Conditions: Alzheimer Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 108
Healthy volunteers: no

Brief summary:
This is a randomized double-blind Placebo-controlled, Phase 2 study comparing bryostatin to placebo for the treatment of moderately severe to severe Alzheimer's disease in subjects not receiving memantine treatment. The study is 15 weeks in duration, including a safety and efficacy evaluation 30 days after the last dose of study drug. Subjects will receive 7 doses of study drug during the study. The primary efficacy endpoint is defined as the change from baseline to Week 13 in the Severe Impairment Battery (SIB) total score.

Detailed description:
Eligible subjects will be stratified based on Mini Mental State Exam (MMSE-2) scores 4-9 vs. 10-15 and will be randomized 1:1 to one of two treatment arms: 20µg bryostatin or placebo for twelve weeks. The first two doses of study drug will be a loading dose 20% higher (i.e., 24µg) than the assigned dose and will be administered one week apart. Thereafter, the assigned dose of 20µg will commence with the third dose and be administered every other week. Drug is administered IV by continuous infusion over 45(±5) minutes. Subjects are scheduled to receive seven doses over 12 weeks.

Arms:
arm 1: 20µg Bryostatin administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. arm 2: Placebo administered IV over 45 minutes every other weekafter 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks.

The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the active drug, intended for IV infusion upon reconstitution and dilution.

Interventions: intervention 1: Bryostatin intervention 2: Placebo
Intervention descriptions: intervention 1: The investigational drug product, bryostatin, is a sterile, pyrogen-free, lyophilized powder intended for IV infusion upon reconstitution and dilution. intervention 2: The placebo is a sterile, pyrogen-free, lyophilized powder identical in appearance to the experimental drug

Protocol document:
Prot_000.pdf: 
 
 
Protocol #: NTRP-101-203 
 
 
CONFIDENTIAL 
Version 3.0 
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Page 1 of 74 
STUDY PROTOCOL 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the Safety, 
Tolerability and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe 
Alzheimer’s Disease Subjects Not Receiving Memantine Treatment 
Protocol Number: 
NTRP-101-203 
Date: 
9 May 2019 
Study Drug: 
Bryostatin 1; matching Placebo 
Investigational new Drug 
Application (IND) Number: 
71,276 
Version: 
3.0 
Planned FPI to LPLV 
Jun 2018 to Jul 2019 
Study Sponsor: 
Neurotrope, Inc. 
 
NCT03560245 
Regulatory Statement 
This study will be performed in compliance with the protocol and in accordance with Good Clinical Practice (GCP) 
(International Conference on Harmonisation [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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SPONSOR’S SIGNATURE PAGE 
Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study 
Assessing Safety, Tolerability and Efficacy of Bryostatin in the 
Treatment of Moderately Severe to Severe Alzheimer’s Disease Subjects 
Not Receiving Memantine Treatment 
Protocol 
Number: 
NTRP-101-203  
Version 3.0, 9 May 2019 
Sponsor’s Authorized Representatives: 
 
 
Alan J Tuchman, MD 
 
 
Acting Chief Medical 
Officer 
Neurotrope, Inc.  
Signature 
 
Date  
Michael Ciraolo, JD, PhD 
 
Chief Operating Officer 
Neurotrope, Inc 
Signature 
 
Date  
Elaine Grenier 
 
Executive Director, 
Clinical Operations 
Neurotrope, Inc. 
Signature 
 
Date 
 
 
 


 
 
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Page 3 of 74 
 
PRINCIPAL INVESTIGATOR’S (PI) SIGNATURE PAGE 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the 
Safety, Tolerability and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe 
Alzheimer’s Disease Subjects Not Receiving Memantine Treatment 
Protocol Number: NTRP-101-203 
Protocol Version and Date:  Version 3.0   9 May 2019 
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  
 
 
 
 
 
 


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


 
 
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Study Administrative Structure 
Clinical Research Organization 
 
Worldwide Clinical Trials 
Operational Headquarters 
1000 Continental Drive 
Suite 290 
King of Prussia, PA  19406 
Tel:  610 964 2000 
Corporate Headquarters 
401 N Maple Drive 
Beverly Hills, CA 90210 
Tel: (310) 786-9100 
Study Medical Monitor/Emergency Contact 
Information 
 
 
Meera Jessani, MD 
Worldwide Clinical Trials 
Tel: 610 964 2012:  
Email: Meera.Jessani@worldwide.com 
 
 
Central Laboratory 
 
 
Eurofins Lancaster Laboratories 
2425 New Holland Pike 
Lancaster, PA 17601 
717.656.2300 
 
Central ECG 
eResearch Technology, Inc. (ERT)  
1818 Market Street, Suite 1000 
Philadelphia, PA 19103-3638 
Tel: (215) 282-5303  
 
 
 
 
 


 
 
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PROTOCOL SYNOPSIS 
 
Name of Company:  
Neurotrope, 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 Efficacy of Bryostatin in the Treatment of Moderately Severe to 
Severe Alzheimer’s Disease Subjects Not Receiving Memantine Treatment 
Study center(s): Approximately 30 sites in United States (US) 
 
Protocol Number: NTRP-101-203 
 
Study Duration: Approximately 12 months 
Study Phase: 2 
 
Objective:  
 
Primary objective:  
To evaluate the safety, tolerability, and efficacy of bryostatin 1 (hereafter referred to as 
bryostatin) for the treatment of moderately severe to 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: 100 randomized subjects (approximately 145 subjects screened) 
Study Design  
This is a randomized double-blind Placebo-controlled, Phase 2 study comparing bryostatin to 
placebo for the treatment of moderately severe to severe Alzheimer’s disease in subjects not 
receiving memantine treatment. The study is 15 weeks in duration, including a safety and 
efficacy evaluation 30 days after the last dose of study drug. Subjects will receive 7 doses of 
study drug during the study. The primary efficacy endpoint is defined as the change from 
baseline to Week 13 in the Severe Impairment Battery (SIB) total score.  
 
Randomization and Treatment 
Eligible subjects will be stratified based on Mini Mental State Exam (MMSE-2) scores 4-9 
vs. 10-15 and will be randomized 1:1 to one of two treatment arms: 20µg bryostatin or 
placebo for twelve weeks. The first two doses of study drug will be a loading dose 20% 
higher (i.e., 24µg) than the assigned dose and will be administered one week apart.  


 
 
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Name of Company:  
Neurotrope, Inc. 
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
Thereafter, the assigned dose of 20µg will commence with the third dose and be 
administered every other week.  Drug is administered IV by continuous infusion over 45(±5) 
minutes. Subjects are scheduled to receive seven doses over 12 weeks.  
 
Evaluation Methods 
Safety and tolerability will be determined through evaluations of adverse events (AE), 
serious adverse events (SAE), physical examination (PE), vital signs, 12-lead 
electrocardiogram (ECG), the Columbia Suicide Severity Rating Scale (C-SSRS), and 
clinical laboratory assessments. 
 
Cognitive improvements will be evaluated primarily with the Severe Impairment Battery 
(SIB) and secondarily with functional improvements in the Alzheimer’s Disease Cooperative 
Study – Activities of Daily Living - Severe Impairment Version (ADCL-ADL-Sev), Clinical 
Global Impression of Improvement (CGI-I), and Neuropsychiatric Inventory (NPI) metrics. 
 
Safety Assessments 
 
• Treatment emergent AEs and SAEs 
• Vital signs, hematology, blood chemistry, physical examination including body 
weight 
• ECG parameters  
• C-SSRS 
 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint is defined as the change from baseline to Week 13 in the SIB 
total score.  
Secondary Efficacy Endpoints   
•  The changes from baseline at Weeks 5, 9 and 15 in the SIB total score  
• The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects 
in the MMSE-2 4-9 stratification group 
• The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects 
in the MMSE-2 10-15 stratification group 
• Individual patient’s slope over time in SIB total score evaluated via Weeks 0, 5, 9, 
and 13 
Exploratory Efficacy Endpoints 


 
 
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Name of Company:  
Neurotrope, Inc. 
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
• 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 10-point Neuropsychiatric Inventory (NPI) total score 
• Clinical Global Impression of Improvement Scale (CGI-I) score 
 
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 assessment. 
The completer analysis set (CAS) will be defined as all randomized subjects who completed 
12 weeks of treatment, and who have a week 13SIB assessment. 
 
