treatment do not 
last. 
3.1 
Hypothesis  
Patients treated with bryostatin will experience a greater improvement in cognitive function 
as measured by the SIB from baseline to the primary efficacy endpoint after two 12 week 
courses of treatment, as compared to patients on placebo during the same time period.  The 
null hypothesis will be rejected at a significance level of a two-sided α = 0.05. The test of the 
null hypothesis will be a superiority test based on the treatment difference in Week 28 SIB 
from baseline means as assessed by general estimating equations (GEE) regression, and only 
an improvement in the SIB score from baseline is of clinical significance.  
  
4 INVESTIGATIONAL PLAN 
4.0 
Overview of Study Design   
This is a randomized double-blind placebo-controlled exploratory study assessing bryostatin 
for the treatment of moderately severe Alzheimer’s disease in subjects not receiving 
memantine treatment.  The first treatment period of the study is 15 weeks in duration, 
including safety and efficacy evaluation 30 days after the last treatment. Eligible subjects will 
be stratified based on SIB total scores at baseline and will be randomized 1:1 to treatment 
with 20µg bryostatin or placebo for two 12-week courses of treatment. The balance by 
treatment arms of baseline SIB total scores will be monitored in real time.  Study drug is 
administered IV by continuous infusion. 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 for 5 doses.  The second treatment period, beginning at Week 15, will be 
identical to the first.  Subjects are scheduled to receive seven doses over 12 weeks during the 
first treatment period and seven doses over 12 weeks in the second period according to the 
original blinded, randomized treatment assignment.  Safety and efficacy assessments will be 


 
 
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done as indicated on the Schedule of Activities (Table 1). The primary endpoint is the total 
SIB score assessment obtained at Week 28, after completion of two courses of treatment. 
 
 
4.1 
Dose Rationale 
The primary objective of treatment for cognitive disorders with bryostatin is activation of 
PKCε, not downregulation as was attempted for the oncology indications.  Bryostatin 
activation of PKCε is dose dependent, where lower doses activate PKCε and increase de-
novo synthesis of the enzyme, while higher doses of bryostatin downregulate PKCε.   
The dosing regimen is based on the recently completed phase 2 study, NTRP101-202, in 
which the safety and efficacy analyses indicated a clear advantage of the 20µg dose over the 
40µg dose.   
The oncology data suggest that the dose-limiting side effect of myalgia is dose dependent and 
cumulative and likely related to the down regulation of PKCε.  This was not seen in the 
NTRP101-201 study, in which there were no reports of myalgia after a single 25µg/m2 dose 
of bryostatin was administered, nor in the recently completed NTRP101-202 study, in which 
myalgia was considered an adverse event of special interest.  In NTRP101-202, in which 
subjects received 7 doses of study drug, myalgia was seen in 5 subjects; 4 of those subjects 
were given the higher 40µg dose of bryostatin. Myalgia observed was mostly mild and 
managed with analgesics. 
Dosing in this study will begin with two initial loading doses at one-week intervals that are 
20% higher than the maintenance dose (i.e., 24µg) to assure enzyme activation. Dosing will 
then continue with 20μg administered every other week for 5 weeks, for a total of 7 doses.  
The first treatment period will occur over 15 weeks, including a follow-up visit 30 days after 
the last dose.  The same treatment regimen will be administered for subjects who qualify for 
a second course of treatment. The total study drug administered to a particular subject is 14 
doses. 
4.2 
Risk/Benefit 
Bryostatin treatment in study NTRP101-202 was shown to be generally safe and well 
tolerated.  The 20μg bryostatin treatment group had similar numbers of TEAEs to the placebo 
treatment group except in injection site reactions and diarrhea. Post hoc analysis in 
NTRP101-202 clearly showed that bryostatin-treated subjects who did not take memantine at 
baseline had significantly better improvement in SIB score compared to the placebo group in 
an MMRM analyses of SIB total score in both the CAS and FAS. Both the pooled bryostatin 
(20μg and 40μg) and 20μg bryostatin treatment groups had significantly better scores than 
the placebo treatment group at Weeks 5, 13, and at 30-day Follow-up. There were no 
statistical differences in SIB score between treatment groups in subjects given memantine at 
baseline.   
Therapeutic antibodies targeting β-amyloid have been associated with the occurrence of 
amyloid related imaging abnormalities (ARIA), which is similar in appearance to cerebral 


 
 
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vasogenic edema and microhemorrhage.  A minority of cases have been associated with 
symptoms of headache, visual disturbance, loss of coordination, or disorientation.  
Asymptomatic ARIA was reported in a clinical study of the small molecule gamma-secretase 
inhibitor BMS-708163.  Bryostatin has a different mechanism of action than antibodies 
directed at amyloid, but in the transgenic mouse model of AD treated with bryostatin a 
decrease of Aβ deposition was observed.  Given the limited bryostatin experience in AD, the 
potential for ARIA and associated clinical events cannot be excluded.  In NTRP101-202, 
however, there was no clinical evidence suggestive of vasogenic edema or microhemorrhage 
that required an MRI scan. 
Subjects in this study, with moderately severe to severe dementia, are those who have had a 
progressive dementia to the degree that their activities of daily living and their ability to care 
for themselves may be compromised.  Subjects with MMSE-2 scores of 15 or less display 
significant cognitive impairments that are disabling.  Most if not all of these subjects will 
have progressed despite treatment and have no alternative treatments available.  Based on the 
available nonclinical and clinical data, and the low risk of ARIA, the potential benefits of 
treatment with bryostatin at the proposed dose in this protocol outweigh the risks. 
4.3 
Study Endpoints 
4.3.1 
Safety Assessments 
• Treatment emergent AEs and SAEs  
• Vital signs, hematology, blood chemistry, and physical examination including 
body weight   
• ECG parameters  
• C-SSRS 
4.3.2 
Primary Efficacy Endpoint 
The primary efficacy endpoint is change from baseline in the SIB total score assessment 
obtained after completion of the second course of treatment (Week 28). 
4.3.3 
Secondary Efficacy Endpoints   
• SIB score at the end of the Week 42 follow-up visit, for subjects who completed week 42  
• The change from baseline (screening) SIB total score at week 13 
• The changes from baseline at Weeks 9, 20, 24 and 30 in the SIB total score  
• The changes from baseline at Weeks 9, 13, 20, 24 and 30 in the SIB total score for 
subjects with baseline MMSE-2 scores of 10-14 and 15-18  
• SIB trends over time; individual-specific slopes of total SIB scores will be obtained for all 
patients. 
 


 
 
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4.3.4 
Exploratory Endpoints 
• Change from baseline in ADCS-ADL-Sev total score at Weeks 13 and 42, for subjects 
who completed week 42 
Change from baseline in MMSE-2 total score at Weeks 13 and 42, for subjects who completed 
week 42Change from baseline in NPI total score at Weeks 13 and 42, for subjects who 
completed week 42 
4.4 
Study Population 
Subjects with moderately severe Alzheimer’s disease defined as a MMSE-2 score of 10-18 
inclusive are eligible to enroll.  Subjects will be permitted to continue present FDA-approved 
treatments for Alzheimer’s disease with the exception of memantine, but no new treatments can 
be initiated.  OTC medications taken for cognitive improvement such as Ginkgo Biloba or other 
empiric medications are permitted while participating in the study but should not be initiated or 
dose modified after screening.  Subjects who are no longer on medications for Alzheimer’s 
disease can also be enrolled. 
4.4.1 
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.16  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 
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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 (dose 
adjustments will be permitted) 
12.  Females participating in the study must meet one the following criteria: 
a. 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 
b.  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  
 
4.4.2 
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 


 
 
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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 Un its (IU) per day within 14 days prior to 
screening 
9. Use of more than 2,600 mg/day of acetaminophen for more than 3 consecutive days 
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 Edition17, 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]18  
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  


 
 
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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. 
 
5 PRODUCTS USED IN THIS STUDY 
Active study drug, bryostatin, and a matching placebo will be provided as described below. 
5.0 
Bryostatin 
The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder 
intended for IV infusion upon reconstitution and dilution.  Bryostatin will be supplied in a 10 
mL vial containing 0.025mg bryostatin, 2.5 mg povidone lyophilized from 40% t-butanol. 
Accompanying each vial of bryostatin will be a 10mL vial containing 2mL of sterile PET 
diluent [60% v/v polyethylene glycol 400, 30% v/v dehydrated ethyl alcohol, and 10% v/v 
Tween-80 (polysorbate 80)].   
5.1 
Placebo 
The placebo is a sterile, pyrogen-free lyophilized powder intended for IV infusion upon 
reconstitution and dilution.  It will be supplied in a 10 mL vial containing 0.0mg bryostatin, 
2.5mg povidone lyophilized from 40% t-butanol. Accompanying each vial of placebo will be 
a 10 mL vial containing 2mL of the same sterile PET diluent as described above for 
bryostatin.  The placebo is identical to bryostatin in appearance, including color, consistency, 
volume, and odor. 
5.2 
Packaging and Labeling of Study Drug Kits 
Study drug kits will contain 7 vials of bryostatin for Infusion or 7 vials of placebo for 
Infusion and 7 vials of PET diluent.  Each kit will be identified by kit number only and 
assigned to a subject via the Interactive Response Technology (IRT), according to the 
established randomization scheme. 
Study drug kits will be labeled in English according to the US FDA’s current Good 
Manufacturing Practice (GMP) and local regulations. 
The kit label will contain the following information: 
Bryostatin or Placebo for Infusion Kit  
Kit # XXXXX 
Store refrigerated at 2-8°C. 


 
 
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Caution New Drug - Limited by Federal Law (US) to Investigational use. 
Each kit contains 7 vials Bryostatin for Infusion, 0.025 mg bryostatin/vial or 7 vials 
Placebo for Infusion, 0.0 mg bryostatin per vial and 7 vials PET Diluent 
Manufactured for Neurotrope by Lyophilization Technology, Inc. 
 
Study drug vials will be labeled in English according to US FDA’s current Good 
Manufacturing Practice (GMP) and local regulations.  
Bryostatin for Infusion or Placebo for Infusion vial label will contain the following 
information: 
Bryostatin for Infusion, 0.025mg bryostatin or Placebo for Infusion 0.0mg bryostatin 
Kit # XXXXX 
Store refrigerated at 2-8°C 
Caution New Drug - - Limited by Federal Law (US) to Investigational use. 
Each vial contains 0.025mg bryostatin or 0.0 mg bryostatin and 2.5 mg povidone C-
17. Contains no antibacterial preservatives 
Reconstitute with 1 mL PET Diluent. Swirl to dissolve 
Further dilute with 9 mL sodium chloride for injection 
Manufactured for Neurotrope by Lyophilization Technology, Inc. 
PET Diluent vial label will contain the following information: 
PET Diluent for Reconstitution of Bryostatin for Infusion or Placebo for Infusion 
Lot #: XXXX 
Volume: 2 mL 
Caution New Drug - - Limited by Federal Law (US) to Investigational use 
Each mL contains Polyethylene Glycol 400 (60%), dehydrated Ethyl Alcohol (30%) 
and Polysorbate 80 (10%). 
For Single Use Only 
Manufactured for Neurotrope by Lyophilization Technology, Inc. 


 
 
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5.3 
Storage and Preparation of Study Drug 
The study drug kits will be stored under refrigeration conditions (2-8°C) in a refrigerator, 
refrigerated cabinet or other refrigerated enclosure, which is securely locked and temperature 
continuously monitored.  Access to the stored study drug kits will be restricted to the 
investigational site pharmacy or designated staff member.   
Study drug will be prepared and dispensed for administration by a qualified member of the 
study staff (e.g., pharmacist, pharmacist-designee, nurse or physician trained in aseptic 
handling techniques).  This individual will be responsible for reconstitution, dilution and 
preparation of study drug (active and placebo) according to the randomization assignment for 
each subject.  The investigational drug is to be administered only according to the conditions 
of this protocol.   
Study drug will be administered by the study PI or his/her designees. Study drug should be 
allowed to come to room temperature prior to administration.  The study drug contains no 
antibacterial preservatives and must be used within eight hours of reconstitution. Study drug 
should be reconstituted with 1mL of PET diluent. After swirling the 10 mL vial to 
completely dissolve the contents, the resulting solution must be diluted immediately with 
9mL of 0.9% sodium chloride (NS) injection, USP.  The necessary volume of this solution to 
achieve the assigned dose (a 9.6 mL loading dose for the first two doses and an 8.0mL 
maintenance dose for the remaining 5 doses) should then be added to an IV infusion bag 
containing 50 mL of normal saline.  Once the infusion bag is filled with the assigned dose, 
the 45±5 minute continuous infusion must be completed within 3 hours of the IV infusion 
bag fill. 
The infusion system (IV infusion bag and tubing) should be made of a polyolefin plastic, 
such as polypropylene or polyethylene, or a combination of both. The use of 
polyvinylchloride (PVC) plastic bags and tubing is NOT to be used as plasticizer from the 
PVC is leached and there is absorption of bryostatin to PVC plastics.   
The prepared infusion bag containing study drug should be labeled with the following 
information: 
Protocol number 
Kit/Subject number 
Date and time prepared 
Instructions for dosing (e.g., entire contents of IV infusion bag infused within 45 
±5 minutes 
 
5.4 
Study Drug Accountability and Disposal 
Neither the Investigational Pharmacy, designated drug preparer, the PI nor any of his/her 
designees may provide drug to any person not enrolled in this study.  Adequate records of 
study drug receipt and use must be maintained in order to comply with governmental 
regulations and with the protocol in addition to preventing unauthorized distribution. 


 
 
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Study drug orders, records of receipts, dispensing records, and inventory forms will be 
examined and reconciled throughout the study.  All study drug that is used during the course 
of the study must be accounted for on a drug accountability form. 
Unless otherwise directed, at the end of the study all unused study medication must be 
destroyed onsite following the site’s specific SOPs after drug accountability has been verified 
by the monitor.  If destruction on site is not possible, study medication should be retained and 
returned to Singota Solutions at the end of the study. A copy of all completed drug 
accountability forms will be collected by the monitor or appropriate designee upon 
completion of the study.  
Note: The medications should not be disposed of prior to monitoring and approval. 
5.5 
Randomization 
Once all eligibility criteria for the study have been met, and the site has received approval by 
the Medical Monitor (MM) and Clinical Assessment Technologies (CAT) group, via the 
EDC system, the subject can be randomized via Interactive Response Technology (IRT) 
system.  Randomization will be stratified by SIB total score at baseline and baseline SIB 
scores will be balanced at baseline between the treatment groups.  Mean values of baseline 
SIB total scores by group will be monitored in real time during the enrollment process. A 
randomization number will be assigned, and drug for that randomization number will be 
shipped to the site for twelve weeks of treatment.  Randomization and scheduling of the first 
study drug infusion should be timed to allow for receipt of study drug prior to the scheduled 
study treatment.  The drug kits will be shipped to the individual who will be responsible for 
kit storage and drug preparation and may not be handled by any other study staff member.  
The study drug kit will not identify the vial containing study drug as either placebo or 
bryostatin.  After completion of Week 13, a second study drug kit will be provided for 
treatment period two.  The IRT system will be used to register subjects for treatment and 
trigger study drug shipments. 
 
     5.6  
Blinding 
 
All subjects, PIs, and investigational clinical site personnel will be blinded to dose 
assignment.  Since there is no known antidote to bryostatin, the blind should only be broken 
in exceptional circumstances and is at the discretion of the PI.  The Medical Monitor should 
be contacted as soon as possible to discuss the situation, but this should not delay any 
treatment. 
In a non-emergency situation, when unblinding is requested, the site should discuss the 
clinical circumstances with the Medical Monitor to determine if breaking the blind will alter 
the subject’s treatment.  The decision to break the blind is ultimately the decision of the PI.   
If the blind is broken for a subject, the PI will record the date and reason for breaking the 
blind in the electronic case report form (eCRF) and study drug treatment will be 


 
 
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discontinued.  However, the subject will continue to be monitored per protocol for safety and 
efficacy.  
5.7 
Study Drug Administration  
Study drug is scheduled to be administered by continuous intravenous infusion only, via a 
pump, at the same rate over 45 minutes (±5 min) once a week for 2 weeks and then every 14 
days ±2 days thereafter. The same treatment schedule will be followed for treatment period 
two.  The entire volume of study drug in the infusion bag is to be administered. Infusion 
times should not be extended or shortened.  If a subject misses a dose, the dose should be 
administered as soon as possible.  The subject should then continue on the original dosing 
schedule.  Provided all efficacy assessments have been completed, if deemed necessary by 
the PI, a short acting sedative may be administered to reduce a subject’s anxiety or agitation 
during the infusion. All medication is to be recorded on the Concomitant Medication eCRF. 
6 STUDY PROCEDURES AND ASSESSMENTS  
Subjects will be randomized to study drug, either bryostatin or placebo treatment.  A follow-
up visit will take place 30 days after the last dose of study drug for all subjects, including 
subjects that have discontinued treatment before completion of the study. Assessments will 
be performed according to the Schedule of Activities. (Table 1). 
 
 


 
 
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Table 1 - Schedule of Activities   
NTRP101-204 
 
Treatment Period 1 
Treatment Period 2 
1° 
End 
point 
Follow-Up 
We e k 
Screening 0 
1 
2 
3 
5 
7 
9 
11 
13 
15 
16 
18 
20 
22 
24 
26 
28 30/FU 
ET 
Day (±2 days) 
Days -28 to 
-2d 
0 
7 
14 
21 
35 
49 
63 
77 
91 105 112 126 140 154 168 182 196 
210 
 
Dose 
 
Rand 1 
2 
 
3 
4 
5 
6 
7 
 
8 
9 
10 
11 
12 
13 
14 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history◊ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Rosen-modified 
Hachinski Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SIB 
X∆ 
 
 
 
 
 
X* 
 
X* 
 
X 
X* 
 
 
X* 
 
X* 
 
X 
X 
X 
MMSE-2 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
 
 
 
X* 
 
X* 
 
X 
 
X 
ADCS-ADL-Sevb 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
NPIb 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
CSSRS 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
 
X* 
 
 
 
X* 
 
 
X 
Labs^^ 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
 
X* 
 
 
 
X* 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECG 
X 
(x3) 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
PE 
X 
 
 
 
 
 
 
X*+ 
 
 
X 
 
 
X* 
 
 
 
X* 
 
 
X 
Vitals 
X 
 
Xc Xc X Xc Xc Xc Xc Xc X Xc Xc Xc Xc Xc Xc Xc 
X 
X 
X 
Randomization 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X◊ 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse Events 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds 
X 
X 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
a Randomization after initial screening procedures indicate eligibility; b The ADCS-ADL-Sev and NPI may be administered via telephone at the 
discretion of the investigator, within the allowed time window for the scheduled visit; cVital signs prior to infusion, then at 30, 60 and 90 
minutes from start of the infusion (+/- 5min). dThe visit window of ±2 Days does not apply to the Screening and Randomization period which is 
a maximum of 28 days. ◊ CT scan if necessary per inclusion criterion #6; ∆Baseline SIB administered during screening must be done within 3 
weeks of the first dose of study drug. If the screening period exceeds 3 weeks, the SIB should be repeated on the day of first dose, prior to 
dosing;*before dose; ^^Labs: CBC including differential, coagulation, clinical chemistry, TSH at screening ( T-3 and T-4 if TSH abnormal), CPK 
at screening and event of myalgia, βhCG if indicated, HbA1C if clinically indicated. + abbreviated physical examination. 
 


 
 
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6.0 
Assessments 
Every effort should be made to ensure that protocol-required tests and procedures are completed 
as described.  However, it is anticipated that from time to time there may be circumstances 
outside the control of the PI that may make it unfeasible to perform a test.  In these cases, the PI 
must take all steps necessary to ensure the safety and well-being of the subject.  When a protocol 
required test cannot be performed, the PI will document the reason for the missed test and any 
corrective and preventative actions which were taken to ensure that the required processes are 
adhered to as soon as possible.  The study team must be informed of these incidents in a timely 
manner. 
6.0.1 Safety 
Overall safety and tolerability will be assessed by the incidence of treatment emergent AEs and 
SAEs and by evaluations of change from baseline in physical examination, vital signs, 12-lead 
ECG, the C-SSRS, clinical chemistry, hematology, and coagulation lab tests.  
6.0.1.1 Laboratory 
Blood samples will be obtained for routine laboratory tests, including hematology, chemistry, 
coagulation and βhCG if indicated as outlined in the Schedule of Activities (Table 2).   
Hematology tests will include CBC with differential, platelet count and coagulation 
(prothrombin time (PT) and partial prothrombin Time (PTT)) studies. 
 
Clinical chemistry tests will include sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), creatinine, estimated creatinine CL, glucose, calcium, CO2, total protein, 
albumin, ALP, ALT, AST, gamma glutamyl transferase (GGT) lactate dehydrogenase (LDH), 
uric acid and bilirubin.  A serum creatine phosphokinase (CPK) will be done at screening and in 
the event of myalgia. A TSH will be done at screening, and T-3 and T-4 will be done if TSH 
result is abnormal. 
 
Samples will be sent to a central lab for testing.  Refer to the Laboratory Manual for detailed 
instructions. 
 
 
6.0.1.2 Physical Examination 
All physical examinations must be performed by the PI or qualified designee (physician, 
physician’s assistant, or nurse practitioner).  The complete physical examination conducted 
during the screening period and at designated subsequent time points should include, but is not 
limited to the following:   
• General appearance 
• Weight 
• Height (screening only) 


 
 
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• Ears  
• Eyes  
• Nose 
• Throat 
• Neck 
• Respiratory system 
• Cardiovascular system 
• Abdomen 
• Musculoskeletal /Neurologic 
• Extremities 
• Skin  
• Lymph nodes 
An abbreviated PE will include but is not limited to the following:  
• General appearance 
• Weight 
• Respiratory system 
• Cardiovascular system  
• Abdomen 
Examination of other systems as needed to explore reports of AEs should be conducted as 
needed by the PI.  Any clinically significant physical findings that were not present on the initial 
physical examination will be considered AEs and documented on the AE eCRF as well as in the 
subject’s source documentation and on the physical examination eCRFs.   
6.0.1.3 Vital Sign Measurements 
Single supine blood pressure and pulse rate will be measured at Screening and at other visits as 
specified in the Schedule of Activities.  
6.0.1.4 Electrocardiogram  
An average of triplicate 12-lead ECGs will be collected at screening.  The triplicate ECG 
measurements should be obtained approximately 2-4 minutes apart.  Single 12-lead ECGs will be 
collected at time points specified in the Schedule of Activities. 
6.0.1.5 Columbia Suicide Severity Rating Scale  
The C-SSRS is an interview-based rating scale to systematically assess suicidal ideation and 
suicidal behavior.  The scale should be administered by an individual with appropriate clinical 
training, who has also taken the specific rater training for the scale, which will be provided by an 
agent of the Sponsor prior to the study start.  If at any visit from baseline on, there are “YES” 
answers on items 4, 5 or on any behavioral question of the C-SSRS, a risk assessment should be 


 
 
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done by a qualified clinician to determine whether it is safe for the subject to continue to 
participate in the study.  A suicidality narrative should be constructed for subjects who have 
undergone any post-baseline risk assessment, using information from the C-SSRS, and available 
information from the NPI, prior screening and baseline information, the clinician assessment and 
the narrative guide.  Subjects who answer “YES” on items 4, 5 or on any behavioral question of 
the C-SSRS on more than one occasion during a study should be discontinued from the study.  
Suicidality AEs or other clinical observations may, based on the judgment of the PI, also trigger 
a risk assessment and a narrative.  When there is a positive response to any question on the C-
SSRS, the PI should determine whether an AE has occurred. 
6.0.2 Efficacy / Psychometric Assessments 
All raters for the efficacy assessments need to be trained and qualified on the administration of 
the scales.  A qualified rater is required for the administration of the SIB, NPI and MMSE-2.  
The same qualified rater should perform a given Efficacy/Psychometric Assessment at 
approximately the same time of day for a given subject throughout the study.  All changes in 
raters for a given assessments must be noted in the subject’s source documents.  The caregiver 
designated to provide assessments (ADCS-ADL-Sev and NPI) at the start of the study should be 
the same individual throughout the study.  Should a change be necessary during the course of the 
study, the reason for the change and the first corresponding visit must be noted in the subject’s 
source document. 
All psychometric tests performed on study subjects on the same day should be administered in 
the following order: SIB followed by MMSE-2, except at the screening visit as described in 
Section 6.2.1. If the MMSE-2 score obtained at screening does not fall within the 10-18 range for 
inclusion, no further screening tests should be performed.  Efficacy tests at subsequent visits 
should be administered prior to dosing. 
6.0.2.1 Rosen-Modified Hachinski Scale 
The Rosen-Modified Hachinski Scale will be evaluated at screening to differentiate Alzheimer’s 
type dementia from multi-infarct dementia.  The 8-item scale results in a score of 0-12; and a 
score of 5 or above is exclusionary for the study. 
6.0.2.2 Severe Impairment Battery  
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.   
6.0.2.3 Mini Mental State Examination, 2nd Edition  
The Standard version of the MMSE-2, with two alternate forms, will be used.  This version has 
the structure and scoring of the original 30-item MMSE-2 and scores are comparable.  The 
MMSE-2 is a brief, widely used test for assessing overall cognitive state.  The MMSE-2 


 
 
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measures selected aspects of cognition such as memory, orientation, attention, language, and 
praxis on a scale of 0-30.  Lower scores indicate greater cognitive impairment.  
6.0.2.4 Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory – 
Severe Impairment Version  
The ADCS-ADL-Sev is a 19-item functional assessment of the performance of activities of daily 
living for subjects with moderate to severe Alzheimer’s disease.  Informants are queried via a 
structured interview format as to whether subjects attempted each item in the inventory during 
the previous 4 weeks, as well as their level of performance.  Each item is rated from the highest 
level of independent performance to complete loss.  Total score ranges from 0-54 with lower 
scores indicating greater functional impairment.  The ADCS-ADL-Sev may be administered via 
telephone at the discretion of the PI, within the allowed time window for the scheduled visit. 
6.0.2.5 Neuropsychiatric Inventory  
The NPI is a caregiver interview-based rating scale assessing 10 behavioral disturbances 
occurring in dementia subjects.  The NPI may be administered via telephone at the discretion of 
the investigator, within the allowed time window for the scheduled visit.  Items are scored for 
both frequency and severity.  Total scores range from 0-120 with higher scores indicating greater 
behavioral disturbances.  For each item, the associated caregiver distress is also assessed.  
6.1 
Visit Procedures 
6.1.1 Screening and Randomization (Days -28 to -2) 
In order to avoid unnecessary screen failures, a prescreening telephone call to rule out clearly 
exclusionary conditions is advised prior to scheduling a screening visit.  In addition, a Pre-
Screening Consent form will be provided, allowing access to medical records prior to a subject’s 
onsite screening visit.  Use of this consent will reduce the occurrence of onsite screening visits 
by subjects ineligible for the study based on medical history.  No study procedures will be 
performed under this preliminary consent.  Informed Consent must be obtained before any study 
related procedures are performed. Screening procedures and randomization will take place within 
an approximate 4-week period prior to first dose administration (Days -28 to -2).   
Subjects who are screen-failed (e.g. due to clinically significant laboratory abnormality or an 
active medical condition) may be re-screened if their medical condition stabilizes or improves as 
assessed by the PI.  Subject who are screen-failed due to MMSE score may be rescreened in 3 
months.  
The Medical Monitor should be consulted prior to re-screening. Subjects who are Screen Failures 
may be rescreened only once. 
The following procedures should be performed first at screening only to avoid unnecessary 
procedures for ineligible subjects:  
• Collection of subject demographic data 
• Review of concomitant medications  
• Review of medical history  


 
 
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• Assessment of neuroimaging (CT or MRI performed within 2 years of screening) 
• Evaluate Rosen-Modified Hachinski Scale 
• Evaluate MMSE-2  
After confirming that these parameters satisfy eligibility criteria, the remaining 
screening procedures should be performed; 
• SIB. The SIB should be done within 3 weeks before the first study drug dose. If 
the screening period exceeds 3 weeks, the SIB should be repeated on the day of 
the first dose, prior to dosing. The repeat SIB score obtained closest to the day of 
dosing should be recorded in the eCRF as an unscheduled visit. 
• NPI 
• ADSC-ADL-SIV 
• Columbia Suicide Severity Rating Scale (C-SSRS) 
• Blood samples for routine safety including hematology, PT, PTT, INR and 
serum-chemistry, CPK, TSH (T-3 and T-4 if indicated), and β-hCG, if indicated 
• 12-lead ECG (x3) 
• Complete physical examination  
• Vital signs 
• Adverse events and concomitant medications 
If changes in the subject’s health or mental status occur during the screening and 
randomization period, including changes in medication affecting the mental status, the 
Medical Monitor should be notified. The Medical Monitor will advise the PI regarding 
any assessments that should be repeated to ensure eligibility requirements are met. 
Sites will not be able to randomize subjects before confirmation that eligibility criteria 
have been met per the review of the Rosen-Modified Hachinski Scale, MMSE-2, 
CSSRS, and other eligibility criteria by the Worldwide Clinical Trials’ Clinical 
Assessment Technologies (CAT) group and Medical Monitor (MM). 
 
6.1.2 Week 0 (Day 0 Dose 1) 
If the subject has had no intervening medical issues or changes in medications between 
the date of randomization and Week 0, dosing may proceed as scheduled.  
A final assessment of the inclusion/exclusion criteria, including any changes in medications or 
health status will be done before dosing to confirm the subject’s eligibility.   
 The following procedures will be done on Day 0: 
• Dosing by IV infusion will be done according to the procedures outlined in Section 5.7. 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 


 
 
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• Adverse events and concomitant medications  
6.1.3 Week 1 (Day 7 ±2 days Dose 2)  
One week after the first dose of study drug, subjects will return for a second infusion.  The 
following procedures will be performed: 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• AEs and concomitant medications 
6.1.4 Week 2 (Day 14 ±2 days/ No dose) 
• 
C-SSRS 
• 
Blood samples for routine safety  
• 
12-lead ECG  
• 
Vital signs  
• 
Adverse events and concomitant medications  
6.1.5 Week 3 (Day 21 ±2 days/ Dose 3)  
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• 
Dosing by IV infusion 
• 
Adverse events and concomitant medications  
6.1.6 Week 5 (Day 35 ±2 days/ Dose 4) 
• Prior to dosing:  
o SIB  
o MMSE-2 
o ADCS-ADL-Sev 
o NPI 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 


 
 
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6.1.7 Week 7 (Day 49 ±2 days/ Dose 5) 
• Prior to dosing: 
o C-SSRS 
o Blood samples for routine safety  
o 12-lead ECG 
o Abbreviated Physical exam 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
6.1.8 Week 9 (Day 63 ±2 days/ Dose 6) 
• Prior to dosing:  
o SIB  
o MMSE-2 
o ADCS-ADL-Sev 
o NPI 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
6.1.9 Week 11 (Day 77±2 days/ Dose 7)  
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
6.1.10 Week 13 (Day 91 ±2 days) 
At Week 13, subjects will undergo efficacy assessments as well as routine safety assessments.  
The following will be performed: 
• SIB  


 
 
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• MMSE-2 
• ADCS-ADL-Sev 
• NPI 
• CSSRS 
• Blood samples for routine safety  
• 12-lead ECG 
• PE 
• Vital signs  
• Adverse events and concomitant medications 
6.1.11 Week 15 ( Day 105 ±2 days Dose 8) 
The following will be performed: 
• Prior to dosing:  
o SIB 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
 
6.1.12 Week 16 ( Day 112 ±2 days Dose 9) 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
6.1.13 Week 18 (Day 126 ±2 days Dose 10) 
• Prior to dosing: 
o C-SSRS 


 
 
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o Blood samples for routine safety  
o 12-lead ECG 
o Abbreviated Physical exam 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
 
6.1.14 Week 20 (Day 140 ±2 days Dose 11) 
• Prior to dosing:  
o SIB  
o MMSE-2 
o ADCS-ADL-Sev 
o NPI 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
 
6.1.15 Week 22 (Day 154 ±2 days Dose 12) 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
 
6.1.16 Week 24 (Day 168 ±2 days Dose 13) 
• Prior to dosing:  
o SIB  
o MMSE-2 


 
 
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o ADCS-ADL-Sev 
o NPI 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
 
6.1.17 Week 26 (Day 182 ±2 days Dose 14) 
• Prior to dosing: 
o C-SSRS 
o Blood samples for routine safety  
o 12-lead ECG 
o Abbreviated Physical exam 
• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Adverse events and concomitant medications 
 
6.1.18 Week 28 (Day 196 ±2 days) 
• SIB  
• MMSE-2 
• ADCS-ADL-Sev 
• NPI 
• Vital signs  
• Adverse events and concomitant medications  
 
6.1.19 Week 30 (Day 210 ±2 days) 
• SIB 


 
 
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• Vital signs 
• Adverse events and concomitant medications  
 
6.1.20 Early Termination  
• SIB  
• MMSE-2 
• ADCS-ADL-Sev 
• NPI 
• CSSRS 
• Blood samples for routine safety  
• PE 
• Vital signs  
• Adverse events and concomitant medications 
6.1.21 Follow-up Visits 
• SIB  
• Vital signs  
• Adverse events and concomitant medications 
6.1.22 Early Treatment Discontinuation and Follow-up 
 
If for any reason, the investigator, subject or caregiver decide to discontinue the study drug or 
withdraw consent from the study, the subject and caregiver should be encouraged to complete an 
early termination (ET) visit and follow-up visit(s) as below: 
• ET visit: 
o If the subject is withdrawn from the study at or before Week 13, subject will not enter 
Treatment Period 2. 
o If possible, schedule ET visits for 30 days (+/-2 days) after the last study drug dose 
administration 
o The ET reason must be documented with as much detail as possible in the EDC and 
in the source documents.  


 
 
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• Follow-up Visits: Despite discontinuation of the study drug dosing, subjects and caregivers 
should be encouraged to return for additional follow-up visits for the duration of the trial, in 
order to monitor for safety and any changes in cognition.   
o The follow-up visits should be scheduled to coincide with the cognitive assessment 
visits scheduled after the study drug discontinuation (i.e., weeks 5, 9, 13, 15, 20, 24, 
28, 30). 
o The below assessments should be completed at all follow-up visits: 
 SIB 
 Vitals 
 Adverse Events 
 Concomitant medications 
o If the subject is willing to return for only one follow-up visit, please schedule this 
visit to occur approximately 30 days (+/-2 days) following the last study drug dosing.  
 