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 4-15 inclusive (applies to Screening Visit only) 
5. Patients must be able to perform at least one item on the SIB and may not have a SIB 
score >93 at screening  
6. Neuroimaging computerized tomography (CT) or Magnetic Resonance Imaging 
(MRI) within the last 24 months consistent with a diagnosis of probable AD without 
any other clinically significant co-morbid pathologies.  If there has been a significant 
change in the subject’s clinical status since the last imaging study that is not 
consistent with progression of the subject’s AD, an imaging study should be 
performed to confirm eligibility  
7. Reliable caregiver(s) or informant(s) who attends the subject at least an average of 3 
hours or more per day for 3 or more days per week and who will agree to accompany 
the subject to the clinic visits and reliably complete the caregiver questions  
8. Adequate vision and motor function to comply with testing 
9. If taking an approved cholinesterase inhibitor for treatment of Alzheimer’s disease, 
must be on a stable dose for at least 3 months prior to entry into study and the dose 
must not change during the study unless a change is required due to an adverse effect of 
the prescribed medication or a clinically significant change in the patient’s status 
10. Subjects who are memantine naïve or have been off memantine for at least 30 days prior 
to initial treatment with study drug 
11. Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks 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, 
dextropropoxyphene, tramadol, and ketobemidone.   
8. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to 
screening 
9. Use of valproic acid within 14 days prior to screening  
10. Use of an active Alzheimer’s vaccine within 2 years prior to screening 
11. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening 
12. Any medical or psychiatric condition that is likely to require initiation of additional 
medication or surgical intervention during the course of the study 
13. Any screening laboratory values outside the reference ranges that are deemed 


 
 
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clinically significant by the PI 
14. Use of an investigational drug within 30 days prior to screening  
15. Suicidality defined as active suicidal thoughts during the 6 months prior to screening 
or at Baseline [Type 4 or 5 on C-SSRS], or history of suicide attempt in previous 
2 years, or at serious suicide risk in PI’s judgment 
16. Major psychiatric illness such as current major depression according to Diagnostic 
and Statistical Manual of Mental Disorders, 5th 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 
17. Diagnosis of alcohol or drug abuse within the last 2 years  
18. Abnormal laboratory tests that suggest an alternate etiology for dementia. If the 
patient has prior history of serum B12 abnormality, anemia with hemoglobin ≤10g/dl, 
thyroid function abnormality, electrolyte abnormality, or positive syphilis serology 
the patient should be revaluated to determine if these potential causes of dementia 
have been addressed. Only if these causes have been ruled out as the cause of the 
dementia can the patient be enrolled. 
19. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 
per central reader) 
20. Acute or poorly controlled medical illness: blood pressure > 180 mmHg systolic or 
100 mmHg diastolic; myocardial infarction within 6 months; uncompensated 
congestive heart failure [New York Heart Association (NYHA) Class III or IV]3  
21. Known to be seropositive for human immunodeficiency virus (HIV)  
22. Known to be seropositive for Hepatitis B or C, unless successful curative treatment 
for Hepatitis C (e.g., Harvoni) has been received and there is documentation that there 
is no Hep B/C virus detected 3 months after completion of treatment  
23. AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or 
International Normalized Ratio (INR) >1.5 
24. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in 
the study drug 
25. Any other concurrent medical condition, which in the opinion of the PI makes the 
subject unsuitable for the clinical study 
 
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. 


 
 
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1 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th 
Edition: DSM-5  – May 27, 2013. American Psychiatric Association. Washington, D.C. 
1 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 NTRP101-202 ....................................................................................................22 
2.1.2 
Methodology ................................................................................................................22 
2.1.3 
Demographics ..............................................................................................................22 
2.1.4 
Safety ...........................................................................................................................23 
2.1.5 
Efficacy ........................................................................................................................24 
2.1.6 
Pharmacokinetics .........................................................................................................26 
2.1.7 
Summary ......................................................................................................................26 
2.2 
Study NTRP101-201 ..........................................................................................................26 
2.2.1 
Results ..........................................................................................................................27 
3 
STUDY OBJECTIVES AND HYPOTHESIS ...............................................................28 
3.0 
Primary Objective ..............................................................................................................28 
3.1 
Hypothesis..........................................................................................................................28 
4 
INVESTIGATIONAL PLAN .........................................................................................28 
4.0 
Overview of Study Design .................................................................................................28 
4.1 
Dose Rationale ...................................................................................................................29 
4.2 
Risk/Benefit .......................................................................................................................29 
4.3 
Study Endpoints .................................................................................................................30 
4.3.1 
Safety Assessments ......................................................................................................30 
4.3.2 
Primary Efficacy Endpoint ..........................................................................................30 
4.3.3 
Secondary Efficacy Endpoints .....................................................................................30 
4.3.4 
Exploratory Endpoints..................................................................................................30 
4.4 
Study Population ................................................................................................................31 
4.4.1 
Inclusion Criteria .........................................................................................................31 
4.4.2 
Exclusion Criteria ........................................................................................................32 
5 
PRODUCTS USED IN THIS STUDY ...........................................................................33 
5.0 
Bryostatin ...........................................................................................................................33 
5.1 
Placebo ...............................................................................................................................34 
5.2 
Packaging and Labeling of Study Drug Kits .....................................................................34 
5.3 
Storage and Preparation of Study Drug .............................................................................35 
5.4 
Study Drug Accountability and Disposal ..........................................................................36 


 
 
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5.5 
Randomization ...................................................................................................................36 
5.6 
Blinding..............................................................................................................................37 
5.7 
Study Drug Administration ................................................................................................37 
6 
STUDY PROCEDURES AND ASSESSMENTS ..........................................................37 
6.0 
Table 1 - Schedule of Activities.........................................................................................38 
6.1 
Assessments .......................................................................................................................39 
6.1.1 
Safety ...........................................................................................................................39 
6.1.2 
Efficacy / Psychometric Assessments ..........................................................................41 
6.2 
Visit Procedures .................................................................................................................42 
6.2.1 
Screening and Randomization (Days -28 to -2) ...........................................................42 
6.2.2 
Week 0 (Day 0 Dose 1) ................................................................................................43 
6.2.3 
Week 1 (Day 7 ±2 days Dose 2) ..................................................................................44 
6.2.4 
Week 2 (Day 14 ±2 days/ No dose) .............................................................................44 
6.2.5 
Week3 (Day 21 ±2 days/ Dose 3) ................................................................................44 
6.2.6 
Week 5 (Day 35 ±2 days/ Dose 4) ...............................................................................44 
6.2.7 
Week 7 (Day 49 ±2 days/ Dose 5) ...............................................................................45 
6.2.8 
Week 9 (Day 63 ±2 days/ Dose 6) ...............................................................................45 
6.2.9 
Week 11 (Day 77±2 days/ Dose 7) ..............................................................................45 
6.2.10 
Week 13 (Day 91 ±2 days) ..........................................................................................46 
6.2.11 
Week 15 or End of Treatment Follow-up Visit ...........................................................46 
6.3 
Concomitant Medications ..................................................................................................47 
6.3.1 
Medications for AD .....................................................................................................47 
6.3.2 
Concomitant Medications for Management of Myalgia ..............................................47 
6.3.3 
Prohibited Medications ................................................................................................47 
7 
ADVERSE EVENTS AND OTHER SAFETY EVALUATIONS ...............................48 
7.0 
Definition of Adverse Events.............................................................................................48 
7.1 
Adverse Event of Special Interest - Myalgia .....................................................................48 
7.2 
Definition of Serious Adverse Event .................................................................................48 
7.3 
Assessment of Intensity .....................................................................................................49 
7.4 
Relationship to Study Drug ................................................................................................49 
7.5 
Table 2 Relationship of AE to Study Drug or Trial-Related Procedures ..........................50 
7.5.1 
Unexpected Adverse Event ..........................................................................................50 
7.6 
Reporting Adverse Events .................................................................................................50 
7.6.1 
SAE reports ..................................................................................................................51 
7.6.2 
Reporting to Regulatory Authorities ............................................................................52 
7.7 
Criteria for Withdrawal of Subjects ...................................................................................52 
7.8 
Criteria for Permanent Discontinuation of Study Drug .....................................................52 
7.9 
Study Discontinuation ........................................................................................................53 
8 
SAFETY MONITORING ...............................................................................................53 
9 
DATA ANALYSIS / STATISTICAL METHODS........................................................53 
9.0 
Sample Size Determination................................................................................................54 
9.1 
Statistical Methods .............................................................................................................55 
9.2 
Exploratory Analysis .........................................................................................................55 
9.3 
Safety Analysis ..................................................................................................................56 
9.4 
Analysis of Primary Efficacy Endpoint .............................................................................56 


 
 
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9.5 
Secondary  Efficacy Endpoints ..........................................................................................56 
9.5.1 
Changes from baseline at Weeks 5, 9 and 15 in the SIB total score............................56 
9.5.2 
The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects 
in the MMSE-2 4-9 stratification group.......................................................................57 
9.5.3 
The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects 
in the MMSE-2 10-15 stratification group...................................................................57 
9.5.4 
Individual patient’s slope over time in SIB total score evaluated via Weeks 0, 5, 9 and 
13 57 
9.6 
Analysis of Exploratory Endpoints ....................................................................................57 
9.7 
Safety Assessments ............................................................................................................57 
9.8 
Analysis of Safety Data .....................................................................................................58 
9.8.1 
Adverse Events ............................................................................................................58 
9.8.2 
Clinical Laboratory Evaluations ..................................................................................58 
9.8.3 
Physical Examination...................................................................................................59 
9.8.4 
Vital Signs ....................................................................................................................59 
9.8.5 
ECG..............................................................................................................................60 
9.8.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ....................................................60 
10 
DATA MONITORING ....................................................................................................60 
10.0 
Source Documentation .......................................................................................................60 
10.1 
Study Documentation and Record Retention .....................................................................60 
10.2 
Site Monitoring ..................................................................................................................61 
10.3 
Quality Assurance and Quality Control .............................................................................62 
10.4 
Audits and Inspections .......................................................................................................62 
11 
ETHICS ............................................................................................................................62 
11.0 
Institutional Review Board ................................................................................................62 
11.1 
Ethical Conduct of the Study .............................................................................................63 
11.2 
Written Informed Consent .................................................................................................63 
12 
STUDY MANAGEMENT ...............................................................................................63 
12.0 
Data Collection and Management ......................................................................................63 
12.1 
Data Quality Control ..........................................................................................................63 
12.2 
Data Management and Data Storage..................................................................................64 
12.3 
Inspection of Records ........................................................................................................64 
12.4 
Retention of Records..........................................................................................................64 
12.5 
Confidentiality ...................................................................................................................65 
12.6 
Protocol Amendments ........................................................................................................65 
12.7 
Protocol Deviations ............................................................................................................65 
12.8 
Data Corrections ................................................................................................................65 
12.9 
Insurance ............................................................................................................................65 
13 
PUBLICATION AND DISCLOSURE POLICY ..........................................................66 
14 
APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS ........................67 
15 
APPENDIX 2  LIST OF REFERENCES ......................................................................72 
16  
APPENDIX 3  SUMMARY OF CHANGES  
 
 
 
 
 
 
 
 
 
  73 
 
 


 
 
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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 
CAS 
Columbia-Classification Algorithm of Suicide Assessment 
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 
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 Harmonisation 
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 
Mitogen Activated Protein 
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  
PAP 
Pharmacokinetic Analysis Plan  
PBMCs 
Peripheral Blood Mononuclear Cells 


 
 
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Abbreviation 
Definition 
 
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 Brain 
Derived Neurotropic Factor (BDNF), prevention of synapse loss, reduced plaque formation and 
restored memory and learning even in the presence of plaques.  


 
 
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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 14, 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 10ug/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 15ug/kg (infusion and bolus).  There were no significant differences in toxicity 
between the two routes of administration.  A more detailed results summary can be found in the 
Investigator’s Brochure. 


 
 
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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 1.05hours 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 0.81hours and an elimination t½ of 28.76hours. 
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, 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.  


 
 
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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 NTRP101-202 
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 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.  
 
2.1.3 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 


 
 
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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). 
 
2.1.4 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. 
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. 


 
 
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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. 
 
2.1.5 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 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 


 
 
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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 40μg bryostatin treatment group.  
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. 
 


 
 
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2.1.6 Pharmacokinetics 
Mean plasma bryostatin concentrations increased approximately proportional to dose for an 
increase in dose between 20 μg and 40 μg, 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 40 μg. 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. 
2.1.7 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. 
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.  
2.2 
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. 


 
 
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The study included single dose PK, and measurement of PKCε in peripheral blood mononuclear 
cells (PBMCs) as a potential biomarker.  
 
2.2.1 Results 
2.2.1.1 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. 
 
2.2.1.2 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. 
2.2.1.3 Efficacy  
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 255μg/m2 bryostatin. 
2.2.1.4 
Pharmacokinetics  
The pharmacokinetics of bryostatin were assessed in 6 subjects following 25 g/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 


 
 
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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. 
2.2.1.5 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. 
2.2.1.6 Conclusions 
This was the first double-blind assessment of the safety of bryostatin treatment in subjects with 
Alzheimer’s disease.  The study met it primary endpoint of safety and tolerability.  Bryostatin 
appears safe and well tolerated in this cohort of subjects with mild to moderate Alzheimer’s 
disease.  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 efficacy of bryostatin for the treatment of moderately severe 
to severe Alzheimer’s disease in subjects not receiving concurrent memantine treatment. 
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 12 weeks 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 two-sample t-test, 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 to severe Alzheimer’s disease in subjects not receiving 
memantine treatment.  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 MMSE-2 scores 4-9 
vs. 10-15 and will be randomized 1:1 to treatment with 20µg bryostatin or placebo for 12 weeks of 


 
 
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treatment.  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.  Subjects are scheduled to receive seven doses over 12 weeks.  
Safety and efficacy assessments will be done as indicated on the Schedule of Activities (Table 1).  
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 appear to 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 40 
µg 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 to assure enzyme activation. Dosing will then continue every 
other week. 
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 (20 μg and 40 μg) 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.  NTRP101-203 will prospectively seek 
to replicate these findings and demonstrate a clear benefit both in terms of safety and efficacy in 
this patient population when comparing the 20µg bryostatin dose to placebo. 
Therapeutic antibodies targeting β-amyloid have been associated with the occurrence of amyloid 
related imaging abnormalities (ARIA), which is similar in appearance to cerebral 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 
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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 defined as the change from baseline to Week 13 in the SIB 
score.  
4.3.3 
Secondary Efficacy Endpoints   
• The changes from baseline at Weeks 5, 9 and 15 in the SIB total score  
• The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects in the 
MMSE-2 4-9 stratification group 
The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects in the 
MMSE-2 10-15 stratification group 
• Individual patient’s slope over time in SIB evaluated via Weeks 0, 5, 9, and 13. 
4.3.4 
Exploratory Endpoints 
• 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 10-point Neuropsychiatric Inventory (NPI) total score 
• Clinical Global Impression of Improvement Scale (CGI-I) score 


 
 
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4.4 
Study Population 
Subjects with moderately severe to severe Alzheimer’s disease defined as a MMSE-2 score of 4-15 
inclusive are eligible to enroll.  Subjects will be permitted to continue present FDA-approved 
treatments for Alzheimer’s disease 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 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 4-15 inclusive (applies to Screening Visit only) 
5. Patients must be able to perform at least one item on the SIB and may not have a SIB score 
>93 at screening  
6. Neuroimaging computerized tomography (CT) or Magnetic Resonance Imaging (MRI) within 
the last 24 months consistent with a diagnosis of probable AD without any other clinically 
significant co-morbid pathologies.  If there has been a significant change in the subject’s 
clinical status since the last imaging study that is not consistent with progression of the 
subject’s AD, an imaging study should be performed to confirm eligibility  
7. Reliable caregiver(s) or informant(s) who attends the subject at least an average of 3 hours or 
more per day for 3 or more days per week and who will agree to accompany the subject to the 
clinic visits and reliably complete the caregiver questions  
8. Adequate vision and motor function to comply with testing 
9. If taking an approved cholinesterase inhibitor for treatment of Alzheimer’s disease, must be on 
a stable dose for at least 3 months prior to entry into study and the dose must not change during 
the study unless a change is required due to an adverse effect of the prescribed medication or a 
clinically significant change in the patient’s status 
10. Subjects who are memantine naïve or have been off memantine for at least 30 days prior to initial 
treatment with study drug   
11. Subjects on neuroleptic medications must be on a stable dose for ≥4 weeks (dose adjustments 
will be permitted) 
12.  Females participating in the study must meet one the following criteria: 
a. Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal ligation) for at 
least 6 months or postmenopausal (postmenopausal females must have no menstrual 
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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 suppressant), 
ketamine, phencyclidine (PCP), methoxetamine (MXE), nitrous oxide (N2O) and the following 
synthetic opioids: penthidine, levorphanol, methadone, dextropropoxyphene, tramadol, and 
ketobemidone.   
8. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to screening 
9. Use of valproic acid within 14 days prior to screening  
10. Use of an active Alzheimer’s vaccine within 2 years prior to screening 
11. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening 
12. Any medical or psychiatric condition that is likely to require initiation of additional medication 
or surgical intervention during the course of the study 


 
 
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13. Any screening laboratory values outside the reference ranges that are deemed clinically 
significant by the PI 
14. Use of an investigational drug within 30 days prior to screening  
15. Suicidality defined as active suicidal thoughts during the 6 months prior to screening or at 
Baseline [Type 4 or 5 on C-SSRS], or history of suicide attempt in previous 2 years, or at 
serious suicide risk in PI’s judgment 
16. Major psychiatric illness such as current major depression according to Diagnostic and 
Statistical Manual of Mental Disorders, 5th 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 
17. Diagnosis of alcohol or drug abuse within the last 2 years  
18. Abnormal laboratory tests that suggest an alternate etiology for dementia. If the patient has 
prior history of serum B12 abnormality, anemia with hemoglobin ≤10g /dl, thyroid function 
abnormality, electrolyte abnormality, or positive syphilis serology the patient should be 
revaluated to determine if these potential causes of dementia have been addressed. Only if 
these causes have been ruled out as the cause of the dementia can the patient be enrolled. 
19. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per central 
reader) 
20. Acute or poorly controlled medical illness: blood pressure > 180 mmHg systolic or 100 mmHg 
diastolic; myocardial infarction within 6 months; uncompensated congestive heart failure [New 
York Heart Association (NYHA) Class III or IV]18  
21. Known to be seropositive for human immunodeficiency virus (HIV)  
22. Known to be seropositive for Hepatitis B or C, unless successful curative treatment for 
Hepatitis C (e.g., Harvoni) has been received and there is documentation that there is no Hep 
B/C virus detected 3 months after completion of treatment  
23. AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or International 
Normalized Ratio (INR) >1.5 
24. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study 
drug 
25. Any other concurrent medical condition, which in the opinion of the PI makes the subject 
unsuitable for the clinical study 
 
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 0.05mg bryostatin, 2.5mg povidone lyophilized from 40% t-butanol. Accompanying 


 
 
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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. 
Caution New Drug - Limited by Federal Law (US) to Investigational use. 
Each kit contains 7 vials Bryostatin for Infusion, 0.05 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, 0.05mg 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. 