6.2 
Concomitant Medications  
During the screening visit, the Caregiver will provide a history of prior medication use during the 
past 6 months and provide a list of currently used medications.  All concomitant medications 
used should be recorded on the eCRF and in the source documents using the generic name for 
the drug.  Assessment of concomitant medications will take place at each study visit.  Any 
changes to chronic medications should be noted as well as new and discontinued medications.  
Subjects taking allowed antidepressant medications may be enrolled in the study (see Appendix 
1).  The dose and dose regimen for these medications should be stabilized for at least 30 days 
prior to enrollment in the study.  Every effort should be made to keep the dose and dose regimen 
of antidepressant medications stable throughout the study. 
6.2.1 Medications for AD 
Subjects taking FDA approved medications for the treatment of AD, with the exception of 
memantine or any drug containing memantine, may be enrolled in the study.  The subject 
must be on a stable dose of permitted medications for at least 3 months prior to entry into the 
study and dose must not change during the study.  Subjects may not initiate additional drugs for 
treatment of AD during the study other than the study drug.  
6.2.2 Concomitant Medications for Management of Myalgia 
Non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen sodium are permitted.  
Use of acetaminophen as an analgesic is contraindicated as it has the ability to inhibit PKC 
activation. 
6.2.3 Prohibited Medications  
Memantine is prohibited.  Subjects previously treated with memantine must stop treatment at 
least 90 days prior to initiation of study drug treatment.  Treatment with other NMDA receptor 
antagonists such as but not limited to dextromethorphan (a cough suppressant), ketamine, 


 
 
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phencyclidine (PCP), methoxetamine (MXE), nitrous oxide (N2O) and the following synthetic 
opioids: penthidine, levorphanol, methadone, dextropropoxyphene, tramadol, and ketobemidone 
is prohibited and a 30-day washout period is required prior to initiation of study drug treatment.   
High dose Vitamin E (> 400 IU / day), Valproic Acid and divalproex sodium are prohibited. 
Gabapentin is prohibited. 
If the PI determines that initiation of any of the prohibited medications is required to ensure the 
subject’s safety, the medication may be initiated with the notification of the Medical Monitor 
and proper documentation of a protocol deviation.  Other restricted concomitant medications are 
listed in Appendix 1. 
 
7 ADVERSE EVENTS AND OTHER SAFETY EVALUATIONS 
7.0 
Definition of Adverse Events 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related.  An AE (also referred to as an adverse experience) can be any 
unfavorable and unintended sign (e.g., clinically significant abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a drug, without any judgment about 
causality.   
The PI is responsible for obtaining information about all medical emergencies during the clinical 
study. The PI’s contact information will be located in the body of the informed consent form 
(ICF) and subjects/caregivers will be encouraged to contact the PI or clinical site personnel 
during any clinical study-related emergency. 
All adverse events spontaneously reported by the subject and/or caregiver in response to an open 
question or revealed by observation will be recorded during the study regardless of relationship 
to the study drug.  All AEs will be monitored and recorded for the progress of the event until it 
resolves or reaches a clinically stable outcome.  Adverse events that are not resolved at the time 
of database lock will be recorded as ongoing.  
The AE and SAE reporting period starts from the time of consent to the last study visit.   
7.1 
Adverse Event of Special Interest - Myalgia  
Myalgia has been reported as the dose limiting toxicity across the oncology studies.  The 
incidence of myalgia appears to be dose dependent and cumulative.  However, it has been 
reported in subjects receiving doses as low as 5μg/m2.  The myalgia has been investigated in 
some studies but not all.  No increase in muscle enzymes were found in the cases investigated.  
EMG was abnormal in one subject who received 65µg/m2 and suggested a patchy myositis. An 
MRI done in another subject was normal.  


 
 
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For all cases of myalgia despite the severity, a narrative will be created documenting onset, 
severity, treatment and outcome.  Muscle enzymes, CPK, will be collected for all cases and 
compared to baseline values.  Additional investigations are at the discretion of the investigator.  
7.2 
Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence that fulfills any of the following criteria: 
• Results in death (fatal) 
• Is life threatening (an event is considered “life threatening” if, in the view of either 
the investigator or sponsor, its occurrence placed the subject at immediate risk of 
death.  It does not include an AE that, had it occurred in a more severe form, might 
have caused death).  
• Requires in-patient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
or 
• Is an important medical event (events that may not result in death, be immediately life 
threatening or require hospitalization; may be considered serious when based upon 
appropriate medical judgment, they jeopardize the subject and may require medical or 
surgical intervention to prevent any of the outcomes listed above.  Examples include; 
allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, convulsions that do not result in hospitalization, or the development of drug 
dependency or drug abuse.   
The following situations may not, by themselves, constitute sufficient grounds to be considered 
as an SAE:  
• Hospitalization solely for a diagnostic purpose, even if related to an AE,  
• Elective hospitalization for an intervention planned before the subject enrollment in 
the study  
• Admission to a day care facility or sleeping laboratory 
7.3 
Assessment of Intensity 
Severity is a clinical determination of the intensity of an AE and will be determined by the PI 
based on the following classification criteria for all AEs occurring during the clinical study: 
Mild - Awareness of signs or symptom, but easily tolerated, may require additional therapy 
Moderate - Discomfort, enough to cause interference with usual activity and to require 
intervention or additional therapies 
Severe - Incapacitating with inability to work or perform usual activity 


 
 
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Note: It should be noted that a severe AE need not be serious in nature and that an SAE is not, by 
definition, severe.  Regardless of intensity, all SAEs and significant events must be reported. 
7.4 
Relationship to Study Drug 
The causal relationship between the investigational drug and each AE will be determined by the 
PI based on his/her medical judgment in consideration of all relevant factors, including pattern of 
reaction, temporal relationship, positive, concomitant medication, co-existing diseases, and 
relevant medical history.  The PI will classify every AE according to its relationship to study 
drug or trial-related procedures.  The categories according to World Health Organization 
guidelines are listed in the following Table 
 
7.5 
Table 2 Relationship of AE to Study Drug or Trial-Related Procedures 
Rating 
Classification Definition 
1 
Probable 
An AE that: 
• 
Occurs at a reasonable time interval after administration 
of the study drug;  
• 
Follows a known response pattern to the study drug and; 
• 
Cannot be reasonably explained by the known 
characteristics of the subject’s clinical state or by other 
therapies. 
2 
Possible 
An AE that: 
• Occurs at a reasonable time interval after administration 
of the study drug;  
• Follows a known response pattern to the study drug, but; 
• Could have been produced by the subject’s clinical state 
or by other therapies. 
•  
3 
Unlikely* 
• An AE for which sufficient information exists to indicate 
that the etiology is unrelated to the study drug; 
• Another etiology is specified. 
*If the AE is classified as unlikely, the PI should provide a likely cause, other illness, 
concomitant medication, or other. 
7.5.1 Unexpected Adverse Event 
An AE is considered “unexpected” if it is not listed in the Investigator’s Brochure (IB) or is not 
listed at the specificity or severity that has been observed.  Unexpected refers to AEs that are 
mentioned in the IB as occurring with a class of drugs or as anticipated from the pharmacological 
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under investigation.  However, an event that is more specific or more severe than described in 
the IB will be considered unexpected. 
7.6 
Reporting Adverse Events 
The PI should instruct all subjects/caregivers on the procedure for reporting AEs/SAEs to the 
appropriate clinical site personnel.  For each AE reported by parents/guardians, clinical site 
personnel should obtain all required information to complete the eCRF.  
The PI or designee should document all AEs/SAEs in subjects’ source documentation and on the 
AE eCRF. 
In addition to standardized reporting procedures, worsening or exacerbation of concurrent 
conditions in subjects will also be reported as AEs, and will follow the designated reporting 
format. 
The following should be recorded with each SAE/AE: 
• The nature of the AE, with a diagnosis wherever possible 
• Date of event 
• Assessment of intensity 
• Is this an SAE? 
• Relationship to study drug or trial-related procedures 
• Action taken regarding study drug treatment 
• Outcome 
If the intensity of an already reported AE increases, then a new AE eCRF must be completed for 
that AE. The date of change would be included as the end date for the originally reported AE, 
and the start date for the new AE of greater intensity.  
The clinical research associate is responsible for source document verification of all safety 
events. 
If the clinical site becomes aware of an SAE, regardless of causality, within 30 days following 
the last administration of investigational product, the SAE should be recorded and reported 
immediately to the Sponsor.  An SAE that occurs more than 30 days after the last dose will NOT 
be collected unless the PI considers that the event is related to the investigational product. 
The sponsor should be informed if the PI becomes aware of any unusual safety information or 
any potential drug-related safety information, even after a subject completes the study 
7.6.1 SAE reports 
All SAEs, whether or not considered associated with study treatment or study-related procedures, 
must be reported on the eCRF immediately and no later than 24 hours after the site becomes 
aware of the event.  Follow-up information must be provided promptly as requested.   


 
 
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The PI is obligated to provide as much information about the event as possible on the eCRF 
provided and as requested by the Sponsor or Medical Monitor.  
In general, this will include a description of the SAE in sufficient detail to allow for a complete 
medical assessment of the case.  The pharmacovigilance physician or designee will review the 
SAE including the SAE criteria, the relationship to study medication, the expected or unexpected 
assessment, and inform the Sponsor by phone and e-mail immediately. 
The following AEs should also be reported to the Sponsor’s designated Medical Monitor 
immediately:  
• severe injection/infusion site reactions (ulceration or necrosis that is severe; operative 
intervention indicated) 
• systemic hypersensitivity reactions 
• myalgia  
All additional follow-up evaluations must be reported by the site to the medical monitor, or 
designee, immediately after notification of the additional information.   
An SAE will be followed until it resolves or reaches a clinically stable outcome.  AEs/SAEs that 
have not resolved by study closure will be considered ongoing. 
An SAE that occurs after the 30-day safety visit will NOT be collected unless the PI determines 
that the event is related to the investigational drug product. 
7.6.2 Reporting to Regulatory Authorities 
The PI, or designee, is responsible for informing the Institutional Review Board (IRB) of any 
unexpected SAEs, as well as any additional SAEs according to the IRB’s policy. 
Any SAE that is serious, suspected to be related to investigational study drug and unexpected 
(SUSAR), will be promptly reported to regulatory authorities by the Sponsor according to 
expedited reporting requirements.  Subsequent relevant information after the initial submission 
of the (IND) Safety Report to the regulatory authorities will be submitted in a follow-up IND 
Safety Report to the regulatory authorities in the expedited period by the Sponsor. 
7.7 
Criteria for Withdrawal of Subjects 
Subjects may be withdrawn from the clinical study for the following reasons: 
• The PI believes withdrawal to be medically necessary or in the best interest of the 
subject 
• Noncompliance with the protocol as judged by the PI (requires discussion with the 
Sponsor)  
• Subjects who are enrolled in violation of inclusion and/or exclusion criteria   
• An AE that presents an unacceptable consequence or risk to the subject as judged by 
the PI, Sponsor or the Medical Monitor 
• Lost to follow up 
• Withdrawal of consent 


 
 
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• Subject is unblinded 
 
Subjects may voluntarily discontinue their participation in the study at any time without 
prejudice to further treatment.  
7.8 
Criteria for Permanent Discontinuation of Study Drug 
Study drug treatment may be discontinued for the following reasons: 
• if sponsor or regulatory authorities discontinue study 
• if the PI believes that discontinuing treatment is in the best interest of the subject 
7.9 
Study Discontinuation 
Synaptogenix has the right to discontinue this clinical study at any time. The PI has the right to 
discontinue participation in this clinical study at any time for any reason.  Clinical study site 
discontinuation should only occur after mutual consultation between the PI and Synaptogenix. 
Should the clinical study be discontinued prematurely, all subjects should be brought in for early 
termination procedures as outlined for the 30-day Follow-up visit.  All clinical study materials 
should be returned to Synaptogenix or designee. 
  
8 SAFETY MONITORING 
A Data Safety Monitoring Board (DSMB) will provide consultation to Synaptogenix to assess 
the implementation and progress of study NTRP101-204 and will review accumulating trial data 
to monitor the safety of bryostatin administered to patients with AD. Safety data will be 
reviewed when 30 subjects have received four doses of study drug, followed by additional safety 
analyses when 60 subjects have received a similar number of doses. Medical decisions relevant 
to this study will be made by the Sponsor in consultation with the Primary Investigator, Medical 
Monitor and Statistician. 
Prior to each safety review, a cut-off date for the data to be provided will be established by the 
Sponsor in consultation with the WCT Supporting Biostatistician.  The format and content of 
data listings will be approved by the Supporting Biostatistician.  Data reports will be provided as 
partially blinded displays (e.g., data is grouped by unblinded treatment using "Group A, B” to 
indicate treatment).  The identity of each group will be available to the safety reviewer via the 
Supporting Statistician. 
Data review documents, safety data tables and listings, will be provided to the DSMB at least 7 
business days prior to scheduled reviews. Serious Adverse Events (SAEs) reported during the 7 
days before the scheduled review and therefore not included in the provided documentation will 
be provided by the WCT Drug Safety Manager as soon as possible before the review date. The 
reviews of the safety data will be summarized for the overall subject group only and will not be 
separated by treatment groups.  


 
 
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9 DATA ANALYSIS / STATISTICAL METHODS 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP).  This separate document will be finalized 
prior to study unblinding and conduct of any statistical analyses.  The SAP may modify and will 
take precedence over the plans outlined in the protocol; however, any major modifications or 
modification of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment. 
The primary efficacy outcome will be the difference in SIB total score from baseline at Week 28 
between treatment arms, after two12-week courses of the study drug have been given.   
9.0 
Sample Size Determination  
The power analysis for the current study is based on a minimum clinically significant difference 
in mean total SIB scores from baseline of 4 points between the placebo and bryostatin arms at 
Week 28. Since the analysis of this primary outcome is based on a linear regression model that 
utilizes the total SIB scores at Weeks 0, 5, 9, 13, 15, 20, 24, and 28, a difference of 
approximately 1.5 points per week in the slope of total SIB scores between the placebo and 
bryostatin arms yields the clinically meaningful difference of 4 points at Week 28. As these 
measures of total SIB scores are correlated within individual, methods of GEE will be used to 
estimate the regression parameters of the linear regression model of total SIB score regressed on 
time. GEE power analysis is based on the following equation: 
 
 
 
 
𝑚𝑚= 
2൫𝑧𝑧𝑎𝑎/2+𝑧𝑧𝑏𝑏൯
2𝜎𝜎2(1−𝜌𝜌)
𝑛𝑛𝑠𝑠𝑥𝑥2𝑑𝑑2
  
 
 
 
 
 
 
 
 
 
 
 
Eq 1 
In equation 1, m is the number of patients per group, 𝑧𝑧𝑎𝑎/2is the type I error rate, 𝑧𝑧𝑏𝑏is the type II 
error rate, σ is the standard deviations of the error (residual) terms, ρ is the within person 
correlation of total SIB scores over time within a person, n is the time points where the total SIB 
score is obtained, 𝑠𝑠𝑥𝑥
2is the variance of the X predictor variable (i.e. time in the current scenario), 
and d is the difference in slopes over time in total SIB measures from baseline between the 
placebo and bryostatin arms.17 
Based on the data from the NTRP101-202 study among patients without memantine, we obtained 
an estimate for σ = 5.3. In addition, the NTRP101-204 study will have SIB total scores measured 
at n = 8 timepoints, giving a value of  𝑠𝑠𝑥𝑥
2 = 127. Assuming a total of 100 patients (50 patients per 
arm), a two-sided type I error rate of 0.05 (i.e. 𝑧𝑧𝑎𝑎/2 = 1.96), and moderate within person correlation 
of outcome measures (i.e. ρ = 0.5), we will have > 99% power to see a difference in slopes over 
time of d = 0.15 points per week. In addition, we will have > 99% power to see this difference if 
we experience a 20% drop out. 
9.1 
Statistical Methods 
The Safety Analysis Set (SAS) is defined as all randomized subjects who received any study 
medication (either partial or completed infusions of bryostatin or placebo).  


 
 
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The Full Analysis Set (FAS), consistent with the modified intention-to-treat (mITT) principles, is 
defined as all randomized subjects who received at least one dose of study medication and who 
have at least one post-baseline efficacy assessment. 
 
The Per Protocol Analysis Set (PP) is defined as all patients completing the study without major 
protocol deviations. To be included, subjects must have received at least 11 of the14 doses 
(80%). 
 
The Completer Analysis Set (CAS) is defined as all randomized subjects who completed two 
courses of treatment, and who have a week 28 SIB assessment.  
Demographics data collected will include age, sex, race, ethnicity, height, and body weight and 
will be summarized by treatment group using descriptive statistics for both the SAS and FAS 
populations. 
Medical history, neuroimaging, prior and concomitant medications, existing disease, years since 
AD onset and diagnosis, baseline medical conditions, and baseline safety and 
neuropsychological assessments will be summarized descriptively by treatment group for both 
the SAS and FAS populations. 
Subject disposition will be summarized by treatment group and will include numbers screened, 
randomized, dosed and withdrawn with reason for withdrawal.  
9.2 
Exploratory Analysis 
Descriptive statistics by visit and randomized treatment group will be provided for all efficacy 
data. These descriptive statistics will include the mean, median, SD, maximum and minimum for 
continuous variables, and frequencies, percentage, and tabulations for categorical variables. 
Summary statistics will also be performed on both the patient demographics and patient clinical 
characteristics. Exploratory plots of the data will also be created, including box plots and 
histograms, in order to determine the distribution of these data as well as to identify any unusual 
or outlying observations.   
 
9.3 
Safety Analysis 
The SAS population will be used for all safety analyses with treatment group determined by the 
treatment actually received.  AEs, safety laboratory, ECGs, physical exam and vital signs data 
will be presented in tabular format and summarized descriptively by treatment group.  No formal 
hypothesis testing will be carried out on these safety assessments.  Incidence and severity of AEs 
will be summarized by treatment dose using System Organ Class (SOC).  AEs will be coded 
according to standard MedDRA terms.  
C-SSRS responses will be mapped onto the Columbia-Classification Algorithm of Suicide 
Assessment (C-CASA) scale, and the frequency distribution of the C-CASA scores will be 
tabulated by treatment group and study visit.  No hypotheses associated with the C-SSRS or C-
CASA scales will be tested. 