 
 
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Each vial contains 0.05 mg 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. 
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 4.8 mL 
loading dose for the first two doses and a 4.0 mL 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 


 
 
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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. 
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. 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.   


 
 
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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 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 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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6.0 
Table 1 - Schedule of Activities 
 
 
NTRP101-203 
 
We e k 
 
Screening 
 
0 
 
1 
 
2 
 
3 
 
5 
 
7 
 
9 
 
11 
 
13 
 
15/ET 
Day (±2 days) 
(Days -28 to -2)d 
0 
7 
14 
21 
35 
49 
63 
77 
91 
105 
Dose 
 
Rand 
1 
2 
 
3 
4 
5 
6 
7 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Rosen-modified 
Hachinski Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
SIB 
X∆ 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
MMSE-2 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
ADCS-ADL-Sevb 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
NPIb 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
 
CGI-I 
 
 
 
 
 
 
X* 
 
X* 
 
X 
 
CSSRS 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
Labs^^ 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
ECG 
X (x3) 
 
 
 
X 
 
 
X 
 
 
X 
 
PE 
X 
 
 
 
 
 
 
X*+ 
 
 
X 
 
Vitals 
X 
 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
Randomization 
 
Xa 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X◊ 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
∆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 (B12, T-3 and T-4 if TSH abnormal), CPK at screening and event 
of myalgia, βhCG if indicated, HbA1C if clinically indicated; ◊ CT scan if necessary per inclusion criterion #6; + abbreviated 
physical examination; 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;c 
Vital 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.  


 
 
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6.1 
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. 
6.1.1 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.  
6.1.1.1 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 B12, 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. 
6.1.1.2 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) 
• Ears  


 
 
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• 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.   
6.1.1.3 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.  
6.1.1.4 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. 
6.1.1.5 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 
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 


 
 
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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. 
6.1.2 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 4-15 range for 
inclusion, no further screening tests should be performed.  Efficacy tests at subsequent visits 
should be administered prior to dosing. 
6.1.2.1 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. 
6.1.2.2 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.   
6.1.2.3 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 
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.  


 
 
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6.1.2.4 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. 
6.1.2.5 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.  
6.1.2.6 Clinical Global Impression of Improvement Scale  
The CGI-I is used to assess global change in the subject’s condition compared to baseline before 
treatment.  The same Clinician must complete the CGI-I scale at each scheduled visit. This is a 
seven-point scale ranging from (1) very much improved to (7) very much worse. 
6.2 
Visit Procedures 
6.2.1 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.  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 to avoid unnecessary procedures for 
ineligible subjects:  
• Collection of subject demographic data 
• Review of concomitant medications  


 
 
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• Review of medical history  
• 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 (B12, T-3 and T-4 if indicated), and β-hCG, if 
indicated 
• 12-lead ECG (x3) 
• Complete physical examination  
• Vital signs 
• AEs 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). 
 
6.2.2 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. 


 
 
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• Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
• AEs and concomitant medications  
6.2.3 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 
6.2.4 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  
6.2.5 Week3 (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  
6.2.6 Week 5 (Day 35 ±2 days/ Dose 4) 
• Prior to dosing:  
o SIB  
o MMSE-2 
o ADCS-ADL-Sev 
o NPI 
o CGI-I 


 
 
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• 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 
6.2.7 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 
• AEs and concomitant medications 
6.2.8 Week 9 (Day 63 ±2 days/ Dose 6) 
• Prior to dosing:  
o SIB  
o MMSE-2 
o ADCS-ADL-Sev 
o NPI 
o CGI-I 
• 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 
6.2.9 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 


 
 
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• Adverse events and concomitant medications 
6.2.10 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  
• MMSE-2 
• ADCS-ADL-Sev 
• NPI 
• CGI-I 
• CSSRS 
• Blood samples for routine safety  
• 12-lead ECG 
• PE 
• Vital signs  
• AEs  
• Concomitant medications 
6.2.11 Week 15 or End of Treatment Follow-up Visit 
For subjects who have completed the study, a follow-up visit will take place at Week 15, 30 days 
after the last dose of study drug. Subjects who have withdrawn from the study will have a 
follow-up visit 30 days after the last dose of study drug. The following will be performed: 
• SIB 
• MMSE-2 
• ADCS-ADL-Sev 
• Vitals 
• AEs and concomitant medications 


 
 
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6.3 
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. 
6.3.1 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.  
6.3.2 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. 
6.3.3 Prohibited Medications  
Memantine is prohibited.  Subjects previously treated with memantine must stop treatment at 
least 30 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, 
phencyclidine (PCP), methoxetamine (MXE), nitrous oxide (N2O) and the following synthetic 
opiods: 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. 
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. 
 


 
 
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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.  
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 


 
 
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• 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 
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 
 


 
 
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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 
properties of the drug, but are not specifically mentioned as occurring with the particular drug 
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. 


 
 
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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.   
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:  


 
 
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• 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 
• 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 


 
 
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• if the PI believes that discontinuing treatment is in the best interest of the subject 
7.9 
Study Discontinuation 
Neurotrope 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 Neurotrope. 
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 Neurotrope or designee. 
  
8 SAFETY MONITORING 
An Independent Safety Monitor will provide consultation to Neurotrope to assess the 
implementation and progress of study NTRP101-203 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 Independent 
Safety Monitor 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.  
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. 


 
 
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Descriptive summaries of safety and efficacy data including number of evaluable subjects, mean, 
median, SD, maximum and minimum for continuous variables will be provided by treatment 
group and scheduled visit.  Categorical variables will be presented showing number evaluable, 
frequencies and percentages.  In addition, the same descriptive statistics will be provided for 
changes from baseline at each post-baseline visit. 
The primary efficacy analyses of the primary endpoint will be conducted on data collected 
through Week 13.  
9.0 
Sample Size Determination  
Based on post hoc analyses of the NTRP 101-202 study for patients not treated with memantine, 
the SIB for the 20ug bryostatin group demonstrated a mean (SD) increase of 4.5 (6.8) points 
from baseline by Week 13. In contrast, patients not treated with memantine in the placebo arm 
showed a decrease in SIB scores at the 13-week time-point from baseline, giving a mean (SD) 
SIB change of -0.9 (6.7) points. This resulted in group difference in means of the 13-week SIB 
measure from baseline SIB changes of 5.4 points.  
Guided by these post hoc results, power analyses were performed based on 50 patients per 
treatment arm, and assuming differences of between 4.0 to 5.5 points in the treatment arm-
specific means of the primary outcome (e.g. the treatment effect). Table 2 below gives the 
estimated power to detect various treatment effects, assuming a two-sided alpha of 0.05. Based 
on these analyses, 50 patients per group will give an approximate 83% power to detect a 
treatment effect of 4.0 points, and an estimated power of 98% to see a treatment effect of 5.5 
points. Power calculation was based the two-sample t-test of the group difference in the mean 
13-week SIB changes from baseline SIB. 
Table 2: Power to detect treatment effect sizes of between 4.0 to 5.5 points; 50 patients per 
group with an available primary efficacy endpoint.  
Diff. in Deltas 
Power 
N1 
N2 
Two-sided Alpha 
4.0 
83% 
50 
50 
0.05 
4.5 
91% 
50 
50 
0.05 
5.0 
95% 
50 
50 
0.05 
5.5 
98% 
50 
50 
0.05 
 
Power analyses were also preformed to determine detectable effect sizes that assume an 
estimated dropout rate of 25% (e.g. 50 patients per group at a baseline, dropping to 37 patients 
per group by Week 13). Table 3 gives the estimated powers for treatment effects of between 4.5 
and 5.5 points, assuming a 25% dropout rate. Note that a minimum treatment effect of 4.5 points 
can be statistically detected with at least 80% power, given 37 patients per group with a primary 
efficacy endpoint.  


 
 
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Table 3: Power to detect treatment effect sizes of between 4.5 to 5.5 points; 37 patients per 
group with an available primary efficacy endpoint.  
Diff. in Deltas 
Power 
N1 
N2 
Two-sided Alpha 
4.5 
80% 
37 
37 
0.05 
5.0 
88% 
37 
37 
0.05 
5.5 
93% 
37 
37 
0.05 
 
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).  
The Full Analysis Set (FAS) used for efficacy analyses, 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 completer analysis set (CAS) will be defined as all randomized subjects who completed 12 
weeks of treatment, and who have a week 13 SIB assessment. 
Demographics 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.   
 