 
 
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9.4 
Analysis of Primary Efficacy Endpoint 
The treatment difference in the primary efficacy endpoint of total SIB scores from baseline at 
Week 28 will be determined from a regression model that utilize SIB values taken at Weeks 0, 5, 
9, 13, 15, 20, 24, 28 and 30. As SIB is a continuous outcome measure, a regression model will be 
used to estimate the treatment difference in mean SIB from baseline at Week 28. Both linear and 
non-linear terms will be considered in these regression models. Since correlation of SIB 
measures over time within a patient will be present, regression coefficients will be estimated 
using the generalized estimating equations (GEE) methodology.18 GEE regression models are 
used to appropriately estimate the population average effects from a sample of individuals when 
the correlations of SIB measures within individuals are unknown. The GEE method accounts for 
the correlation structure in the model. However, the estimates of model coefficients and their 
standard errors models are unbiased even if the working correlation model is incorrectly 
specified. The primary analysis will be conducted on FAS population. The PP and CAS 
populations will be used as supportive analyses.  All statistical tests for efficacy will be two-
sided tests, with α=0.05. 
   
Based on the review of patients not treated with memantine in the NTRP 101-203 clinical trial, 
the expected number of patients who will drop out of the study prematurely will not be 
significant.  However, missingness will be accounted for using weighted GEE methods.19 The 
GEE regression models will be carried out in SAS/STAT PROC GEE version 13.2. This SAS 
procedure will allow for implementation of weighted GEE methodology that can account for 
data missing a random. One additional patient may be randomized for each patient who 
discontinues the study prior to the primary endpoint (Week 28, Day 196).  
 
9.5 
Secondary Efficacy Endpoints 
Multiple comparisons arising from the listed secondary outcomes will be controlled by using the 
false discovery rate. This procedure will allow control of the type I error rate over the set of 
secondary outcomes that is less stringent then controlling for multiple comparisons using a 
familywise error rate (e.g. Bonferroni correction). 
9.5.1 SIB total score from baseline at the Week 42 follow-up visit  
Treatment differences in SIB total score from baseline at Week 42, for subjects who completed 
that visit, will be estimated using an ANCOVA model that will adjust for baseline SIB total 
scores, baseline MMSE-2 scores, age, and gender.  
9.5.2 SIB total score from baseline at Week 13 
An ANCOVA model as described in Section 9.5.1 will be created to estimate the difference in 
SIB total scores at Week 13. Again, as with the SIB difference at Week 42.  The ANCOVA 
model will adjust for baseline SIB, baseline MMSE-2 scores, age, and gender.  
 


 
 
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9.5.3 SIB total scores from baseline at Weeks 9, 20, 24 and 30 
The linear regression models using the method of GEE as described in Sections 9.4 and 9.5.2 
will be used to estimate the treatment difference in mean SIB total scores from the original 
baseline (i.e. at screening) at Weeks 9, 20, 24 and 30. As described in Section 9.4, weighted GEE 
will be used to account for data that are missing at random. 
9.5.4 SIB total scores from baseline at Weeks 5, 9, 15, 20, and 24 for subjects with 
baseline MMSE-2 scores of 10-14 and 15-18 
The estimation of the treatment differences at Weeks 9, 20, 24 and 30 for patients within each 
MMSE-2 group will be based on GEE linear regression model utilizing SIB total scores from 
baseline at these five time points. As described in Section 9.4, weighted GEE will be used to 
account for data that are missing at random. 
9.5.5 Individual patient’s SIB trends over time 
For the secondary endpoint of SIB trends over time, individual-specific slopes of total SIB scores 
will be obtained for all patients. These slopes will be estimated by using SIB data at Week 0, 5, 9, 
13, 15, 20, 24, and 28. An overall population averaged slope will then be estimated for each 
treatment arm, and standard inference methods will be used to test if the mean treatment-specific 
slopes are 1) statistically different from 0, and 2) statistically different from each other.  Both 
slopes will be considered using absolute SIB total scores as well as SIB total scores from baseline 
over Weeks 0 to 28.  
   
9.6 
Analysis of Exploratory Endpoints  
The following exploratory endpoints will be analyzed:  
• Change from baseline in ADCS-ADL-Sev total score at Week 13 and Week 42, for 
subjects who completed week 42 
• Change from baseline in MMSE-2 total score at Week 13 and Week 42, for subjects who 
completed week 42 
Change from baseline in NPI total score at Week 13 and Week 42, for subjects who 
completed week 42 
Similar analysis methods that incorporate the method of GEE as described under the analyses for 
the primary and secondary endpoints will be used for analysis of the exploratory endpoints. 
 
9.7 
Safety Assessments 
Unblinded summaries and listings of safety data will be provided to the Data Safety Monitoring 
Board, as described in Section 8. Analyses will be performed by an independent unblinded 
statistician so that study investigators and other sponsor personnel (and contractors) involved in 
study monitoring, data processing and other aspects of the study remain blinded.   


 
 
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9.8 
Analysis of Safety Data 
For continuous variables, data will be summarized by treatment using n, mean, SD, minimum 
and maximum values. For categorical variables, data will be summarized by treatment using 
frequency and percentage.  
 
9.8.1 Adverse Events 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA). Treatment Emergent AE’s (TEAE) are defined as events with an onset on 
or after the first randomized treatment. TEAEs will be summarized by treatment group, System 
Organ Class, and preferred term. The following TEAE summaries will be provided: 
• Overall (i.e., regardless of severity or relationship to treatment) 
• By severity grade (mild, moderate, severe, life threatening or death for SAEs) 
• By relationship to clinical trial treatment (definitely related, probably related, possibly 
related, unlikely related, unrelated)    
Unless otherwise specified, at each level of subject summarization, a subject will be counted 
only once.  If there is more than one occurrence of an event, the event of the worst severity or the 
worst-case relationship category will be summarized. 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
AEs leading to premature discontinuation of clinical trial treatment, AEs that lead to study 
discontinuation, AEs that lead to death and Serious Adverse Events (SAEs) will also be 
summarized by treatment group and relationship.   
9.8.2 Clinical Laboratory Evaluations 
All available results of the clinical laboratory evaluations will be listed and summarized as 
follows:   
9.8.2.1 Laboratory Values over Time  
Summary statistics of raw data and change from baseline values for each laboratory parameter 
will be presented by treatment group and time point. Data will be summarized as appropriate for 
the variable type. 
• For continuous data, summaries will include the number of observations, mean, SD, 
median, minimum, and maximum values. 
• For categorical data, frequency counts and percentages will be used. 


 
 
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For change from baseline summaries, subjects with an undefined change from baseline, because 
of missing data, will be excluded. 
9.8.2.2 Individual Subject Changes (Shift Tables) 
Individual subject changes will be identified through shift tables. Shift tables will be presented 
for each laboratory parameter with counts and percentages of subjects, by treatment group and 
time point, for shift (change) from baseline, using the normal ranges from the laboratory. 
9.8.2.3 Individual Clinically Significant Abnormalities 
Clinically significant laboratory abnormalities (i.e., those laboratory abnormalities recorded as 
AEs) will be listed. 
All results of laboratory evaluations will be presented as by-subject listings. 
 
9.8.3 Physical Examination  
All physical examination findings will be listed and/or summarized by treatment group.  Shift 
tables will also be presented to show any abnormality shifts from baseline to post baseline visits. 
9.8.4 Vital Signs  
Tabulations of raw data and change from baseline values will be presented by time point for each 
vital sign parameter.   
Tabulations will include the number of observations, mean, standard deviation, median, and 
minimum and maximum values.  For change from baseline summaries, subjects with an 
undefined change from baseline, because of missing data, will be excluded.    
9.8.5 ECG 
All ECG findings will be listed and/or summarized. Shift tables will also be presented to show 
any abnormality shifts from baseline to post baseline visits. 
9.8.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
All data from C-SSRS will be listed. Descriptive summaries will be presented for each of the 
subscales (i.e. Suicidal Ideation and Suicidal Behavior). 
10 DATA MONITORING  
10.0 
 Source Documentation 
In accordance with ICH-GCP guidelines, source documents may include, but are not limited to 
the following: 


 
 
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• Clinic, office, hospital charts 
• Copies of transcribed health care provider notes, which have been certified for 
accuracy after production 
• Recorded data from automated instruments such as x-rays and other imaging reports, 
sonograms, computed axial tomography scans, magnetic resonance images, 
radioactive images, electrocardiograms, electroencephalograms 
• Records of telephone contacts 
• Diaries, evaluation checklists, or questionnaires that are completed directly by 
subjects or caregivers and serve as their own source 
• Laboratory results and other laboratory test results 
• Correspondence regarding a subject’s treatment between physicians or memoranda 
sent to the IRB.   
10.1 
 Study Documentation and Record Retention 
The PI, or designees, must enter all results collected during the clinical study into eCRFs.  eCRF 
completion guidelines will be reviewed with clinical site personnel at the PI’s Meeting and site 
initiation visits.  PIs are responsible for approval of all entered or corrected data.  The PI, or 
designees, must review and approve the data before database lock, or before any scheduled 
interim analyses, as required by the sponsor. 
The medical records (source documents) upon which the eCRFs are based must be kept at the 
clinical site for at least a period of 2 years following the date a marketing application is approved 
for the drug for the indication for which it is being investigated; or, if no application is to be filed 
or if the application is not approved for such indication, until 2 years after the investigation is 
discontinued and the FDA is notified.  Synaptogenix must be informed if the records are passed 
on to any other person or institution during this period.  Records related to the study will be 
maintained by Synaptogenix or its designee for a minimum of 5 years per 21 Code of Federal 
Regulations (CFR) 58.195 (b) 2.  
10.2 
 Site Monitoring 
The Sponsor or its designee will be allowed to conduct site visits at the investigation facilities to 
monitor any aspect of the study.  The PI will provide Synaptogenix, or its designee, with 
documentation of IRB approval of the Study Protocol and the Informed Consent prior to study 
initiation and IRB approval of any subsequent amendments to the protocol or revision to the 
Informed Consent.  Before a study site can enter a subject into the study, the Sponsor or a 
designee will: 
• Determine the adequacy of the facilities 
• Discuss with the PI(s) and other personnel their responsibilities with regard to protocol 
adherence, and the responsibilities of Synaptogenix or its representatives.  This will be 
documented in a clinical study agreement between Synaptogenix and the PI. 


 
 
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During the study, a monitor from Synaptogenix or representative will have regular contacts with 
the investigational site, for the following: 
• Provide information and support to the PI(s) 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that investigational product accountability checks 
are being performed 
• Perform source data verification.  This includes a comparison of the data in the eCRFs 
with the subject’s medical records at the hospital or practice, and other records relevant to 
the study.  This will require direct access to all original records for each subject (e.g. 
clinic charts). 
• Record and report any protocol deviations not previously sent to Synaptogenix 
• Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been reported and those SAEs that met criteria for reporting have been forwarded to 
the EC/IRB/ Independent Ethics Committee (IEC). 
• The monitor will be responsible for immediately reporting any site not adhering to the 
study protocol to the project manager and Sponsor. Noncompliance may result in site 
suspension or closure.  
The monitor will be available between visits if the PI(s) or other staff needs information or 
advice.  
10.3 
 Quality Assurance and Quality Control 
To ensure compliance with GCP and all applicable regulatory requirements, Synaptogenix, Inc. 
or its representative may conduct a quality assurance audit. 
10.4 
 Audits and Inspections 
Authorized representatives of Synaptogenix, a regulatory authority or an IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of an audit or 
inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines of the International 
Conference on Harmonization, and any applicable regulatory requirements.  The PI should 
contact Synaptogenix immediately if contacted by a regulatory agency about an inspection. 


 
 
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11 ETHICS 
11.0 
 Institutional Review Board  
The PI must obtain IRB approval before initiating any study activities.   
The final study protocol, including the final version of the Informed Consent Forms, must be 
approved in writing by an IRB.  The PI must submit written approval to Synaptogenix or its 
representative, before he or she can enroll any participant into the study. 
The PI is responsible for informing the IRB of any amendment to the protocol in accordance 
with local requirements.  In addition, the IRB must approve all advertising used to recruit 
subjects for the study.  The protocol must be re-approved by the IRB upon receipt of 
amendments and annually, as local regulations require. 
The PI is also responsible for providing the IRB with reports of any reportable serious adverse 
drug reactions from this or any other study conducted with the investigational product.  
Synaptogenix, will provide this information to the PI. 
In addition to SAEs that are suspected unexpected serious adverse reactions (SUSARs), the PI or 
designee will report any additional SAEs that may be required according to the IRB policy. 
Progress reports will be provided to the IRB according to local regulations and guidelines. 
11.1 
 Ethical Conduct of the Study 
The conduct of this study will be consistent with ICH Guidance E6, GCP, and U.S. federal 
regulatory requirements, as applicable.  This study will be conducted in accordance with 
applicable local law(s) and regulation(s) and the principles of protection of healthy human 
subjects participating in clinical medical research that have their origin in the Declaration of 
Helsinki. The PI must agree to the direct access to source documents and inspection of clinical 
study-related records by the regulatory authority/Synaptogenix representatives. 
11.2 
 Written Informed Consent 
Written informed consent must be obtained from caregiver and subject (if possible) or legally 
acceptable representative if different from caregiver.  A pre-screening consent, allowing access 
to medical records in advance of the on-site screening visit, will be provided for this study.  The 
purpose of this consent, which must be IRB-approved before use, is to avoid unnecessary site 
visits by subjects whose medical history excludes them from eligibility.  The pre-screening 
consent and medical record review is not required but strongly recommended. 
The PI should confirm to the extent possible that the subject has the necessary caregiver support 
and will be able to attend scheduled study visits for the duration of the study.  
Before starting the clinical study, the PI must have the IRB’s written approval or favorable 
opinion of the written ICF and any other written information to be provided to parents or 
guardians of subjects. The written approval of the IRB together with the approved subject’s 


 
 
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information/ICF must be in the clinical study files. The process of obtaining informed consent 
must be in accordance with applicable regulatory requirements and must adhere to ICH E6(R1) 
guidelines and the ethical principles in the Declaration of Helsinki. Written informed consent 
must be obtained and documented before any clinical study-specific procedure takes place. 
Participation in the clinical study and dates of informed consent given by subjects should be 
documented in the subjects’ files. 
 
12 STUDY MANAGEMENT 
12.0 
 Data Collection and Management 
For all written documentation such as source documents, the data collected during the study must 
be legibly printed using a permanent ink pen.  A single line should be drawn through any 
incorrect information.  Opaque correction fluids or tapes are not permitted.  All corrections or 
deletions to any of the source documents must be dated and initialed.  All corrections or 
deletions to the eCRF will be documented via an electronic audit trail.  The PI or designee will 
electronically sign each subject’s final eCRF to signify that all of the information is correct and 
complete. 
12.1 
 Data Quality Control 
Periodic on-site review of communications between the PI and investigational site study 
monitors, and review of eCRF data and source documents are the responsibility of the Sponsor, 
or designee.  The eCRF data for each subject will be reviewed against source documents at the 
study sites by the investigational site study monitor. 
The PI and investigational site will allow study related quality control monitoring and audits, 
EC/IRB/IEC review, and/or regulatory inspection and will cooperate in providing direct access 
to source data and documentation. 
12.2 
 Data Management and Data Storage 
Study procedures will be documented on source documents that will be retained at the site(s).  
An Electronic Data Capture (EDC) system will produce eCRFs that will be used to collect 
assessment data for this study.  All study data entered into the eCRF will be compliant with 
regulatory requirements and 21CFR part 11.  The system will allow differing levels of access and 
will accommodate roles for the PI, Medical Monitor, CRO, and Sponsor.  All data changes made 
within the system will be subjected to an audit trail.  In compliance with GCP, source 
documentation supporting the eCRF data should indicate the subject’s participation in the study 
and should clearly document the dates and details of study procedures, AEs, and subject status.  
The eCRFs will identify study subjects with unique identifiers.  Data are recorded from the 
source documents, directly onto the eCRF at the site.   
Electronic CRF data items will undergo quality control standards of operation.  Unresolved 
errors, omissions, or requests for clarification will trigger a query to the Investigational Site for 
resolution via electronic queries.  The database will be corrected for completeness and accuracy.  


 
 
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Prior and concomitant medications will be entered into the eCRF and coded using the World 
Health Organization Drug Reference List (WHO-DRL).  Medical history, concurrent medical 
conditions, and AEs will be coded using MedDRA. 
A quality assurance audit will be conducted to verify the accuracy and completeness of the 
database and will be done prior to declaring database lock.  The database will not be altered after 
lock, unless joint written agreement is obtained between the CRO and the Sponsor. 
12.3 
 Inspection of Records 
Synaptogenix, Inc., will be allowed to conduct site visits to the investigation facilities for the 
purpose of monitoring any aspect of the study.  The PI agrees to allow the monitor to inspect the 
drug storage area, study drug stock, drug accountability records, subject charts and study source 
documents, and other records relative to study conduct. 
12.4 
 Retention of Records 
A searchable offline version of the eCRF will be forwarded to the Sponsor for storage.  A copy 
of each completed eCRF will remain in the PI’s study file on a compact disk.  All source 
documentation, eCRFs and administrative records will be retained by the PI for a minimum of 
2 years following agency approval of the medication for the indication under study or following 
notification that the investigational application is closed for this indication.  However, this may 
be adjusted based on the applicable local requirements.  After this time, the documentation will 
either be destroyed or transferred to Synaptogenix or designee.  No study documentation should 
be destroyed or moved to a new location without prior written approval by Synaptogenix.  
12.5 
 Confidentiality 
All study findings and documents will be regarded as confidential.  The PIs and members of their 
research teams must not disclose such information without prior written approval from 
Synaptogenix or its representatives. 
The anonymity of participating subjects must be maintained.  A Protected Health Information 
statement will be provided to each subject either as a part of the Informed Consent document or 
as a separate form.  Subjects will be identified on eCRFs and other documents by their initials, 
birth date, and subject number.  Documents that identify the subject by name (e.g., the signed 
Informed Consent Form) must be maintained in strict confidence by the PIs. 
12.6 
 Protocol Amendments 
Minimally, any change that significantly affects the safety of subjects, the scope of the 
investigation, or the scientific quality of the study will be effected by means of a protocol 
amendment approved by the Sponsor.  Any changes that affect subject safety or welfare must be 
submitted to the relevant IRB and approved before implementation.  
The PI will provide written agreement of the protocol amendment via the approval signature 
page.  The PI will notify the IRB of the amendment and obtain approval prior to implementation.  


 
 
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If the change is intended to eliminate an immediate hazard, the amendment will be implemented 
immediately, prior to IRB notification.  
12.7 
 Protocol Deviations 
Should a deviation from the protocol be deemed crucial for the safety and well-being of a 
particular subject, such a deviation will be instituted for that subject only.  The PI or other 
attending physician should contact the Medical Monitor as soon as possible.  In addition, the PI 
or designee should document in the source document the reasons for the protocol deviation and 
the ensuing events. No protocol deviations for any Inclusion or Exclusion criterion will be 
permitted in this study. 
12.8 
 Data Corrections 
For all written documentation such as source documents, the data collected during the study must 
be legibly printed using a permanent ink pen.  A single line should be drawn through any 
incorrect information.  Opaque correction fluids or tapes are not permitted.  All corrections or 
deletions to any of the source documents must be dated and initialed.  All corrections or 
deletions to the eCRF will be documented via an electronic audit trail.  The PI will electronically 
sign each subject’s final eCRF to signify that all of the information is correct and complete. 
12.9 
 Insurance 
The Sponsor has taken out a liability insurance policy, which covers the liability of PIs.  This 
policy is in accordance with local laws and requirements.  
The Sponsor’s insurance does not relieve the PI or the collaborators of any obligation to maintain 
their own liability insurance policy as required by the applicable law. 
13 PUBLICATION AND DISCLOSURE POLICY 
Study findings are an integral part of the overall commercialization plan for this investigational 
compound. To this end, the contents of this protocol and any amendments and results obtained 
during the study shall be kept confidential by the investigator, the investigator’s staff, and the 
IRB/IEC, and shall not be disclosed in whole or in part to others, or used for any purpose other 
than reviewing or performing the study, without the review and prior written consent of the 
Sponsor. These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Trial Agreement 
executed between the Sponsor/CRO and the institution/investigator. All persons assisting in the 
performance of this study must be bound by the obligations of confidentiality and non-use set 
forth in either the Confidentiality Agreement or Clinical Trial Agreement executed between the 
institution/investigator and the Sponsor/CRO.  Additionally, the publication plan of the Sponsor, 
considering, among other items, proprietary patent issues and competitive strategic goals, must 
be complied with prior to the public disclosure of any aspect of this study by abstract, verbal 
presentation, invited lecture, journal article, or journal letter. Matters regarding authorship and 
the order of authorship on publications reporting the results of single study findings are covered 
in a separate agreement. 
 


 
 
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14 APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS 
Drugs Allowed (Y) and Not Allowed (N) as Concomitant medications in this study. 
 
Drug Class 
                 Usage 
(p.r.n.)      Chronic Use 
 
Restrictions 
 
Analgesics 
(Y)  
(Y) 
Only non-opioid containing 
analgesics can be administered 
chronically. 
 
Use of acetaminophen as an 
analgesic is contraindicated as it 
has the ability to inhibit PKC 
activation. However, prn 
administration for pain may be 
used with a maximum dose of 
2,600 mg/day (e.g., 2x650mg 
cap twice a day) for no more 
than 3 days/week. 
 
Combination products 
containing codeine, 
hydrocodone or oxycodone may 
be used on a p.r.n. basis only 
(not to exceed 5 consecutive 
days) and not within 24-hours 
before a clinic visit. 
 
Opioid analgesics are 
contraindicated as they have the 
ability to act as an NMDA 
antagonist.  
 
Anesthetics 
• General 
• Local 
 
(N) 
(Y) 
 
(N) 
(N) 
 
 
Anorexics 
(N) 
(N) 
 
 
Anticholinergics 
(N) 
(N) 
Includes Cogentin.  
Anticholinergics for bladder 
control are to be avoided if 
possible. When needed 
some, such as Detrol is 
allowed. Call Medical 
Monitor. 
 
Anticoagulants 
(N) 
(Y) 
Heparin is not allowed  
 
Anticonvulsants 
(N) 
(N) 
Divalproex, Valproate, 
Topiramate and gabapentin are 
prohibited. Anticonvulsants with 
 


 
 
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Drugs Allowed (Y) and Not Allowed (N) as Concomitant medications in this study. 
 
Drug Class 
                 Usage 
(p.r.n.)      Chronic Use 
 
Restrictions 
 
no known significant cognitive 
effects, such as Lamictal, 
Pregabalin, Levetiracetam are 
allowed. Call the medical 
monitor for other 
anticonvulsants. Patient must 
have been on a stable dose for 3 
months prior to screening.  
 
Antidepressants 
(N) 
(Y) 
 
MAO inhibitors, antidepressants with 
anticholinergic effects (e.g. 
tricyclics), and chronic use of 
sedating antidepressants (e.g. 
mirtazipine) are not allowed. 
Sedating antidepressants can be used 
sparingly at low dose, as needed for 
sleep; avoid using 12 hrs prior to 
efficacy assessments.  
 Dose and medication must be stable 
for 1 month prior to Screening.   
Antiemetics 
(Y) 
(N) 
Antiemetics with sedative 
properties (e.g. first generation 
antihistaminics) are not allowed. 
Antiemetics such as phosphoric 
acid preparations (Emetrol, 
Emecheck), Pepto-Bismol, and cola 
syrup are allowed.  
 
Antifungal agents 
• Systemic 
• Topical 
 
(N) 
(Y) 
 
(N) 
(Y) 
 
 
Antihistamines 
(Y) 
Call 
Non-sedating antihistaminics such 
as Allegra (fexofenadine), Zyrtec 
(cetirizine) etc are allowed. 
Sedating antihistaminics are not 
allowed. See cough and cold 
preparations for combination 
products. 
Anti-inflammatory 
drugs 
(Y) 
(Y) 
Indomethacin and systemic 
corticosteroids are not allowed. 
 
Anti-neoplastics 
(N) 
(Y) 
Tamoxifen is allowed.  Dose    must
be stable for 3 months prior to 
Screening. 
 


 
 
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Drugs Allowed (Y) and Not Allowed (N) as Concomitant medications in this study. 
 
Drug Class 
                 Usage 
(p.r.n.)      Chronic Use 
 
Restrictions 
 
Anti-obesity 
(N) 
(Y) 
Xenical (orlistat) Cetilistat, 
Lorcaserin (Belviq) are allowed. 
Others such as Qsymia (a 
combination of phenermine and 
topiramate) are not allowed. Call 
Med Monitor. Dose must be stable 
for at least one month prior to 
Screening. 
 
Anti-Parkinson’s 
drugs 
(N) 
(N) 
Includes dopaminergic agents, 
amantadine, selegiline, Cogentin, 
and MAO inhibitors. 
 
Antipsychotics 
(Y) 
(Y) 
Clozapine and antipsychotics with 
anticholinergic effects are not 
allowed. Limit use to low doses and 
only if absolutely needed.  Call 
Medical Monitor. Doses must be 
stable for at least one month prior to 
Screening. 
Anxiolytics 
(Y) 
(N) 
Limited use of short/medium acting 
benzodiazepines if needed is allowed
Do not use within 12 hrs before 
efficacy assessments.  
 
Cholinesterase 
inhibitors 
(N) 
(Y) 
Alzheimer’s disease medications 
such as Aricept (donepezil) Exelon 
(rivastigmine), and Reminyl 
(galantamine) must be on a stable 
dose for at least 3 months prior to 
Screening.  Usage must continue 
unchanged throughout the study. 
Cough/Cold 
preparations 
 
(Y) 
Call 
Decongestants containing 
dextromethorphan or narcotics are 
not permitted.  Preparations 
containing pseudoephedrine or 
phenylpropanolamine are not 
permitted. See Antihistamines. 
Ginko biloba 
(N) 
(Y) 
Dose must be stable for at least 
one month prior to Screening. 
 
Hormones 
(N) 
(Y) 
Medication and dose must be stable 
for 3 months prior to Screening. 
 


 
 
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Drugs Allowed (Y) and Not Allowed (N) as Concomitant medications in this study. 
 
Drug Class 
                 Usage 
(p.r.n.)      Chronic Use 
 
Restrictions 
 
Hormone 
suppressants 
(N) 
(Y) 
Proscar (finasteride) is allowed. 
Dose must be stable for 3 months 
prior to Screening. 
 
Hypoglycemic 
agents 
 
(N) 
(Y) 
Oral hypoglycemic agents and 
insulin are allowed.  Dose must be 
stable for 3 months prior to 
Screening. 
 
Hypolipidemics 
 
  (N) 
(Y) 
Statins are allowed. Dose must be 
stable for at least one month prior to
Screening. 
 
Insulin 
 
(N) 
(Y) 
Patients must be well controlled 
and stable. 
 
Laxatives 
 
(Y) 
(Y) 
Fiber-based products and Colace 
(docusate sodium) are allowed. 
 
Muscle relaxants 
(N) 
(N) 
 
 
Psychotropic drugs 
not otherwise 
specified (including 
herbal products) 
(N) 
(N) 
Call medical monitor 
 
Sedatives/hypnotics 
 
(Y) 
(Y) 
Zolpidem, zaleplon, trazodone, 
chloral hydrate, mirtazapine, and 
the occasional use of 
benzodiazepines for sleep is 
allowed. Where possible, these 
should not be used within 12 hrs 
prior to efficacy tests. 
 
Steroids 
• Systemic 
• Topical 
• Inhalant 
 
(N) 
(Y) 
(Y) 
 
(N) 
(Y) 
(Y) 
 
 
Stimulants 
(N) 
(N) 
Includes Ritalin, Concerta, 
any methylphenidate 
preparations, Cylert 
(pemoline), etc. 
 
Tocopherol 
(Vitamin E) 
(N) 
(Y) 
Dose more than 400 IU per 
day not allowed; Dose must 
be stable for at least one 
month prior to Screening. 
 
Vaccines for AD 
N 
N 
Patients treated with active 
vaccine against amyloid/tau 
within 2 years are not allowed.  
 


 
 
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15 APPENDIX 2  
LIST OF REFERENCES 
 
1 McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas CH, Phelps CH. 
2011. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the 
National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for 
Alzheimer's disease. Alzheimer’s & Dementia : The Journal of the Alzheimer's Association, 
7:263–9. 
2 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition: DSM-5  – May 27, 2013. American Psychiatric Association. Washington, D.C. 
3 http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-
Heart-Failure_UCM_306328_Article.jspList of References 
4 Nelson PT, Head F, Schmitt FA, e al. 2011. Alzheimer’s disease is not “brain aging”: 
neuropathological, genetic and epidemiological human studies. Acta Neuropathol. 121:571-87. 
5 Hongpaisan J and Alkon DL. 2007. A structural basis for enhancement of long-term associative 
memory in single dendritic spines regulated by PKC. PNAS. 104 (49):19571-19576l. 
6 Sun, M ad Alkon DL. 2014. The “memory kinases”: roles of PKC isoforms in signal processing 
and memory formation. Progress in Molecular Biology and Translational Science. Elsevier Inc. 
Vol. 122 
7 Kern A, Roempp B, Prager K, Walter J, Behl C. 2006. Down-regulation of endogenous 
amyloid precursor protein processing due to cellular aging. J Biol Chem 281:2405-2413. 
8 Battaini F, Elkabes S, Bergamaschi S, Ladisa V, Lucchi L, De Graan PN, Schuurman T, Wetsel 
WC, Trabucchi M, Govoni S. 1995. Protein kinase C activity, translocation, and conventional 
isoforms in aging rat brain. Neurobiol Aging 16:137-148. 
9 Battaini F, Pascale A. 2005. Protein kinase C signal transduction regulation in physiological 
and pathological aging. Ann N Y Acad Sci 1057:177-192. 
10 Battaini F, Pascale A, Paoletti R, Govoni S. 1997. The role of anchoring protein RACK1 in 
PKC activation in the ageing rat brain. Trends Neurosci 20:410-415. 
11 Larbi A, Douziech N, Fortin C, Linteau A, Dupuis G, Fulop T, Jr. 2005. The role of the 
MAPK pathway alterations in GM-CSF modulated human neutrophil apoptosis with aging. 
Immun Ageing 2:6. 
12 Anderson JJ, Holtz G, Baskin PP, Wang R, Mazzarelli L, Wagner SL, Menzaghi F. 1999. 
Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged 
rats: correlation with spatial memory deficits. Neuroscience 93:1409-1420. 
13 Hongpaisan J, Sun M and Alkon DL. 2011. PKCɛ activation prevents synaptic loss, Aβ 
elevation, and cognitive deficits in Alzheimer’s disease transgenic mice. The Journal of 
Neuroscience 32 (2):630-643. 


 
 
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14 Schroot LM, Jackson K, Yi P et al. 2015. Acute oral Bryostatin-1 administration improves 
learning deficits in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Current 
Alzheimer Research 12: 222-31. 
15 Etcheberrigaray R, Tan M, Dewachter I et al. 2004. Therapeutic effects of PKC activation in 
Alzheimer’s disease transgenic mice. PNAS: 101 (30): 11141-11146. 
16Farlow MR, Thompson RE, Wei LJ, Tuchman AJ, Grenier E, Crockford D, Wilke S, Benison 
J, Alkon DL. A randomized, double-blind, placebo-controlled, phase II study assessing safety, 
tolerability, and efficacy of bryostatin in the treatment of moderately severe to severe 
Alzheimer's disease. J. Alzheim. Dis. 67: 555-570, 2019. 
17Diggle RJ, Liang K-Y, and Zeger SL. Analysis of Longitudinal Data.  (New York: Oxford 
University Press Inc). 1994: page 30. 
 
18Liang KY, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika. 
1986; 73(1):13-22. doi: 10.1093/biomet/73.1.13. 
19Fitzmaurice GM, Laird NM, and Ware JH (2011). Applied Longitudinal Analysis. Hoboken, 
NJ: John Wiley & Sons.  
 
 
16 APPENDIX 3  
SUMMARY OF CHANGES 
16.1 Protocol Version 2.0  June 1, 2020 
General global edits: 
Several corrections and clarifications were made to address discrepancies in the text. Key 
changes are noted below. 
Synopsis and relevant sections: 
• The version and date were updated. 
• Subjects will be stratified by baseline SIB total scores, which will be balanced between 
treatment groups. 
• The anticipated start and stop dates were updated to reflect the delays resulting from the 
widespread COVID-19 pandemic. These dates are only estimates at this time, pending 
further evaluation of the potential impact on subject participation. 
• The number of subjects has been modified from 46 to 100. 


 
 
Protocol #: NTRP-101-204
 
 
CONFIDENTIAL 
 
Version 6.0 
September 7, 2022 
Page 80 of 82 
 
• All subjects will proceed to a second course of treatment, 7 doses beginning at Week 15.  
• The primary endpoint is at Week 28, after 2 courses of treatment have been administered.  
• The final follow-up visit will be at week 30.  
• The Schedule of Activities has been revised to illustrate the new visit schedule and 
procedures to be performed. 
Protocol sections 4.0 and 9.0: 
Revisions were made to be consistent with the planned statistical analysis.  For the primary 
endpoint analysis, the test of the null hypothesis will be a superiority test based the treatment 
difference in Week 13 SIB from baseline means as assessed by general estimating equations 
(GEE) regression models.  Secondary and exploratory endpoints will be similarly assessed. 
Section 6.1.1: 
The option to utilize a Pre-Screening Consent Form was added. The purpose of the Pre-
Screening Consent is to allow access to medical records prior to a subject’s onsite screening 
visit. Use of this consent will reduce the occurrence of onsite screening visits by subjects 
ineligible for the study based on medical history.  No study procedures will be performed 
under this preliminary consent. 
 
16.2 Protocol Version 3.0  June 30, 2020 
 
Synopsis and Section 4.4.1: 
Inclusion criterion #5 has been revised. Patients must have a baseline SIB total score of at least 
60 and may not have a SIB score >93 at screening. Previous versions of the protocol required 
only that subjects be able to complete at least one item on the SIB, but for the moderately severe 
AD subjects eligible for this study, a range of scores between 60 and 93 is appropriate. 
Section 6.1.21 added: Early Treatment Discontinuation and Follow-up 
If for any reason, the investigator, subject or caregiver decide at Week 13 that further study drug 
treatments should not be administered, the subject will not enter Treatment Period 2, but will be 
encouraged to continue follow-up visits.  The visits will take place at Weeks 15, 20, 24, and 30.  
All procedures listed for these visits should be performed, with the exception of study drug 
infusion, infusion-related vitals, and ECG.  Subjects who discontinue treatment are not eligible to 
resume treatment.  Subjects may discontinue follow-up at any time after Week 15, the 30-day 
follow-up visit for Treatment Period 1. 
 


 
 
Protocol #: NTRP-101-204
 
 
CONFIDENTIAL 
 
Version 6.0 
September 7, 2022 
Page 81 of 82 
 
16.3 
Protocol Version 4.0  June 7, 2021 
General global edits: 
Several corrections and clarifications were made to address discrepancies in the text. Key 
changes are noted below. 
• The version and date were updated. 
• The name change of the sponsor from Neurotrope to Synaptogenix has been reflected in 
the text. 
Synopsis: 
The medical monitor’s name and contact information have been updated. 
Synopsis and Section 9.5: 
The secondary analyses has been changed, removing analyses of SIB total scores at Weeks 5 and 
15 and adding an analysis at Week 30. 
Synopsis and Section 4.4.2, Exclusion Criterion 9: 
Restriction of the use of acetaminophen has been revised to allow no more than 2,600 
mg/day of acetaminophen for more than 3 consecutive days within 14 days prior to 
screening. 
Synopsis and Section 9.1: 
The per protocol analysis set has been further defined. To be included, subjects must have 
received at least 11 of the14 doses (80%).   
Section 2.1.1.3: 
ClinicalTrials.gov study identifier for study NTRP101-203, NCT03560245, has been provided to 
facilitate review of adverse events that occurred in that study.  
Section 2.1.2.3: 
ClinicalTrials.gov study identifier for study NTRP101-202, NCT02431468, has been provided to 
facilitate review of adverse events that occurred in that study.  
Sections 6.0.1.1 and 6.1.1: 
B12 testing has been removed for follow-up of abnormal TSH at screening. 
Section 6.1.22 has been added to describe procedures for early treatment discontinuation follow-
up. 