 
 
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9.3 
Safety Analysis 
The SAS population will be used for all safety analyses with treatment group determined by the 
treatment actually received. 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). 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. 
Subject disposition will be summarized by treatment group and will include numbers screened, 
randomized, dosed and withdrawn with reason for withdrawal. 
9.4 
Analysis of Primary Efficacy Endpoint 
The primary endpoint for this study is the change from baseline to Week 13 in the SIB total 
score. The primary analysis will be conducted on FAS population. The CAS population will be 
used as a supportive analysis.  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 101-202 clinical trial, 
the expected number of patients who will drop out of the study prematurely will not be 
significant. For efficacy evaluations, multiple imputation methods will be used to handle missing 
data. This imputation method is a robust method to impute missing measurements. The 
imputation will be carried out in SAS version 9.4 or later using PROC MI. Each imputation 
model will include the stratification factor (i.e., MMSE-2 score (4-9 vs. 10-15)) as a covariate in 
the model.. 
 
9.5 
Secondary  Efficacy Endpoints 
 
9.5.1 Changes from baseline at Weeks 5, 9 and 15 in the SIB total score 
The change from baseline at Week 5, 9 and 15 in the SIB total score will be summarized 
descriptively and compared using ANCOVA adjusted for baseline SIB total score. If the 
normality assumption is not met, a non-parametric method or a rank-ANCOVA analysis will be 
used. 
 
 


 
 
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9.5.2 The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for 
subjects in the MMSE-2 4-9 stratification group 
Similar analysis methods as the primary endpoint will be used for analysis of this endpoint. 
9.5.3 The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for 
subjects in the MMSE-2 10-15 stratification group 
Similar analysis methods as the primary endpoint will be used for analysis of this endpoint. 
9.5.4 Individual patient’s slope over time in SIB total score evaluated via Weeks 0, 5, 9 
and 13  
 
Individual-specific SIB slopes will be estimated for all patients over each person’s available SIB 
outcome measures. An indicator will be assigned to each patient depending on the sign of the 
SIB slope β (i.e. I=-1 if β <0; 1 if β >0; no value otherwise). The proportions of patients with I=1 
and, respectively, -1 will be compared using logistic regression to assess the overall trend 
between treatments. In addition, an overall population averaged slope will be estimated for each 
treatment arm, and two-sample t-test will be used to assess the difference between treatments. 
   
9.6 
Analysis of Exploratory Endpoints  
The following exploratory endpoints will be analyzed:  
Change from baseline in ADCS-ADL-Sev total score 
Change from baseline in MMSE-2 total score 
Change from baseline in NPI total score 
CGI-I score 
Similar analysis methods as the primary endpoint 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 Independent Safety 
Monitor 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:   


 
 
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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. 
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.   


 
 
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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: 
• 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, urine dip-stick results 
• Correspondence regarding a subjects’ 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 


 
 
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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.  Neurotrope 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 Neurotrope 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 Neurotrope, 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 visit the study site to: 
• 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 Neurotrope , or its representatives.  This will be 
documented in a clinical study agreement between Neurotrope and the PI. 
During the study, a monitor from Neurotrope, 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 Neurotrope  
• 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). 


 
 
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• 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, Neurotrope, Inc. or 
its representative may conduct a quality assurance audit. 
10.4 
 Audits and Inspections 
Authorized representatives of Neurotrope, 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 Neurotrope immediately if contacted by a regulatory agency about an inspection. 
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 Form, must be 
approved in writing by an IRB.  The PI must submit written approval to Neurotrope 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.   
Neurotrope,   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. 


 
 
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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/Neurotrope 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. 
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 
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. 


 
 
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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.  
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 
Neurotrope, 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 Neurotrope or designee.  No study documentation should be 
destroyed or moved to a new location without prior written approval by Neurotrope.  


 
 
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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 
Neurotrope 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 (eg, 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.  
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.  


 
 
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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. 
 
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) 
 
 
Antacids 
 
(Y) 
(Y) 
 
Antianginal agents 
(Y) 
(Y) 
 
 
Antiarrhythmics 
(N) 
(Y) 
Dose must be stable for 1 
month prior to Screening. 
 
Antiasthma agents 
(Y) 
(Y) 
 
 
Antibiotics 
(Y) 
Call  
Call Medical Monitor. 
 
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. 
 


 
 
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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 
 
Anticoagulants 
(N) 
(Y) 
Heparin is not allowed  
 
Anticonvulsants 
(N) 
(N) 
Divalproex, Valproate, 
Topiramate are prohibited. 
Anticonvulsants with 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 dosed 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.   
Antidiarrheal 
preparations  
 
(Y) 
(N) 
Kaolin, Imodium and Pepto-
Bismol preparations are 
allowed. Call Medical 
Monitor for others. 
 
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 


 
 
Protocol #: NTRP-101-203 
 
 
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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 
 
preparations for combination 
products. 
Antihypertensives 
 
(N) 
(Y) 
Diupres (reserpine), Catapres 
(clonidine), Minipress (prazosin), 
Inderal (propranalol), Wytensin 
(guanabenz), Tenex (guanfacine) 
and Aldomet (methyldopa) are not 
allowed.  All others - medication 
and dose must be stable for 1 
months prior to Screening. 
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. 
 
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. 
 
Antiviral agents 
(Y) 
(Call) 
Zovirax, Valtrex, Famvir are 
allowed. For others, call Medical 
Monitor 
 
Anxiolytics 
(Y) 
(N) 
Limited use of short/medium acting 
benzodiazepines if needed is allowed
Do not use within 12 hrs before 
efficacy assessments.  
 
BPH agents 
(N) 
(Y) 
Alpha-1 blockers (Hytrin, Flomax, 
Cardura) and finasteride are 


 
 
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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 
 
permitted.  Drug and dose must be 
stable for 3 months prior to 
Screening. 
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. 
Diuretics 
(N) 
(Y) 
Medication and dose must be stable 
for 1 months prior to Screening. 
 
Ginko biloba 
(N) 
(Y) 
Dose must be stable for at least 
one month prior to Screening. 
 
H2 Blockers 
 
(Y) 
(Y) 
For patients on chronic therapy, 
medication and dose must be 
stable for 1 months prior to 
Screening. 
 
Hormones 
(N) 
(Y) 
Medication and dose must be stable 
for 3 months prior to Screening. 
 
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 
 


 
 
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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 
 
 
(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. 


 
 
Protocol #: NTRP-101-203 
 
 
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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. 
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. 
 
16 APPENDIX 3  
SUMMARY OF CHANGES 
16.1 
Version 2.0, 21 Aug 2018 
Global changes:  
• Neurotrope change of address and logo have been updated. 
• Spelling correction: ADCS-ADL-Sev replaces ADCS-ADL-Siv in the list of 
abbreviations and wherever it occurs in the document 
• IRT (Interactive Response Technology) replaces IwRS (Interactive Web Response 
System) in the list of abbreviations and wherever it occurs in the document. 
Inclusion criterion #4 clarification: MMSE-2 inclusion range of 4-15 applies to screening 
criterion only and may deviate from this range during study participation. 
Inclusion criterion #5: The upper limit SIB score for inclusion has been changed from 97 to 93 to 
optimize measurement of improvement. 
Exclusion Criterion #4: Text has been added to describe parameters for eligibility with medical 
history of cancer: 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. 
Section 5.3: Since all site personnel are blinded, there is no need to exclude individuals preparing 
study drug from participation in safety or efficacy assessments. The sentence “The individual 
designated to prepare the study drug may not participate in any study subject safety or efficacy 
evaluations.” has been removed. 
Section 5.5: Text has been added to describe randomization procedure details. The text now 
reads: “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 


 
 
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the EDC system, the subject can be randomized via Interactive Response Technology (IRT) 
system.”   
Section 6.0, Table 1 Schedule of Activities: A footnote has been added to clarify time window 
for the screening window. The visit window of ±2 Days for scheduled study visits does not 
apply to the screening and randomization period which is a maximum of 28 days. 
Section 6.1.2: Text has been clarified to be consistent with Section 6.2.1. The MMSE-2 should 
be administered and assessed before administering the SIB at screening. For all study visits after 
randomization, the SIB should be administered first. 
Section 6.2.1 Text has been added to describe subject re-screening: 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.  
Subjects 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.  
Section 14, Appendix 1 Restricted Concomitant Medications: Memantine has been removed 
from the list of allowed AD medications. 
 
16.2 Version 3.0, 18 April 2019 
No changes have been made to study procedures. 
The primary efficacy endpoint was described in previous versions as the change in the Severe 
Impairment Battery (SIB) scale score after 12 weeks of treatment from baseline (taking the 
change in the average of SIB measures observed during the Week 13 to Week 15 time window 
from SIB at baseline).   
The revised text is: The primary efficacy endpoint is defined as the change from baseline to 
Week 13 in the SIB total score.  This change was made to assure consistency with the primary 
analysis endpoint as analyzed in study NTRP101-202, for which NTRP101-203 is considered a 
confirmatory study. 
Secondary endpoints were added to analyze the changes from baseline at Weeks 5, 9, 13 and 15 
in the SIB total score for subjects enrolled in the MMSE-2 4-9 stratification group and the 
MMSE-2 10-15 stratification group. Similar analysis methods as the primary endpoint will be 
used for analysis of these endpoints. 
 

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN  
FOR PROTOCOL NTRP-101-203 
 
  
Sponsor: 
 
Neurotrope, Inc. 
1185 Avenue of the 
Americas. 
3rd Floor 
New York, NY 10036 
Tel : (973)242-0005 
Fax : (973)242-0009 
 
 
 
Protocol Number: 
NTRP-101-203 
 
 
Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 2 
Study Assessing the Safety, Tolerability and Efficacy of 
Bryostatin in the Treatment of Moderately Severe to Severe 
Alzheimer’s Disease Subjects Not Receiving Memantine 
Treatment 
 
 
Protocol Date / Version: 
Version 3.0 / 9 May 2019 
 
 
 
 
 
 
SAP Author: 
Amarex, Clinical Research 
20201 Century Boulevard 
Germantown, MD  20874 
USA 
Telephone:   1-866-AMAREX-1 
 
 
1-301-528-7000 
 
Facsimile: 
1-301-528-2300 
 
 
Plan Version: 
SAP –Version 1.0 
 
 
Plan Date: 
9 May 2019 
 
 
 
 
 
 
 
--- confidential---  


Protocol: NTRP-101-203 
Statistical Analysis Plan 
Neurotrope, Inc  
 
 
 
 
 
 
 
 
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Protocol Number:  
NTRP-101-203 
Protocol 
Version/Date: 
Version 3.0 / 9 May 2019 
Protocol Name: 
A Randomized, Double-Blind, Placebo-Controlled, Phase 
2 Study Assessing Safety, Tolerability and Efficacy of 
Bryostatin in the Treatment of Moderately Severe to 
Severe Alzheimer’s Disease Subjects Not Receiving 
Memantine Treatment 
 
Sponsor: 
Neurotrope, Inc. 
1185 Avenue of the Americas. 
3rd Floor 
New York, NY 10036 
Prepared by: 
Amarex Clinical Research 
20201 Century Boulevard 
Germantown, Maryland  20874 
SAP Version: 
SAP –Version 1.0 
SAP Date: 
9 May 2019 
 
 
 
I have read and approve the Statistical Analysis Plan specified above and agree with its 
content: 
 
 
 
 
Statistician, Amarex 
 
Date 
 
 
 
Neurotrope, Inc. Representative  
 
 
Date 


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Statistical Analysis Plan 
Neurotrope, Inc  
 
 
 
 
 
 
 
 
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TABLE OF CONTENTS 
 
Section   
Page 
LIST OF ABBREVIATIONS ........................................................................................................... 5 
1. 
INTRODUCTION ........................................................................................................................... 7 
2. 
PROTOCOL DESIGN AND OBJECTIVE .................................................................................. 7 
2.1 
Design Overview ................................................................................................................ 7 
2.2 
Treatment Groups ............................................................................................................... 8 
2.3 
Randomization .................................................................................................................... 8 
2.4 
Blinding .............................................................................................................................. 8 
2.5 
Study Objective .................................................................................................................. 9 
2.6 
Efficacy Assessments ......................................................................................................... 9 
2.6.1 
Primary Efficacy Endpoint ................................................................................... 9 
2.6.2 
Secondary Efficacy Endpoints.............................................................................. 9 
2.6.3 
Exploratory Endpoints: ......................................................................................... 9 
2.7 
Safety Assessments ........................................................................................................... 10 
3. 
SAMPLE SIZE DETERMINATION AND RATIONALE, STATISTICAL POWER, 
AND SIGNIFICANCE LEVEL ................................................................................................... 10 
4. 
INTERIM ANALYSIS ................................................................................................................. 11 
5. 
PRIMARY HYPOTHESIS TO BE TESTED ............................................................................. 11 
6. 
ANALYSIS POPULATIONS ....................................................................................................... 11 
6.1 
Full Analysis Set ............................................................................................................... 11 
6.2 
Safety Analysis Set ........................................................................................................... 12 
6.3 
Completer Analysis Set .................................................................................................... 12 
7. 
DATA CONVENTION AND RELATED DEFINITIONS ........................................................ 12 
7.1 
Baseline Definition ........................................................................................................... 12 
7.2 
Duplicate Data .................................................................................................................. 12 
7.3 
Handling of Missing Data ................................................................................................. 12 
7.3.1 
Handling of Missing Data for Efficacy Evaluations ........................................... 12 
7.4 
Multicenter Clinical Trials ................................................................................................ 13 
7.5 
Multiple Comparisons and Multiplicity ............................................................................ 13 
7.6 
Covariates and Prognostic Factors .................................................................................... 13 
7.7 
Stratification Factors and Subgroups ................................................................................ 13 
7.8 
Standard Calculations ....................................................................................................... 14 
7.8.1 
Age ..................................................................................................................... 14 
7.8.2 
Height ................................................................................................................. 14 
7.8.3 
Weight ................................................................................................................ 14 
7.8.4 
Change from Baseline ........................................................................................ 14 
8. 
STATISTICAL METHODS ........................................................................................................ 14 
8.1 
Disposition and Baseline Characteristics .......................................................................... 14 
8.1.1 
Subject Disposition and Withdrawals ................................................................. 15 
8.1.2 
Demographics and Baseline Characteristics ....................................................... 15 
8.1.3 
Prior and Concomitant Medications ................................................................... 15 
8.1.4 
Treatment Administration and Compliance ........................................................ 15 
8.2 
Analysis of Efficacy Data ................................................................................................. 16 


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8.2.1 
Primary Efficacy Endpoint ................................................................................. 16 
8.2.2 
Secondary Efficacy Endpoints............................................................................ 16 
8.2.3 
Exploratory Endpoints ........................................................................................ 17 
8.3 
Analysis of Safety Data .................................................................................................... 18 
8.3.1 
Adverse Events ................................................................................................... 18 
8.3.2 
Clinical Laboratory Evaluations ......................................................................... 18 
8.3.3 
Physical Examination ......................................................................................... 19 
8.3.4 
Vital Signs .......................................................................................................... 19 
8.3.5 
ECG .................................................................................................................... 19 
8.3.6 
Columbia Suicide Severity Rating Scale (C-SSRS) ........................................... 19 
9. 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ..................................................................... 21 
10. 
APPENDIX 2 – PLANNED TLG ................................................................................................ 22 
10.1 
Planned by-subject listings ............................................................................................... 22 
10.2 
Planned Summary Tables ................................................................................................. 23 
11. 
VERSION HISTORY ................................................................................................................... 24 
12. 
REFERENCES .............................................................................................................................. 25 


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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
ASA 
American Statistical Association  
CBC 
Complete Blood Count 
C.I. 
Confidence Interval 
CM 
Concomitant Medications 
CMED 
Concomitant Medications 
CRO 
Contract Research Organization 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
ECG 
Electrocardiogram 
EOS 
End of study 
FAS 
Full Analysis Set 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
IA 
Interim analysis 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
Kg 
Kilogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
mITT 
Modified Intent-to-Treat 
n 
Number in sample 
PI 
Principal Investigator 
PK 
Pharmacokinetic  
PT 
MedDRA preferred term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SIB 
Severe Impairment Battery 
SD 
Standard Deviation 
SOC 
MedDRA system organ class 
SOP 
Standard Operating Procedure 


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TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
U.S. 
United States of America 
WHO 
World Health Organization 


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1. 
INTRODUCTION 
This Statistical Analysis Plan describes the planned analyses and reporting for the clinical trial 
protocol NTRP-101-203, sponsored by Neurotrope, Inc. The reader of this Statistical Analysis Plan 
(SAP) is encouraged to review the complete protocol as this plan contains only a limited overview 
of protocol information.  The main objective of this plan is to provide details pertaining to statistical 
methodology, data conventions, and processes used for the analysis of data from this trial.  
The format and content of this SAP are structured to provide sufficient detail to meet the 
requirements specified by the International Conference on Harmonization (ICH) E9: Guidance on 
Statistical Principles in Clinical Trials.  All work planned and presented in this Statistical Analysis 
Plan will follow the ethical guidelines published by the American Statistical Association (ASA). 
The following documents were reviewed in preparation of this Statistical Analysis Plan: 
• Version 3.0, protocol 18 April 2019 
• ASA Ethical Guidelines for Statistical Practice (2016) 
• The Royal Statistical Society: Code of Conduct (2014) 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3, 1996) 
• ICH Guidance on the Structure and Content of Clinical Study Reports (ICH E3(R1), 2013) 
• ICH Guideline on General Considerations for Clinical Trials (ICH E8, 1997) 
• ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9, 1998) 
• ICH Guidance on the Statistical Principles for Clinical Trials (ICH E9(R1), 2017) 
 
2. 
PROTOCOL DESIGN AND OBJECTIVE 
2.1 Design Overview 
This is a randomized double-blind Placebo-controlled, Phase 2 study comparing bryostatin to 
placebo for the treatment of moderately severe to severe Alzheimer’s disease in subjects not 
receiving memantine treatment. The study is 15 weeks in duration, including safety and efficacy 
evaluation 30 days after the last treatment. Eligible subjects will be stratified based on MMSE-2 