 
 
Protocol #: NTRP-101-204
 
 
CONFIDENTIAL 
 
Version 6.0 
September 7, 2022 
Page 82 of 82 
 
Section 9.4: 
Text was added to address handling of early study drop-outs. Patients who drop out of the study 
prior to the first efficacy assessment will be replaced. 
Section 14, Appendix 1: 
Restricted concomitant medications have been revised as follows: 
• Prn administration of acetaminophen for pain may be used with a maximum dose of 
2,600 mg/day (e.g., 2x650mg cap twice a day) for no more than 3 days/week. 
• Antacids, antianginal medications, antiarrhythmics, antiasthma agents, antibiotics, 
antidiarrheal preparations, antihypertensives, antiviral agents, BPH agents, diuretics, and 
H2 blockers have been removed from the list. 
16.4 
Protocol Version 5.0  December 20, 2021 
Global changes: The protocol version and date have been updated. 
The protocol previously stated that blood samples will be drawn to measure the presence or 
absence of bryostatin after the initial dose of study drug on Day 0, and again after dosing on Day 
105.  However, the specialized laboratory where the testing was to be done has been unable to 
perform the test with adequate sensitivity.  We have been given approval by the NIH, which is a 
sponsor of the study, to remove the test. The test is not included in any of the planned safety or 
efficacy analyses.  For this reason, it is no longer necessary to draw blood samples at these two 
timepoints. The text affected by this revision are in Section 6, Table 1, Schedule of Activities, 
Section 6.0.1.1, Laboratory, Section 6.1.2, Week 0, and Section 6.1.11, Week 15. 
The previous version of the protocol stated that patients who discontinue the study prior to the 
first efficacy assessment (Week 5, Day 35) will be replaced. The protocol has been revised to 
allow one additional patient to be added to the study for each patient who discontinues prior to 
the primary endpoint (Week 28, Day 196). Revised text in Section 9.4 as well as the synopsis 
reflect this change.   
Section 9.4 has been revised to add Week 30 SIB scores to the data to be used in the regression 
models, and to state that both linear and non-linear terms will be considered in the regression 
models to be employed in analyses. Details will be provided in the statistical analysis plan. 
16.5   Protocol Version 6.0   September 1, 2022 
The protocol previously included a follow-up visit at Week 42. The Week 42 visit has been 
removed. However, data collected at this visit for subjects who completed the visit prior to 
implementation of this amendment will be included in the analyses as described. 
References to PKCε testing and analysis have been removed, since no PKCε samples were 
collected for this trial. 

SAP_001.pdf: 
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Page 1 of 35 
 
 
Statistical Analysis Plan 
Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing 
the Safety, Tolerability and Long-term Efficacy of Bryostatin in the Treatment of 
Moderately Severe Alzheimer’s Disease Subjects Not Receiving Memantine 
Treatment 
Protocol Number: NTRP-101-204 
Protocol Version: 6.0 / September 07, 2021 
 
SAP Version 1.0 
SAP Issue Date: 15 November, 2022 
SAP Author: Alexei Kiselev, MSc 
 
Previous SAP Versions 
New Document 
 
 


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Page 2 of 35 
SAP Amendments before database lock 
Version  Issue Date 
Section 
Revision / Addition 
Rationale 
 
 
 
 
 
 
 
 


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Page 3 of 35 
Table of Contents 
1 
INTRODUCTION ............................................................................................... 5 
2 
STUDY OBJECTIVES ....................................................................................... 5 
3 
ENDPOINTS ....................................................................................................... 5 
3.1 
Primary Endpoint ............................................................................................................ 5 
3.2 
Secondary Endpoints ...................................................................................................... 6 
4 
SAMPLE SIZE .................................................................................................... 6 
5 
RANDOMIZATION ........................................................................................... 7 
6 
PLANNED ANALYSES ..................................................................................... 8 
6.1 
Analysis Sets ................................................................................................................... 8 
6.1.1 
Enrolled Set ............................................................................................................... 8 
6.1.2 
Full Analysis Set ....................................................................................................... 8 
6.1.3 
Per-Protocol Set ........................................................................................................ 9 
6.1.4 
Safety Analysis Set ................................................................................................... 9 
6.1.5 
Completer Analysis Set............................................................................................. 9 
6.2 
Derived Data ................................................................................................................... 9 
6.2.1 
Race........................................................................................................................... 9 
6.2.2 
Baseline ................................................................................................................... 10 
6.2.3 
Duration / Study Day / Time ................................................................................... 10 
6.2.4 
Conventions for Missing and Partial Dates ............................................................ 10 
6.2.5 
Missing / Partial Start / Stop Date of Adverse Events (AE) and Concomitant 
Medications ........................................................................................................................... 10 
6.2.6 
Missing Date of Study Drug Dosing ....................................................................... 11 
6.2.7 
Missing Diagnosis Dates......................................................................................... 12 
6.2.8 
Exposure to Study Drug .......................................................................................... 12 
6.2.9 
Inexact Values ......................................................................................................... 13 
6.2.10 
Electrocardiogram Data .......................................................................................... 13 
6.2.11 
Columbia-Suicide Severity Rating Scale (C-SSRS) ............................................... 13 
6.2.12 
Unscheduled Visits ................................................................................................. 14 
6.3 
Conventions .................................................................................................................. 14 
6.3.1 
Decimal Places ........................................................................................................ 15 
6.4 
Subject Disposition ....................................................................................................... 15 
6.5 
Protocol Deviations ....................................................................................................... 16 


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Page 4 of 35 
6.6 
Baseline Comparability ................................................................................................. 16 
6.7 
Medical History ............................................................................................................ 17 
6.8 
Prior and Concomitant Medications ............................................................................. 17 
6.9 
Exposure to Study Drug ................................................................................................ 17 
6.10 
Treatment Compliance .................................................................................................. 18 
6.11 
Efficacy Analyses ......................................................................................................... 18 
6.11.1 
Primary Endpoint .................................................................................................... 18 
6.11.2 
Primary Efficacy Analysis ...................................................................................... 18 
6.11.3 
Supportive Analysis ................................................................................................ 20 
6.11.4 
Other Secondary Endpoints .................................................................................... 21 
6.11.5 
Exploratory Endpoints ............................................................................................ 22 
6.12 
Safety Analyses ............................................................................................................. 23 
6.12.1 
Adverse Events ....................................................................................................... 23 
6.12.2 
Laboratory Data ...................................................................................................... 24 
6.12.3 
Vital Signs ............................................................................................................... 25 
6.12.4 
Electrocardiogram Data .......................................................................................... 26 
6.12.5 
Physical Examination.............................................................................................. 26 
6.12.6 
Columbia Suicide Severity Rating Scale ................................................................ 27 
7 
INTERIM ANALYSIS ......................................................................................27 
8 
DATA SAFETY MONITORING BOARD ANALYSIS .................................27 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................28 
10 REFERENCES ..................................................................................................29 
11 LIST OF TABLES, FIGURES AND LISTINGS .............................................29 
 


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1 INTRODUCTION 
This document details the planned statistical analyses for Synaptogenix, Inc., protocol NTRP-101-
204 study titled “A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the 
Safety, Tolerability and Long-term Efficacy of Bryostatin in the Treatment of Moderately Severe 
Alzheimer’s Disease Subjects Not Receiving Memantine Treatment”. 
The proposed analyses are based on the contents of the final version 6.0 of the protocol (dated 07-
Sep-2021). 
This is a randomized double-blind placebo-controlled, Phase 2 study comparing bryostatin-1 
(referred to as ‘bryostatin’ hereafter) to placebo for long-term efficacy in the treatment of 
moderately severe Alzheimer’s disease (Mini Mental State Examination, 2nd edition [MMSE-2] 
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 of either bryostatin or placebo (consistent with the treatment received in first 
12 weeks), 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. 
 
2 STUDY OBJECTIVES 
To evaluate the safety, tolerability and long-term efficacy of bryostatin for the treatment of 
moderately severe Alzheimer’s disease in subjects not receiving concurrent memantine treatment, 
including: 1) determining how long the therapeutic effects will last; and 2) assessing whether a 
second treatment would be equally effective if the therapeutic effects of the first treatment do not 
last. 
 
3 ENDPOINTS 
3.1 Primary Endpoint 
The primary efficacy endpoint is change from baseline in the Severe Impairment Battery (SIB) 
total score assessment obtained after completion of the second course of treatment (Week 28). 
 
 


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Page 6 of 35 
3.2 Secondary Endpoints 
Secondary Efficacy Endpoints  
• 
SIB score at the end of the Week 42 follow-up visit  
• 
The change from baseline (screening) SIB total score at Week 13  
• 
The changes from baseline at Weeks 5, 9, 15, 20 and 24 in the SIB total score  
• 
The changes from baseline at Weeks 5, 9, 13, 15, 20 and 24 in the SIB total score for 
subjects with baseline MMSE-2 scores of 10-14 and 15-18  
• 
SIB trends over time; individual-specific slopes of total SIB scores will be obtained for all 
patients.  
 
Exploratory Endpoints  
• 
Change from baseline in Alzheimer’s Disease Cooperative Study – Activities of Daily 
Living – Severe Impairment Version (ADCS-ADL-Sev) total score at Weeks 13 and 42  
• 
Change from baseline in MMSE-2 total score at Weeks 13 and 42  
• 
Change from baseline in Neuropsychiatric Inventory (NPI) total score at Weeks 13 and 42  
 
Safety Assessments  
• 
Treatment emergent adverse events (AEs) and serious adverse events (SAEs)  
• 
Vital signs, hematology, blood chemistry, and physical examination including body weight  
• 
Electrocardiogram (ECG) parameters  
• 
Columbia Suicide Severity Rating Scale (C-SSRS)  
 
4 SAMPLE SIZE 
The power analysis for the current study is based on a minimum clinically significant difference 
in mean total SIB scores from baseline of 4 points between the placebo and bryostatin arms at 
Week 28. Since the analysis of this primary outcome is based on a linear regression model that 
utilizes the total SIB scores at Weeks 0, 5, 9, 13, 15, 20, 24, and 28, a difference of approximately 
0.15 points per week in the slope of total SIB scores between the placebo and bryostatin arms 
yields the clinically meaningful difference of 4 points at Week 28. General estimating equations 
(GEE) power analysis is based on the following equation:  


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Page 7 of 35 
 
𝑚𝑚=
2൫𝑧𝑧𝛼𝛼/2+𝑧𝑧𝛽𝛽൯
2𝜎𝜎2(1−𝜌𝜌)
𝑛𝑛𝑠𝑠𝑥𝑥2𝑑𝑑2
 
 
 
 
 
 
 
Eq 1 
In equation 1, m is the number of patients per group, 𝑧𝑧𝑎𝑎/2 is the type I error rate, 𝑧𝑧𝑏𝑏 is the type II 
error rate, σ is the standard deviations of the error (residual) terms, ρ is the within person correlation 
of total SIB scores over time within a person, n is the time points where the total SIB score is 
obtained, 𝑠𝑠𝑥𝑥2 is the variance of the X predictor variable (i.e. time in the current scenario), and d is 
the difference in slopes over time in total SIB measures from baseline between the placebo and 
bryostatin arms. 
Based on the data from the NTRP101-202 study among patients without memantine, we obtained 
an estimate for σ = 5.3. In addition, the NTRP101-204 study will have SIB total scores measured 
at n = 8 timepoints, giving a value of 𝑠𝑠𝑥𝑥2 = 127. Assuming a total of 100 patients (50 patients per 
arm), a two-sided type I error rate of 0.05 (i.e. 𝑧𝑧𝑎𝑎/2 = 1.96), and moderate within person correlation 
of outcome measures (i.e. ρ = 0.5), we will have > 99% power to see a difference in slopes over 
time of d = 0.15 points per week. In addition, we will have > 99% power to see this difference if 
we experience a 20% drop out. 
The GEE methodology is an appropriate approximation for estimating power under the mixed 
model with repeated measures (MMRM) when time as continuous. The GEE and Mixed model 
give equal parameter estimates under the conditions of an exchangeable working correlation for 
the GEE model and a random intercept for the Mixed model. In addition, the GEE was initially 
proposed for the primary analysis of the trial; however, it was later determined that the MMRM 
would be generally more commonly used.  
 
5 RANDOMIZATION 
Once all eligibility criteria for the study have been met, and the site has received approval by the 
Medical Monitor (MM) and Clinical Assessment Technologies (CAT) group, via the Electronic 
Data Capture (EDC) system, the subject can be randomized via Interactive Response Technology 
(IRT) system. Randomization will be stratified by SIB total score at baseline and baseline SIB 
scores will be balanced at baseline between the treatment groups. Mean values of baseline SIB 
total scores by group will be monitored in real time during the enrollment process. A randomization 
number will be assigned, and drug for that randomization number will be shipped to the site for 


Worldwide Clinical Trials Controlled Quality Management Document 
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Protocol Number: 
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Page 8 of 35 
twelve weeks of treatment. Randomization and scheduling of the first study drug infusion should 
be timed to allow for receipt of study drug prior to the scheduled study treatment. The drug kits 
will be shipped to the individual who will be responsible for kit storage and drug preparation and 
may not be handled by any other study staff member. The study drug kit will not identify the vial 
containing study drug as either placebo or bryostatin. After completion of Week 13, a second study 
drug kit will be provided for treatment period two. The IRT system will be used to register subjects 
for treatment and trigger study drug shipments. 
 
6 PLANNED ANALYSES 
All statistical analyses described in this Statistical Analysis Plan (SAP) were finalized and 
approved by the trial Principal Investigator (PI), Dr. Miao-Kun Sun, Chief Scientific Officer, Dr. 
Daniel Alkon, Lead Statistician, Richard Thompson, and  WCT Statistician, prior to the complete 
unmasking of the data. In addition, the methods described herein are given precedence over the 
analytical plans outlined in the clinical protocol. However, no SAP prepared in advance of the data 
can be final until the data are unmasked. The final Clinical Study Report (CSR) may contain 
additional tables or statistical tests if warranted by the data obtained. The justification for any such 
additional analyses will be fully documented in the final CSR. 
 
6.1 Analysis Sets 
 
6.1.1 Enrolled Set 
The Enrolled Set includes all those subjects who gave informed consent. 
 
6.1.2 Full Analysis Set 
The Full Analysis Set (FAS), consistent with the modified intention-to-treat (mITT) principles, is 
defined as all randomized subjects who received at least one dose of study medication and who 
have at least one post-baseline efficacy assessment.  
 


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Page 9 of 35 
6.1.3 Per-Protocol Set 
The Per Protocol Analysis Set (PP) is defined as all patients completing the study without major 
protocol deviations.  
Major protocol deviations will include but not limited to: 
• Non eligibility 
• Prohibited concomitant medications 
• Informed consent withdrawal 
• Unable to commit visit schedule 
• Missed 3 or more doses  
 
6.1.4 Safety Analysis Set 
The Safety Analysis Set (SAS) is defined as all randomized subjects who received any study 
medication (either partial or completed infusions of bryostatin or placebo).  
 
6.1.5 Completer Analysis Set 
The Completer Analysis Set (CAS) is defined as all randomized subjects who completed two 
courses of treatment, and who have a Week 28 SIB assessment. 
 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
 
6.2.1 Race 
The race will be categorized into two racial groups: White, if only White race selected, and non-
White – in all other cases. The listings will reflect the original selected categories.  
 


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Page 10 of 35 
6.2.2 Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives the first dose of study drug.  
 
6.2.3 Duration / Study Day / Time  
Study day will be calculated as the number of days from first dose of study drug.  
• date of event – date of first dose of study drug + 1, for events on or after first dose  
• date of event – date of first dose of study drug, for events before first dose  
 
6.2.4 Conventions for Missing and Partial Dates 
All rules explained below for partial / missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the below rules). 
 
6.2.5 Missing / Partial Start / Stop Date of Adverse Events (AE) and 
Concomitant Medications 
Missing and partial start and stop date will be imputed for analysis purposes as follows. 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved, or the subject has stopped taking 
the concomitant medication, the stop date will be imputed as the date of the subject’s last clinic 
visit in the study. 
• If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 
• If the month and year are known, the stop date will be imputed as the last day of that month 
unless the stop date corresponds to the same month as the subject’s last clinic visit in which 
case the date of subject’s last clinic visit in the study will be used instead. 
Missing start date will be imputed as follows: 


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• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the subject’s screening date or the stop date of the event / 
concomitant medication whichever the earlier. 
Partial start date (year present, but month and day missing) 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date will 
be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is latest. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• If the stop date occurs before the start of study drug, the start date of the event / concomitant 
medication will be imputed as the “01-Jan” of the same year. 
Partial start date (month and year present, but day missing) 
• If the stop date occurs on or after the start of study drug or the event / concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month and 
year unless this partial start date is in same month as the first dose of study drug in which 
case the date of first dose of study drug will be used.  
• If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
If the start time is missing it will be imputed only in the case where the start date of the concomitant 
medication / event corresponds to the date of the first dose of study drug. The time will be imputed 
as the same time as the first dose of study drug. In all other cases the time will not be imputed. 
 