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scores 4-9 vs. 10-15 and will be randomized 1:1 to treatment with 20μg bryostatin or placebo for 12 
weeks of treatment. 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. Subjects are scheduled to receive seven doses over 12 
weeks.  
2.2 Treatment Groups 
There are two treatment groups in this trial. The two treatment groups to be evaluated in this trial 
are described below  
Table 2-2-1: Treatment Groups 
Group 
Description 
Active Treatment 
20 µg bryostatin 
Control Treatment 
placebo 
2.3 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. 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. 
2.4 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 


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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 discontinued. However, the subject will 
continue to be monitored per protocol for safety and efficacy.  
2.5 Study Objective 
The primary objective of this study is to evaluate the safety, tolerability and efficacy of bryostatin 
for the treatment of moderately severe to severe Alzheimer’s disease in subjects not receiving 
concurrent memantine treatment. 
2.6 Efficacy Assessments 
2.6.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is defined as the change from baseline to Week 13 in the SIB total 
score.  
2.6.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• The changes from baseline at Weeks 5, 9 and 15 in the SIB total score  
• The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects in the 
MMSE-2 4-9 stratification group 
• The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for subjects in the 
MMSE-2 10-15 stratification group 
• Individual patient’s slope over time in SIB total score evaluated via Weeks 0, 5, 9 and 13. 
2.6.3 Exploratory Endpoints:  
The exploratory endpoints for this study are: 
• 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 


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• Change from baseline in 10-point Neuropsychiatric Inventory (NPI) total score 
• Clinical Global Impression of Improvement Scale (CGI-I) score 
2.7 Safety Assessments 
• Treatment emergent AEs and SAEs 
• Vital signs, hematology, blood chemistry, and physical examination including body weight 
• ECG parameters 
• C-SSRS 
3. 
SAMPLE SIZE DETERMINATION AND RATIONALE, STATISTICAL POWER, 
AND SIGNIFICANCE LEVEL 
Based on post hoc analyses of the NTRP 101-202 study for patients not treated with memantine, the 
SIB for the 20ug bryostatin group demonstrated a mean (SD) increase of 4.5 (6.8) points from 
baseline by Week 13. In contrast, patients not treated with memantine in the placebo arm showed a 
decrease in SIB scores at the 13-week time-point from baseline, giving a mean (SD) SIB change of 
-0.9 (6.7) points. This resulted in group difference in means of the 13-week SIB measure from 
baseline SIB changes of 5.4 points. 
Guided by these post hoc results, power analyses were performed based on 50 patients per 
treatment arm, and assuming differences of between 4.0 to 5.5 points in the treatment arm-specific 
means of the primary outcome (e.g. the treatment effect). Table 3-1 below gives the estimated 
power to detect various treatment effects, assuming a two-sided alpha of 0.05. Based on these 
analyses, 50 patients per group will give an approximate 83% power to detect a treatment effect of 
4.0 points, and an estimated power of 98% to see a treatment effect of 5.5 points. Power calculation 
was based the two-sample t-test of the group difference in the mean 13-week SIB changes from 
baseline SIB.  
Table 3-1: Power to detect treatment effect sizes of between 4.0 to 5.5 points; 50 patients per 
group with an available primary efficacy endpoint. 
Diff. in Deltas 
Power 
N1 
N2 
Two-sided Alpha 
4 
83% 
50 
50 
0.05 
4.5 
91% 
50 
50 
0.05 


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5 
95% 
50 
50 
0.05 
5.5 
98% 
50 
50 
0.05 
 
Power analyses were also performed to determine detectable effect sizes that assume an estimated 
dropout rate of 25% (e.g. 50 patients per group at a baseline, dropping to 37 patients per group by 
Week 13). Table 3-2 gives the estimated powers for treatment effects of between 4.5 and 5.5 points, 
assuming a 25% dropout rate. Note that a minimum treatment effect of 4.5 points can be 
statistically detected with at least 80% power, given 37 patients per group with a primary efficacy 
endpoint. 
Table 3-2: Power to detect treatment effect sizes of between 4.5 to 5.5 points; 37 patients per 
group with an available primary efficacy endpoint. 
Diff. in Deltas 
Power 
N1 
N2 
Two-sided Alpha 
4.5 
80% 
37 
37 
0.05 
5 
88% 
37 
37 
0.05 
5.5 
93% 
37 
37 
0.05 
4. INTERIM ANALYSIS  
No interim analyses are planned. 
5. PRIMARY HYPOTHESIS TO BE TESTED 
The primary hypothesis to be tested for this study is below: 
H0:  µActive = µControl (i.e. mean change from baseline in SIB total score between the two groups is 
the same)  
H1: µActive ≠ µControl (i.e. mean change from baseline in SIB total score between the two groups is 
different)  
6. ANALYSIS POPULATIONS 
6.1 Full Analysis Set 
The Full Analysis Set (FAS) used for efficacy analyses 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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6.2 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).   
6.3 Completer Analysis Set 
The Completer Analysis Set (CAS) is defined as all randomized subjects who completed 12 weeks 
of treatment, and who have a week 13 SIB assessment.  
7. 
DATA CONVENTION AND RELATED DEFINITIONS   
7.1 Baseline Definition 
For all parameters, baseline will be defined as the last available value before the randomized 
treatment.   
7.2 Duplicate Data  
For unplanned duplicate data within a protocol-specified visit, the last measured value will be used 
for the analysis. If it is not possible to identify the “last measured value” the average of the 
duplicate values will be used. No data will be excluded.  All collected data will be listed.  
7.3 Handling of Missing Data  
Every effort will be made to obtain required data at each scheduled evaluation from all subjects 
who have been randomized to minimize missing data. However, in the event when there is missing 
data the following imputation methods will be used. 
7.3.1 Handling of Missing Data for Efficacy Evaluations  
For efficacy evaluations, multiple imputation methods will be used to handle missing data. The 
imputation will be carried out in SAS version 9.4 or later using PROC MI. Each imputation model 
will include the stratification factor (i.e., MMSE-2 score (4-9 vs. 10-15)) as a covariate in the 
model.  
7.3.1.1 Multiple Imputation for Continuous variables  
If the missing data point is continuous in nature with monotone pattern, predictive mean 
matching will be used in the model.    
This method imputes a value randomly from a set of observed values whose predicted values are 
closest to the predicted value for the missing value from the simulated regression model. 


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If the missing data point is continuous in nature with arbitrary pattern, a fully conditional 
specification (FCS) will be used, using the predictive mean matching method with joint 
distribution for all variables.    
7.3.1.2 Multiple Imputation for Categorical variables 
If the data point is categorical in nature with monotone pattern, logistic method will be used in 
the model. With this method, a logistic regression model is fitted for a categorical variable with 
covariates. All the categorical endpoints in the study have binary classification variables, and for 
these based on the fitted regression model, a new logistic regression model is simulated from the 
posterior predictive distribution of the parameters and is used to impute the missing values for each 
variable. 
If the data point is categorical in nature with arbitrary pattern, a fully conditional specification 
(FCS) will be used using logistic regression approach with joint distribution for all variables. 
7.4 Multicenter Clinical Trials  
This is a randomized study with multiple centers.  
7.5 Multiple Comparisons and Multiplicity 
There will be no need to adjust for multiple testing or multiplicity for this phase 2 trial. For all 
effectiveness endpoints, inference will be based on type I error rate of 0.05. 
7.6 Covariates and Prognostic Factors 
In the efficacy analysis, the stratification factors and baseline values such as age, sex, or disease 
severity may be used as covariates in the analysis of all the primary, secondary, and additional 
efficacy endpoints.  
7.7 Stratification Factors and Subgroups 
This is a randomized study and stratified so that the groups have similar distribution of MMSE-2 
score (4-9 vs. 10-15). The stratification will ensure balance between each treatment group in each 
stratum. 


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7.8 Standard Calculations  
7.8.1 Age 
Age will be calculated as the number of completed years between the date of informed consent and 
the subject’s birth date.  
Age (years) = integer of [(date of informed consent – date of birth)/ 365.25] 
7.8.2 Height 
For summary purposes height will be expressed in centimeters.  Entries made in inches will be 
converted to centimeters using the formula noted below.  
Height (cm) = Height (in)*2.54 
7.8.3 Weight 
For summary purposes weight will be expressed in kilograms.  Entries made in pounds will be 
converted to kilograms using the formula noted below.  
Weight (kg) = Weight (lb)/ 2.2046 
7.8.4 Change from Baseline 
For any of the effectiveness measurements change from baseline will be calculated using the 
formula noted below.  
Change from baseline =  
Post Baseline Measurement – Baseline Measurement 
8. STATISTICAL METHODS 
All data collected during this study will be presented in subject data listings.  
All statistical analyses will be performed using SAS® for Windows, version 9.4 or later.  For 
continuous variables, descriptive statistics (n, mean, standard deviation, median, minimum and 
maximum) will be presented by treatment group. For categorical variables both frequencies and 
percentages will be presented by treatment group.  
8.1 Disposition and Baseline Characteristics  


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8.1.1 Subject Disposition and Withdrawals 
There will be a detailed accounting of all subjects that signed the informed consent to participate in 
this trial.  The following will be summarized by treatment group:   
• The number of subjects who signed the informed consent 
• The number of subjects who are screen failures 
• The number of subjects who are randomized 
• The number of randomized subjects in each stratum 
• The number of subjects who received at least one study treatment  
• The number of subjects who completed the study 
• The number of subjects who discontinued  
o Reasons for discontinuation prior to completion will also be summarized 
descriptively by treatment group.   
In addition, there will also be a listing of all discontinued subjects, which will provide the clinical 
trial center, treatment group and the specific reason for discontinuation.   
8.1.2 Demographics and Baseline Characteristics 
Demographic (age, sex, race, ethnicity, height and body weight) and other basic baseline 
characteristics will be summarized and/or listed, descriptively, by treatment group.   
Medical history and Rosen-modified Hachinski Scale results will be provided as by-subject listings.  
8.1.3 Prior and Concomitant Medications 
Prior and concomitant medications will be summarized.   
All prior and concomitant medications recorded in the case report form will be coded to the drug 
substance level (i.e., generic term) using the most recent version of WHO Drug dictionary.        
Descriptive summaries, by treatment group, will be prepared using the coded terms. All prior and 
concomitant medications recorded in the case report form will be listed.   
8.1.4 Treatment Administration and Compliance 
All treatment administration and compliance data will be listed and summarized.   


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8.2 Analysis of Efficacy Data 
The primary analysis will be conducted on FAS population. The CAS population will be used as a 
supportive analysis.  All statistical tests for efficacy will be two-sided tests, with α=0.05.   
8.2.1 Primary Efficacy Endpoint  
The primary endpoint for this study is the change from baseline to Week 13 in the SIB total score.  
The change from baseline to Week 13 in the SIB total score will be summarized descriptively and 
compared using Analysis of Covariance (ANCOVA) adjusted for baseline SIB total score.  
If the normality assumption is not met, a non-parametric method or a rank-ANCOVA analysis (i.e., 
an ANCOVA analysis on rank-transformed data) will be used. 
8.2.2 Secondary Efficacy Endpoints 
8.2.2.1 The changes from baseline at Weeks 5, 9 and 15 in the SIB total score 
The change from baseline at Week 5, 9 and 15 in the SIB total score will be summarized 
descriptively and compared using ANCOVA adjusted for baseline SIB total score.  
If the normality assumption is not met, a non-parametric method or a rank-ANCOVA analysis will 
be used. 
8.2.2.2 The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for 
subjects in the MMSE-2 4-9 stratification group 
The change from baseline at Week 5, 9, 13 and 15 in the SIB total score for subjects in the MMSE-
2 4-9 stratification group will be summarized descriptively. Similar analysis methods as the primary 
endpoint will be used for analysis of this endpoint. 
8.2.2.3 The changes from baseline at Weeks 5, 9, 13 and 15 in the SIB total score for 
subjects in the MMSE-2 10-15 stratification group 
 
The change from baseline at Week 5, 9, 13 and 15 in the SIB total score for subjects in the MMSE-
2 10-15 stratification group will be summarized descriptively. Similar analysis methods as the 
primary endpoint will be used for analysis of this endpoint. 


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8.2.2.4 Individual patient’s slope over time in SIB total score evaluated via Weeks 0, 5, 9 
and 13  
Individual-specific SIB slopes will be estimated for all patients over each person’s available SIB 
outcome measures. An indicator will be assigned to each patient depending on the sign of the SIB 
slope β (i.e. I=-1 if β <0; 1 if β >0; no value otherwise). The proportions of patients with I=1 and, 
respectively, -1 will be compared using logistic regression to assess the overall trend between 
treatments. In addition, an overall population averaged slope will be estimated for each treatment 
arm, and two-sample t-test will be used to assess the difference between treatments. 
8.2.3 Exploratory Endpoints 
The exploratory endpoints will be analyzed as follows:  
8.2.3.1 Change from baseline in ADCS-ADL-Sev total score 
The change from baseline in ADCS-ADL-Sev total score will be calculated for each subject using 
the formula in Section 7.8.4. Similar analysis methods as the primary endpoint will be used for 
analysis of this endpoint. 
8.2.3.2 Change from baseline in MMSE-2 total score 
The change from baseline in MMSE-2 total score will be calculated for each subject using the 
formula in Section 7.8.4. Similar analysis methods as the primary endpoint will be used for analysis 
of this endpoint. 
8.2.3.3 Change from baseline in NPI total score 
The change from baseline in NPI total score will be calculated for each subject using the formula in 
Section 7.8.4. Similar analysis methods as the primary endpoint will be used for analysis of this 
endpoint. 
8.2.3.4 CGI-I score  
CGI-I score will be summarized descriptively. Similar analysis methods as the primary endpoint 
will be used for analysis of this endpoint. 
 


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8.3 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.  
8.3.1 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.   
8.3.2 Clinical Laboratory Evaluations 
All available results of the clinical laboratory evaluations will be listed and summarized as follows:   
8.3.2.1 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. 


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• 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. 
For change from baseline summaries, subjects with an undefined change from baseline, because of 
missing data, will be excluded. 
8.3.2.2 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. 
8.3.2.3 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. 
8.3.3 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. 
8.3.4 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.    
8.3.5 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. 
8.3.6 Columbia Suicide Severity Rating Scale (C-SSRS) 
All data from C-SSRS will be listed. Descriptive summaries will be presented for each of the 


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subscales (i.e. Suicidal Ideation and Suicidal Behavior). 
 


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9. APPENDIX 1: SCHEDULE OF ASSESSMENTS  
 
 
NTRP101-203 
 
We e k 
 
Screening 
 
0 
 
1 
 
2 
 
3 
 
5 
 
7 
 
9 
 
11 
 
13 
 
15/ET 
Day (±2 days) 
(Days -28 to -2)d 
0 
7 
14 
21 
35 
49 
63 
77 
91 
105 
Dose 
 
Rand 
1 
2 
 
3 
4 
5 
6 
7 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Rosen-modified 
Hachinski Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
SIB 
X∆ 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
MMSE-2 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
ADCS-ADL-Sevb 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
NPIb 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
 
CGI-I 
 
 
 
 
 
 
X* 
 
X* 
 
X 
 
CSSRS 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
Labs^^ 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
ECG 
X (x3) 
 
 
 
X 
 
 
X 
 
 
X 
 
PE 
X 
 
 
 
 
 
 
X*+ 
 
 
X 
 
Vitals 
X 
 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
Randomization 
 
Xa 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
X◊ 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
∆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 (B12, T-3 and T-4 if TSH abnormal), CPK at screening and event of 
myalgia, βhCG if indicated, HbA1C if clinically indicated; ◊ CT scan if necessary per inclusion criterion #6; + abbreviated physical 
examination; 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;c Vital 
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.  
 
 


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10. APPENDIX 2 – PLANNED TLG 
10.1 Planned by-subject listings  
DISPOSITION/WITHDRAWALS (LISTINGS 16.2.1.X) 
ELIGIBILITY (LISTINGS 16.2.2.X) 
EXCLUDED SUBJECTS (LISTINGS 16.2.3.X) 
DEMOGRAPHICS, 
POPULATION, 
AND 
BASELINE 
CHARACTERISTICS 
(LISTINGS 16.2.4.X) 
DRUG COMPLIANCE AND DRUG CONCENTRATION LISTINGS (LISTINGS 
16.2.5.X) 
EFFICACY RESPONSE (LISTINGS 16.2.6.X) 
ADVERSE EVENT DATA (LISTINGS 16.2.7.X) 
SAFETY DATA (LISTINGS 16.2.8.1.X) 
 
 
 
 


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10.2 Planned Summary Tables  
 
POPULATION DISPOSITION  
POPULATION DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
CONCOMITANT MEDICATION USAGE 
EFFICACY SUMMARIES 
SAFETY SUMMARIES  
ADVERSE EVENT SUMMARIES  
SERIOUS ADVERSE EVENTS  
LABORATORY 
VITAL SIGNS AND PE 
OTHER SAFETY 
 
 
 


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11. 
VERSION HISTORY  
This is the first version of this document. 
 
 
 


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12. 
REFERENCES 
1. 
ASA. (2016) Ethical Guidelines for Statistical Practice. Prepared by the 
Committee on Professional Ethics, April, 2016.  
2. 
The Royal Statistical Society: Code of Conduct (2014). 
3. 
E8 General Considerations for Clinical Trials, ICH Guidance, Federal Register, 
1997. 
4. 
E9 Statistical Principles for Clinical Trials, ICH Guideline, Federal Register, 
1998 
5. 
Guideline for the Format and Content of the Clinical and Statistical Section of 
an Application, 1988. 
6. 
Guideline for Industry:  Structure and Content of Clinical Study Reports (ICH 
E3), July 1996. 
7. 
Yuan, Yang. "Sensitivity analysis in multiple imputation for missing 
data." Proceedings of the SAS Global Forum 2014 Conference:[http://support. 
sas. com/resources/papers/proceedings14/SAS270-2014. pdf]. 2014.