6.2.6 Missing Date of Study Drug Dosing 
In this trial, patients will receive their assigned treatment via infusion under the direction of a 
clinician. Any missing date on the administration of the study drug will occur if the clinician 
neglects to record the date the infusion was given. If a date of dosing is missing, efforts will be 
made to determine the date of infusion from additional sources of information including healthcare 
facility visitation logs, contact with health care providers, or family members who would have 
scheduled the infusion visit. If alternative records on are not available to determine an infusion 
date, then for all administration visits, excepting 3rd and 8th doses, the missing infusion date will 


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Page 12 of 35 
be imputed as 7 days plus the date of the previously weeks’ infusion since the doses are given on 
a weekly basis. For 3rd and 8th doses, the missing infusion date will be imputed as respectively 14 
and 28 days plus the date of the previously weeks’ infusion, according to the Schedule of 
Activities. 
 
6.2.7 Missing Diagnosis Dates   
If the month and year are present but the day is missing, the diagnosis date will be set to first day 
of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” for 
that year.  
 
6.2.8 Exposure to Study Drug  
Total volume of bryostatin infused (mg) during the study will be calculated as: 
 
∑[0.024 ∙𝐿𝐿𝑖𝑖+ 0.020 ∙(1 −𝐿𝐿𝑖𝑖)]
𝑖𝑖
∙ቂ𝐶𝐶𝑖𝑖+ (1 −𝐶𝐶𝑖𝑖) ∙
𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖
59.6∙𝐿𝐿𝑖𝑖+58.0∙(1−𝐿𝐿𝑖𝑖)ቃ 
 
 
Eq 2 
0.024 (mg) – loading dose of bryostatin, 0.020 (mg) – maintenance dose of bryostatin, according 
to Section 4.1 of the Protocol, 
59.6 (mL) – total solution volume for loading dose, 58.0 (mL) – total solution volume for 
maintenance dose, according to Section 5.3 of the Protocol, 
Li – sign for loading dose, equals to 1 if dose is loading and equals to 0 if dose is maintenance,  
Ci – sign for completed dose, equals to 1 if subject received the full intended infusion and equals 
to 0 otherwise,  
TVIi – total volume infused (mL), in case of incomplete infusion 
i – number of an infusion. The sum should be calculated for all performed infusions. 
Planned dose of bryostatin is the sum of doses of full infusions for whole study: for each of 2 
courses there are 2 infusions of loading dose 24 mcg and 5 infusions of maintenance dose 
20 mcg. Totally planned dose equals to 2⸱(2⸱54+5⸱20)=416 mcg. 
This value will be used for calculation of fraction of subjects received at least 80% of planned 
dose. 


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Page 13 of 35 
 
6.2.9 Inexact Values 
In the case where a variable is recorded as “> x”, “≥ x”, “< x” or “≤ x”, a value of x will be taken 
for analysis purposes.  
 
6.2.10 Electrocardiogram Data 
For ECG data recorded on continuous scales, if more than one value is recorded at a time point, 
the mean value rounded to the integer will be presented. For overall interpretation if more than 
one value is recorded, the most severe (worst case) of the respective readings will be taken. 
 
6.2.11 Columbia-Suicide Severity Rating Scale (C-SSRS) 
The following outcomes are C-SSRS categories and have binary responses (yes / no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1  
Wish to be Dead 
Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behavior 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non fatal) 
Category 10 Completed Suicide 
Suicidal Ideation since baseline – A “yes” answer at any time during double blind treatment to any 
one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 


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Page 14 of 35 
Suicidal Behavior since baseline – A “yes” answer at any time during double blind treatment to 
any one of the 5 suicidal behavior questions (categories 6-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 
 
6.2.12 Unscheduled Visits 
Only scheduled post-baseline laboratory, electrocardiogram, physical examination, and vital signs 
values will be tabulated. Post-baseline repeat / unscheduled assessments will only be listed in the 
relevant appendices to the CSR. 
 
6.3 Conventions 
All data listings, summaries, figures, and statistical analyses will be generated using SAS version 
9.3 or higher1. 
Summaries will be presented by treatment group for efficacy endpoints and overall. Treatment 
group labels will be displayed as follows: 
 
Bryostatin 
(0.20 mg) 
Placebo 
 
 
Overall columns are to be included within the table shells as follows: 
Parameters 
Columns 
Demography 
Treatment and overall 
Baseline 
Treatment and overall 
Disposition 
Treatment and overall 
Efficacy 
Treatment 
AEs 
Treatment 
Other safety 
Treatment 
 
Listings will be sorted in the following order: treatment group, subject, parameter, and visit unless 
otherwise stated. All data will be listed, subjects who were not randomized will be displayed after 
the randomized treatment groups.  


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Page 15 of 35 
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, inter-quartile range, standard deviation, and minimum and maximum.  
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.  
 
6.3.1 Decimal Places 
Decimal places for derived data described in Section 6.1.4 will be determined by the scale of 
measurement unless otherwise stated. No decimal places will be displayed if the smallest 
calculated value is ≥ 100; 1 decimal place will be displayed when the smallest value is within the 
interval (10, 100), with 10 being inclusive; 2 decimal places will be displayed when the smallest 
value is within (1, 10), with 1 being inclusive; and so on for even smaller scales of measurement.  
Derived data known in advance of the results will be given as an integer. For example day, month, 
year, number of days and total scores (for rating scales) will be presented with zero decimal places.  
Means, medians and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g. standard deviation) will have two more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw data. 
Percentages will be displayed with one decimal place.  
P- Values will be quoted to 3 decimal places. 
 
6.4 Subject Disposition 
Subject disposition will be summarized and listed as follows: 
• The number of subjects, who entered the study, were randomized, and who are in each 
analysis set will be summarized by treatment group and overall for the Enrolled Set.  
• The number of subjects who failed screening and the reasons for failure will be tabulated 
for the Enrolled Set. 
• Eligibility Criteria vioaltions will be presented for Enrolled Set. 


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Page 16 of 35 
• The number of early withdrawals and the reasons for withdrawals will be tabulated by 
treatment group and overall for the Enrolled Set. 
• Number of subjects in the SAS by site 
• Number of subjects by visit for the SAS 
 
6.5 Protocol Deviations 
Protocol deviations will be summarized by treatment group and overall.  
Also a listing of protocol deviations will be provided.  
 
6.6 Baseline Comparability 
The comparability of treatment groups with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 
Standard continuous or categorical variable summaries will be presented by treatment group 
determined by the treatment actually received for the following variables based on the SAS and 
on the FAS.  
• Demographic data 
• Disease history 
• Medical history  
• Neuroimaging 
• Neuropsychological assessments at screening: 
o Severe Impairment Battery (SIB) 
o Mini Mental State Examination, 2nd edition (MMSE-2) 
o Alzheimer’s Disease Cooperative Study – Activities of Daily Living - Severe 
Impairment Version (ADCL-ADL-Sev) 
o Neuropsychiatric Inventory (NPI) metrics 
o Columbia Suicide Severity Rating Scale (C-SSRS) 
• Physical examination by body system at screening 
• Rosen-modified Hachinski Scale  


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Page 17 of 35 
All Baseline data will also be listed. 
 
6.7 Medical History 
Separate tabulations of previous and ongoing conditions at screening will be presented by 
randomized treatment group and overall for the SAS and the FAS. Medical History will be 
considered as previous if the start date and end date is less than date of first dose. Medical History 
will be considered as ongoing if the start date is greater than or equal to date of first dose or if end 
date is greater than or equal to date of first dose. Conditions will be coded using Medical Dictionary 
of Regulated Activities (MedDRA, version 23.0 or later) primary system organ class (SOC) and 
preferred term (PT). 
All Medical History data will also be listed. 
 
6.8 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
randomized treatment group and overall for the SAS and the FAS. Prior medications are defined 
as all medications starting before the date of first dose of study drug. Concomitant medications are 
defined as medications taken on or after the date of first dose of study drug. Concomitant 
medications will be coded using WHO Drug dictionary version March 2020 (or later) and 
summarized using Anatomic Therapeutic Chemical (ATC) Level 2. 
 
6.9 Exposure to Study Drug 
Data on exposure will be presented by randomized treatment group, overall, and by visit/whole 
study for the Safety Analysis Set. Following parameters will be presented in a table: 
• For each visit: 
o Subjects who had an infusion 
o Subjects that received full infusion 
o Subjects that had at least 1 interruption 
o Subjects that received partial infusion 
• For whole study 


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Page 18 of 35 
o Subjects that received all full infusions 
o Subjects that had at least 1 interruption 
o Subjects that received at least 1 partial infusion 
o Subjects who received 1 unfusion, >=2 infusion and so on. 
o Total volume of bryostatin infused 
o Subjects who had >=80% of planned dose 
All data on exposure will also be listed. 
 
6.10 Treatment Compliance 
Number and percentage of subjects receiving at least 80% of planned dose will be presented. 
 
6.11 Efficacy Analyses 
All statistical tests will be performed using a two-tailed 5% overall significance level, unless 
otherwise stated. All comparisons between treatments will be reported with 95% confidence 
intervals for the difference.  
 
6.11.1 Primary Endpoint 
The primary efficacy endpoint is the change from the pre-treatment baseline in the SIB total score 
at Week 28, after two 12-week courses of treatment.  
 
6.11.2 Primary Efficacy Analysis 
The primary efficacy analysis will be performed using linear mixed model with repeated measures 
(MMRM) with SIB measured at baseline as covariate, visit treated as a continuous as well as 
categorical variable, treatment and treatment by visit interaction. Categorical visit will be used to 
identify the ordering of measurements within a subject, while continuous visit will be used as 
covariate alone as well as in interaction with treatment.  
Week of planned visits will be used as values of categorical variable of visit. Actual study day of 
visits (calculated in weeks) will be used as values of continuous variable of visit. The dependent 


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Page 19 of 35 
variable will be the change from baseline in SIB total score at weeks 5, 9, 13, 15, 20, 24, 28, and 
30.  
Correlation between repeated observations within a subject will be accounted for by specifying an 
unstructured correlation. If this model does not converge then the following covariance matrices 
will be used in this particular order until the model converges: Toeplitz, compound symmetry, and 
first-order autoregressive. 
Analysis will be performed using PROC MIXED in SAS, and the resulting F-tests will be based 
on using Kenward-Roger’s adjusted degrees of freedom.  
The treatment groups will be compared at all timepoints using a two-sided test at a 5% significance 
level, with the primary comparison being the difference in group means of SIB from baseline at 
Week 28.  
The sample SAS code below implements the model detailed above with an unstructured covariance 
matrix (TYPE = UN in the REPEATED statement). The code assumes that AVISITN has 8 values 
(one for each post-baseline visit), and TRT01PN representing treatment is coded as 1 = bryostatin, 
2 = placebo. 
 
proc mixed data = <input-dataset>;  
  class subjid trt01pn avisitn; 
  model sibdiff = sibbase trt01pn avisitd trt01pn* avisitd / 
ddfm = kr outpred = pred; 
  repeated avisitn / type = un subject = subjid; 
  estimate "Bryostatin vs Placebo at week 28" trt01pn 1 -1 
trt01pn* avisitd 28 -28 / cl;  
run; 
 
Variables names: 
subjid – unique number of subject, 
avisitn – visit as categorical variable, 
avisitd – visit as continuous variable, 
sibbase – SIB at baseline, 


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Page 20 of 35 
sibdiff – SIB difference from baseline, 
trt01pn – treatment group. 
 
As a sensitivity analysis the same model but using only categorical visit will be used. The 
following SAS code implements this model (the variable designations are the same): 
 
proc mixed data = <input-dataset>;  
  class subjid trt01pn avisitn; 
  model sibdiff = sibbase trt01pn avisitn trt01pn* avisitn / 
ddfm = kr outpred = pred; 
  repeated avisitn / type = un subject = subjid; 
  estimate "Bryostatin vs Placebo at week 28" trt01pn 1 -1 
trt01pn* avisitn 0 0 0 0 0 0 1 0 0 0 0 0 0 0 -1 0 / cl;  
run; 
 
Patients that have missing SIB outcome data will be included in the primary analysis if they have 
complete SIB data for at least one follow-up timepoint (i.e., available case analysis). Although 
there is no universally acceptable, adequate method for analyzing longitudinal clinical trial data 
under ITT with missing primary endpoints, the available case analysis using a generalized linear 
mixed model approach such as MMRM will produce unbiased estimates of the treatment effect if 
the missingness is ignorable (i.e. missing completely at random or missing at random)2,3.  
 
6.11.3 Supportive Analysis 
Supportive sensitivity analysis for primary endpoint will performed in the same manner as primary 
analysis, for PP and CAS populations.  
Using MMRM for available cases as described in section 6.11.2 assumes that missingness in the 
SIB outcome measures is non-ignorable. However, at least some missing data at a given timepoint 
may be dependent on outcome values that are unobserved and therefore unmeasured, giving rise 
to non-ignorable missingness or missingness not at random (MNAR). Reasons for missing data 
will be recorded to help determine if missingness not at random is present. Determining the timing, 


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Page 21 of 35 
frequency, and possible reasons for missing data is critical in helping to determine the underlying 
mechanism of the missed data, particular since all methods for handling missing data are based on 
unverifiable assumptions.3  
If the reasons for missingness provides clinical evidence that MNAR is present, then sensitivity 
analyses that make reasonable assumptions about missing data will be performed. In the proposed 
sensitivity analyses, intermediate missed SIB values will be replaced with a ‘best’ case and ‘worst’ 
case, where the ‘best’ and ‘worst’ case SIB scores will be determined for each patient based on 
their observed data. In these sensitivity analyses, only intermediate missed SIB data will be filled 
in with the best- and worst-case values, giving rise to a monotonic missing data set. Under this 
scenario, it is reasonable to assume that data lost to follow-up is ignorable3.   
 
6.11.4 Other Secondary Endpoints 
Analysis of secondary efficacy endpoints will be conducted on the FAS population. 
6.11.4.1 SIB total score at the Week 42 follow-up visit 
This endpoint will be analyzed using an Analysis of Covariance (ANCOVA) model with SIB score 
at Week 42 as dependent variable; treatment group as factor, and baseline SIB total score, baseline 
MMSE-2 score, age and gender as covariates.  
6.11.4.2 The change from baseline in SIB total score at Week 13 
This endpoint will be analyzed using the same ANCOVA model as described in Section 6.11.6.1.  
6.11.4.3 SIB total scores from baseline at Weeks 9, 20, 24 and 30 
This endpoint will be analyzed using the same MMRM model as described in Section 6.11.2 with 
corrections for obtaining results on corresponding visits. 
6.11.4.4 SIB total scores from baseline at Weeks 9, 20, 24 and 30for subjects with baseline 
MMSE-2 scores of 10-14 and 15-18 
This endpoint will be analyzed using the same MMRM model as described in Section 6.11.2 with 
additional fixed effect for grouped baseline MMSE-2 scores (10-14 and 15-18) and corrections for 
obtaining results on corresponding visits. 


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Page 22 of 35 
6.11.4.5 Individual patient’s SIB trends over time  
Assessment of slopes in treatment groups and comparison of these slopes will be performed using 
the MMRM model for primary efficacy analysis, as it described in Section 6.11.2. This approach 
will be used for absolute SIB values collected from baseline over Weeks 0 to 28 as well as for 
changes from baseline for these time points: 
 
proc mixed data = <input-dataset>;  
  class subjid trt01pn avisitn; 
  model sibdiff = VAR trt01pn avisitd trt01pn* avisitd / ddfm = 
kr outpred = pred; 
  repeated avisitn / type = cs subject = subjid; 
  estimate "Slope, Bryostatin" time 1 time*trt_no 1 0 / cl; 
  estimate "Slope, Placebo" time 1 time*trt_no 0 1 / cl; 
  estimate "Slope Difference" time*trt_no 1 -1 / cl; 
run; 
 
Variables names: 
subjid – unique number of subject, 
avisitn – visit, 
VAR=sib – SIB absolute total score for the first model,  
VAR=sibdiff – SIB difference from baseline for the second model,  
trt01pn – treatment group. 
 
6.11.5 Exploratory Endpoints 
Analysis of exploratory endpoints will be conducted on the FAS population. 
The following exploratory endpoints will be analyzed:  
 


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Page 23 of 35 
6.11.5.1 • Change from baseline in ADCS-ADL-Sev total score at Week 13 and Week 42 
Analysis of this endpoint will be similar to analysis of primary efficacy endpoint. Analysis will 
be performed using  the same MMRM model as described in Section 6.11.2.  
6.11.5.2 • Change from baseline in MMSE-2 total score at Week 13 and Week 42 
Analysis of this endpoint will be similar as described in Section 6.11.7.1 but for post-baseline 
changes in MMSE-2 total score.  
6.11.5.3 • Change from baseline in NPI total score at Week 13 and Week 42 
Analysis of this endpoint will be similar as described in Section 6.11.7.1 but for post-baseline 
changes in MMSE-2 total score.  
 
6.12 Safety Analyses 
The safety analyses will be presented by the treatment received for the Safety Analysis Set. 
 
6.12.1 Adverse Events 
Adverse events will be coded using Medical Dictionary of Regulated Activities (MedDRA, version 
23.0 or later) primary system organ class (SOC) and preferred term (PT). 
Treatment Emergent AEs (TEAEs) are defined as events with an onset on or after the first 
randomized treatment.  
Severity grade will be defined by variable “Severity/Intensity” of the CRF. Maximum severity will 
be assumed for an AE with missing severity.  
Relationship to study drug will be defined by variable “Causality” of the CRF. Maximum relationship 
will be assumed for an AE with missing causality.  
An AE will be considered as resulting in discontinuation of study treatment if variable “Action taken 
with Study Treatment“ equals to “DRUG WITHDRAWN”.  
An AE will be considered as lead to study discontinuation if the subject didn’t complete the study 
with primary reason for termination equals to “ADVERSE EVENT“ and the AE has number equals 
to value of variable “Adverse Event Number” on page “End Of Study” of the CRF. 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 24 of 35 
An AE will be considered as AE of Special Interest (AESI) if variable “Was this event considered 
Adverse Event of Special Interest (AESI)?” equals to “YES”. 
 
The following tables will be presented, by SOC and PT, both sorted alphabetically, with 
summaries for each treatment group and overall:  
• Overview of AEs 
• TEAEs  
• TEAEs by maximal severity grade 
• TEAEs by maximal relationship to study treatment  
• Serious TEAEs (TESAEs) 
• TEAEs resulting in discontinuation of study treatment 
• TEAEs resulting in discontinuation of study treatment by maximal relationship to study 
treatment 
• TEAEs that lead to study discontinuation by maximal relationship to study treatment 
• TESAEs by maximal relationship to study treatment  
• Treatment Emergent Adverse Events of Special Interest (TEAESI) 
Following listings on AEs will be provided: 
• Pre-treatment AEs 
• TEAEs 
• Serious TEAEs 
• TEAEs resulting in discontinuation of study treatment 
• TEAE with fatal outcome 
 
6.12.2 Laboratory Data 
Laboratory data will be collected at Screening, Weeks 2, 7, 13, 18, 26 and 42. 
Hematology tests will include CBC with differential, platelet count and coagulation (prothrombin 
time (PT) and partial prothrombin Time (PTT)) studies.  
Clinical chemistry tests will include sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, estimated creatinine CL, glucose, calcium, CO2, total protein, albumin, ALP, 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 25 of 35 
ALT, AST, gamma glutamyl transferase (GGT) lactate dehydrogenase (LDH), uric acid and 
bilirubin.  
A serum creatine phosphokinase (CPK) will be done at screening and in the event of myalgia. A 
Thyroid-Stimulating Hormone (TSH) analysis will be done at screening, and B12, T-3 and T-4 
will be done if TSH result is abnormal.  
Test for βhCG will be performed if indicated.  
Test for HbA1C will be performed if clinically indicated. 
 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit only for hematology tests and clinical chemistry tests. 
Each measurement (continuous data) will be classed as below, within, or above normal range, 
based on ranges supplied by the laboratory used. Shift tables in relation to the normal range from 
baseline to each follow-up visit will be presented. 
Data on CPK, TSH (and corresponding tests), βhCG and HbA1C will not be tabulated. 
All laboratory data will be presented in listings. 
 
6.12.3 Vital Signs 
Vital signs will be collected at Screening and each study visit. At dosing visits, collection will be 
performed prior to infusion and at 30, 60 and 90 minutes from start of the infusion (+/- 5 minutes) 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm)  
• Respiration rate (breath / min) 
• Body temperature 
For the calculation of descriptive statistics the values of body temperature measured in Fahrenheit 
will be transformed using the following formula: [value in °C] = ([value in °F] − 32) × 5/9. 
All data on vital signs will be listed. 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
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prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 26 of 35 
 
6.12.4 Electrocardiogram Data 
Electrocardiogram (ECG) will be performed at Screening (triplicate), Weeks 2, 7, 13, 18 and 26. 
Descriptive statistics for ECG interpretation results will be presented in a table. Interpretation 
results and changes from baseline will be presented in a shift table. 
Electrocardiogram data will also be presented in a listing. 
 
6.12.5 Physical Examination 
Physical examination (PE) will be performed at Screening, Weeks 7 (abbreviated), 13, 18, 26 and 
42. It will include, but is not limited to the following: 
• General appearance  
• Weight 
• Height (screening only)  
• Ears  
• Eyes  
• Nose  
• Throat  
• Neck  
• Respiratory system  
• Cardiovascular system  
• Abdomen  
• Musculoskeletal /Neurologic  
• Extremities  
• Skin  
• Lymph nodes  
An abbreviated PE will include but is not limited to the following:  
• General appearance  
• Weight  
• Respiratory system  
• Cardiovascular system  


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 27 of 35 
• Abdomen  
For the calculation of descriptive statistics, the values of weight measured in LB will be 
transformed using the following formula: [value in °KG] = [value in °LB] × 0.45359. 
Values of weight and changes from baseline will be tabulated with descriptive statistics. 
Assessment results and changes from baseline for each body system will be presented in shift 
tables. 
Results of physical examinations will be listed. 
 
6.12.6 Columbia Suicide Severity Rating Scale 
Columbia Suicide Severity Rating Scale (C-SSRS) will be collected at screening, Weeks 2, 7, 13, 
18, 26 and 42. Results will be presented in a table with descriptive statistics and in a listing. 
 
7 INTERIM ANALYSIS 
No interim analyses are planned.  
 
8 DATA SAFETY MONITORING BOARD ANALYSIS 
Safety data will be reviewed by Data Safety Monitoring Board (DSMB) when 30 subjects have 
received four doses of study drug, followed by additional safety analyses when 60 subjects have 
received a similar number of doses. Following tables and listings will be prepared for DSMB 
review: 
Tables: 
• Demographic data 
• Disease history 
• Medical history 
• Summary of TEAEs  
• Summary of TEAEs by relationship to clinical trial treatment  
• Summary of Serious TEAEs  
• Summary of Serious TEAEs by relationship to clinical trial treatment  


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 28 of 35 
• Summary of Adverse Events of Special Interest (AESI) 
• Summary of AESI by relationship to clinical trial treatment  
Listings: 
• Demographic data 
• Disease history 
• Medical history 
• Pre-treatment AEs 
• TEAEs 
• Serious TEAEs 
• TEAEs resulting in discontinuation of study treatment 
• TEAE with fatal outcome 
 
9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
1. The control of false discovery rate (FDR) excluded because it was planned for the 
secondary (not primary) endpoints and this is a phase 2 study. 
2. For the 4th secondary endpoint: <The changes from baseline at Weeks 5, 9, 13, 15, 20 and 
24 in the SIB total score for subjects with baseline MMSE-2 scores of 10-14 and 15-18> the 
list of visits changed from Weeks 9, 15, 20 and 24 to Weeks 9, 20, 24 and 30. 
3. For efficacy analysis the GEE models replaced with MMRM models as more suitable 
approach for analysis of longitudinal data in neurology studies. 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 29 of 35 
10 REFERENCES 
1. SAS Institute Inc., Cary, NC, 27513, USA 
2. Chakraborty H, Gu H. A Mixed Model Approach for Intent-to-Treat Analysis in 
Longitudinal Clinical Trials with Missing Values. RTI Press, Research Triangle Park 
(NC); 2009. PMID: 30896910. 
3. Committee for Medicinal Products for Human Use. Guideline on Missing Data in 
Confirmatory Clinical Trials.  London: European Medicines Agency; 2010. 
 
11 LIST OF TABLES, FIGURES AND LISTINGS 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.1  
Demographics Data 
 
 
14.1.1  
Disposition 
 
 
14.1.1.1 
Subject Disposition, Analysis Sets 
IP 
 
14.1.1.2 
Screen Failures 
IP 
 
14.1.1.3 
Inclusion/Exclusion Criteria not met, Screen Failures 
IP 
 
14.1.1.4 
Subject Disposition, Early Withdrawal 
IP 
 
14.1.1.5 
Safety Analysis Set by Site 
IP 
 
14.1.1.6 
Subject Visits 
IP 
 
14.1.1.7 
Protocol Deviations 
IP 
 
14.1.2  
Demographics 
 
 
14.1.2.1 
Demographics. Safety Analysis Set 
IP 
 
14.1.2.2 
Demographics. Full Analysis Set 
IP 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1 
Prior Medical History. Safety Analysis Set 
IP 
 
14.1.3.2 
Prior Medical History. Full Analysis Set 
IP 
 
14.1.3.3 
Ongoing Medical History. Safety Analysis Set 
IP 
 
14.1.3.4 
Ongoing Medical History. Full Analysis Set 
IP 
 
14.2  
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1 
Severe Impairment Battery. Full Analysis Set 
Stat IP 
 
14.2.1.2 
Severe Impairment Battery. Per-Protocol Analysis Set 
Stat IP 
 
14.2.1.3 
Severe Impairment Battery. Completers Analysis Set 
Stat IP 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 30 of 35 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.2.1.4 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at week 28 in Severe Impairment 
Battery. Main Analysis 
Stat IP 
 
14.2.1.5 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at week 28 in Severe Impairment 
Battery. Sensitivity Analysis: Visit included as 
categorical predictor 
Stat IP 
 
14.2.1.6 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at week 28 in Severe Impairment 
Battery. Supportive Analysis: Best Case Approach 
Stat IP 
 
14.2.1.7 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at week 28 in Severe Impairment 
Battery. Supportive Analysis: Worst Case Approach 
Stat IP 
 
14.2.1.8 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at week 28 in Severe Impairment 
Battery. Supportive Analysis: Per-Protocol Analysis Set 
Stat IP 
 
14.2.1.9 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at week 28 in Severe Impairment 
Battery. Supportive Analysis: Completers Analysis Set 
Stat IP 
 
14.2.2 
Secondary Efficacy Endpoints 
 
 
14.2.2.1 
Analysis of Covariance model for Severe Impairment 
Battery at Week 42 follow-up visit 
Stat IP 
 
14.2.2.2 
Analysis of Covariance model for Change from Basleine 
of Severe Impairment Battery at Week 13 
Stat IP 
 
14.2.2.3 
Mixed Model with Repeated Measures Analysis of 
Changes from Baseline at weeks 9, 20, 24 and 30 in 
Severe Impairment Battery 
Stat IP 
 
14.2.2.4 
Mixed Model with Repeated Measures Analysis of 
Changes from Baseline at weeks 9, 20, 24 and 30 in 
Severe Impairment Battery for subjects with baseline 
MMSE-2 scores of 10-14 and 15-18 
Stat IP 
 
14.2.2.5 
Individual subject’s trends of SIB over time 
Stat IP 
 
14.2.2.6 
Individual subject’s trends of SIB changes from baseline 
over time 
Stat IP 
 
14.2.3 
Exploratory Endpoints 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 31 of 35 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.2.3.1 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at weeks 13 and 42 in 
Alzheimer’s Disease Cooperative Study – Activities of 
Daily Living - Severe Impairment Version 
Stat IP 
 
14.2.3.2 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at weeks 13 and 42 in Mini 
Mental State Examination, 2nd edition 
Stat IP 
 
14.2.3.3 
Mixed Model with Repeated Measures Analysis of 
Change from Baseline at weeks 13 and 42 in 
Neuropsychiatric Inventory 
Stat IP 
 
14.3  
Safety Data 
 
 
14.3.1  
Displays of Adverse Events 
 
 
14.3.1.1 
Overview of Adverse Events 
IP 
 
14.3.1.2 
Treatment Emergent Adverse Events 
IP 
 
14.3.1.3 
Patients with Treatment Emergent Adverse Events by 
Maximal Severity 
IP 
 
14.3.1.4 
Patients with Treatment Emergent Adverse Events by 
Maximal Relationship to Study Treatment 
IP 
 
14.3.1.5 
Serious Treatment Emergent Adverse Events 
IP 
 
14.3.1.6 
Treatment Emergent Adverse Events Resulting in 
Discontinuation of Study Treatment 
IP 
 
14.3.1.7 
Patients with Treatment Emergent Adverse Events 
Resulting in Discontinuation of Study Treatment by 
Maximal Relationship to Study Treatment 
IP 
 
14.3.1.8 
Patients with Treatment Emergent Adverse Events that 
Lead to Study Discontinuation by Maximal Relationship 
to Study Treatment 
IP 
 
14.3.1.9 
Patients with Serious Treatment Emergent Adverse 
Events by Maximal Relationship to Study Treatment 
IP 
 
14.3.1.10 
Treatment Emergent Adverse Events of Special Interest 
IP 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1 
Hematology, Measured Values and Changes from 
Baseline by Visit 
IP 
 
14.3.4.2 
Hematology, Shifts from Baseline to Post-Baseline Visits 
IP 
 
14.3.4.3 
Clinical chemistry, Measured Values and Changes from 
Baseline by Visit 
IP 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
Synaptogenix, Inc. 
Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
This document is the property of Worldwide Clinical Trials Inc. and may not be duplicated, copied, altered or removed from company without 
prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 32 of 35 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
14.3.4.4 
Clinical chemistry, Shifts from Baseline to Post-Baseline 
Visits 
IP 
 
14.3.5  
Extent of Exposure, Dosage Information and 
Compliance 
 
 
14.3.5.1 
Exposure 
IP 
 
14.3.6  
Vital Signs and Physical Examination 
 
 
14.3.6.1 
Vital Signs, Measured Values and Changes from 
Baseline by Visit 
IP 
 
14.3.6.2 
Weight and BMI, Measured Values and Changes from 
Baseline by Visit 
IP 
 
14.3.6.3 
Physical Examination 
IP 
 
14.3.7  
Other Safety 
 
 
14.3.7.1 
Electrocardiogram, Measured Values and Changes from 
Baseline by Visit 
IP 
 
14.3.7.2 
Electrocardiogram, Shift in Overall interpretation from 
Baseline to Post-Baseline Visits 
IP 
 
14.3.7.3 
Columbia-Suicide Severity Rating Scale (C-SSRS) at 
Screening 
IP 
 
14.3.7.4 
Columbia-Suicide Severity Rating Scale (C-SSRS) at 
Post-baseline Visits 
IP 
 
14.3.8  
Concomitant Medication 
 
 
14.3.8.1 
Prior Medications. Safety Analysis Set 
IP 
 
14.3.8.2 
Prior Medications. Full Analysis Set 
IP 
 
14.3.8.3 
Concomitant Medications. Safety Analysis Set 
IP 
 
14.3.8.4 
Concomitant Medications. Full Analysis Set 
IP 
 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
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prior approval from Worldwide Quality Assurance or in compliance with Worldwide Standard Operating Procedures. 
REF: Worldwide-TMP-QA-001f-1.3 
 
Page 33 of 35 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell 
Number (if 
repeat) 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1 
Mean Values with 95% Confidence Intervals of Severe 
Impairment Battery. Full Analysis Set 
IP 
 
14.2.1.2 
Mean Values with 95% Confidence Intervals of Severe 
Impairment Battery. Per-Protocol Analysis Set 
IP 
14.2.1.1 
14.2.1.3 
Mean Values with 95% Confidence Intervals of Severe 
Impairment Battery. Completers Analysis Set 
IP 
14.2.1.1 
14.2.1.4 
LS Mean Values with 95% Confidence Intervals of 
Change from Baseline in Severe Impairment Battery. 
Main Analysis 
IP 
14.2.1.1 
14.2.1.5 
LS Mean Values with 95% Confidence Intervals of 
Change from Baseline in Severe Impairment Battery. 
Sensitivity Analysis 
IP 
14.2.1.1 
 
 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
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Protocol Number: 
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STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
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Page 34 of 35 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1  
Early Withdrawals 
IP 
 
16.2.1.2 
Subject Visits 
IP 
 
16.2.1.3 
Screen Failures 
 
 
16.2.1.4 
Eligibility Criteria 
 
 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations  
IP 
 
16.2.3 
Subjects Excluded from The Efficacy Analyses 
 
 
16.2.3.1  
Analysis Sets  
IP 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1  
Demographic Data  
IP 
 
16.2.4.2 
Prior and Ongoing Medical History  
IP 
 
16.2.4.3 
Prior and Concomitant Medications 
IP 
 
16.2.4.4 
Non-Pharmacological Procedures 
IP 
 
16.2.4.5 
Rosen-modified Hachinski lschemic score 
IP 
 
16.2.5  
Compliance 
 
 
16.2.5.1  
Exposure 
IP 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1 
Severe Impairment Battery. Questions 1-20 
IP 
 
16.2.6.2 
Severe Impairment Battery. Questions 21-40 
IP 
 
16.2.6.3 
Severe Impairment Battery. Total Scores 
IP 
 
16.2.6.4 
Alzheimer Disease Cooperative Study - Activities of 
Daily Living - Severe Impairment Version 
IP 
 
16.2.6.5 
Alzheimer Disease Cooperative Study - Activities of 
Daily Living - Severe Impairment Version. Total Scores 
IP 
 
16.2.6.6 
Mini Mental State Examination Version 2 
IP 
 
16.2.6.7 
Mini Mental State Examination Version 2. Total Scores 
IP 
 
16.2.6.8 
Neuropsychiatric Inventory 
IP 
 
16.2.6.9 
Neuropsychiatric Inventory. Total Scores 
IP 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1 
Pre-Treatment Adverse Events 
IP 
 
16.2.7.2 
Treatment Emergent Adverse Events 
IP 
 
16.2.7.3 
Serious Treatment Emergent Adverse Events 
IP 
 


Worldwide Clinical Trials Controlled Quality Management Document 
Sponsor: 
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Protocol Number: 
NTRP-101-204 
STATISTICAL ANALYSIS PLAN. PHASE 2-3-4 
 
QMD Ref: Worldwide-TMP-ST-005-7.0 Effective: 12Aug2019 
Governing QMD: Worldwide-SOP-ST-001 
Confidentiality Statement 
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Page 35 of 35 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.7.4 
Treatment Emergent Adverse Events resulting in 
discontinuation of study treatment 
IP 
 
16.2.7.5 
Treatment Emergent Adverse Events with Fatal 
Outcome 
IP 
 
16.2.8  
Individual Laboratory Measurements and Other 
Safety 
 
 
16.2.8.1 
Hematology Results 
IP 
 
16.2.8.2 
Clinical Chemistry Results 
IP 
 
16.2.8.3 
Screening Clinical Chemistry Results 
IP 
 
16.2.8.4 
Vital Signs 
IP 
 
16.2.8.5 
Temperature 
IP 
 
16.2.8.6 
Weight and BMI 
IP 
 
16.2.8.7 
Physical Examinations 
IP 
 
16.2.8.8 
Electrocardiogram Results 
IP 
 
16.2.8.9 
Pregnancy Urine Test 
IP 
 
16.2.8.10 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
IP