Clinical trial NCT02431468
Conditions: Alzheimer's Disease
Sponsor: Neurotrope Bioscience, Inc.
Start date: 2015-11-01; Completion date: 2017-02-01
Enrollment: 147 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized double-blind placebo-controlled study comparing different doses of bryostatin for the treatment of moderately severe to severe Alzheimer's disease. The study is 15 weeks in duration, including a safety and efficacy evaluation 30 days after the last dose of study drug.

Detailed description:
This study will enroll 150 moderately severe to severe Alzheimer's disease subjects. Subjects will be randomly assigned 1:1:1 to treatment with two different doses of bryostatin 1 or placebo. The primary analysis will take place after 12 weeks of treatment (7 doses).

Arms: arm 1: Bryostatin 20 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 24 micrograms administered weekly. A total of 7 doses administered over 12 weeks. arm 2: Bryostatin 40 micrograms administered IV over 45 minutes every other week after 2 initial loading doses of 48 micrograms administered weekly. A total of 7 doses administered over 12 weeks. arm 3: Placebo administered IV over 45 minutes every other week after 2 initial doses administered weekly. A total of 7 doses administered over 12 weeks.
Interventions: intervention 1: Bryostatin 1 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. Placebo 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 active drug, intended for IV infusion upon reconstitution and dilution.

Protocol documents:
Prot_000.pdf: 
 
 
Protocol #: NTRP-101-202 
 
 
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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  
Protocol Number: 
NTRP-101-202 
Amendment Date: 
3 March 2017 
Study Drug: 
Bryostatin 1; matching Placebo 
Investigational new Drug 
Application (IND) Number: 
71,276 
Version: 
4.0 
Planned FPI to LPLV 
Jan 2016 to Feb 2017 
Study Sponsor: 
Neurotrope BioScience, Inc. 
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 
 


 
 
Protocol #: NTRP-101-202 
 
 
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PRINCIPAL INVESTIGATOR’S (PI) SIGNATURE PAGE 
Protocol Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Study Assessing the 
Safety, Tolerability and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe 
Alzheimer’s Disease  
Protocol Number: NTRP-101-202 
Protocol Version and Date:  Version 4.0  March 3, 2017 
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 BioScience, Inc. 
205 East 42nd Street, 16th Floor 
New York, NY 10017 
Phone : (973)242-0005 
Fax :     (973)242-0009 
Kenneth Gorelick, MD 
 
 
Acting Chief Medical Officer 
Neurotrope BioScience, Inc. 
Mobile:  610-659-8236 
Email:  KGorelick@neurotropebioscience.com  
David Crockford 
 
Vice President, Regulatory Affairs 
Neurotrope BioScience, Inc. 
Mobile:  (978) 992-1445 
Email   dcrockford@neurotropebioscience.com 
 
Elaine Grenier 
Director, Head of Clinical Operations 
Neurotrope BioScience, Inc. 
 
Mobile: (415) 548-0368 
Email:   egrenier@neurotropebioscience.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 
 
 
Idil Cavus, MD PhD 
Worldwide Clinical Trials 
Mobile: (203) 623-2622 
Fax: (203) 779-5678  
E-mail: idil.avus@wwctrials.com 
Central Laboratory 
 
ACM Global 
160 Elmgrove Park 
Rochester, NY 14624 USA 
Central ECG 
eResearch Technology, Inc. (ERT)  
1818 Market Street, Suite 1000 
Philadelphia, PA 19103-3638 
Tel: (215) 282-5303  
Pharmacokinetic and Pharmacodynamic Plasma 
Sample Analysis Laboratory 
 
Intertek Pharmaceutical Services 
10420 Wateridge Circle 
San Diego, CA 92121 
(858) 558-2599, x241  
 
Blanchette Rockefeller Neurosciences Institute 
Eight Medical Center Drive 
Morgantown, WV 26505-3409 
(304) 293-0930 
 
 
 


 
 
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PROTOCOL SYNOPSIS 
 
Name of Company:  
Neurotrope BioScience, Inc.
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
Title of Study: 
  
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 
Study center(s): Approximately 30 sites in United States (US) 
 
Protocol Number: NTRP101-202 
 
Study Duration: Approximately 14 months 
Study Phase: 2 
 
Objectives:  
 
Primary objective:  
To evaluate the safety and tolerability of bryostatin 1 (hereafter referred to as bryostatin) for 
the treatment of moderately severe to severe Alzheimer’s disease (AD). 
Secondary objective:  
To evaluate the efficacy of bryostatin in the treatment of moderately severe to severe AD.  
Exploratory objectives: To characterize the pharmacokinetics of bryostatin in subjects with 
AD following administration of 20 or 40µg of bryostatin administered as a 45-minute 
intravenous (IV) infusion over 12 weeks.  
To characterize the pharmacodynamics of bryostatin in subjects with AD following 
administration of 20 or 40µg of bryostatin administered as a 45-minute infusion over 12 
weeks. 
 
Study Drug:   Bryostatin 1 or matching Placebo for Infusion  
Drug is administered IV over 45(±5) minutes.  
 
Number of Subjects: 150 randomized subjects (approximately 250 subjects screened) 
Study Design  
This is a randomized double-blind Placebo-controlled, Phase 2 exploratory study comparing 
two different doses of bryostatin to placebo for the treatment of moderately severe to severe 
Alzheimer’s disease. 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 the change from baseline in the 
Severe Impairment Battery (SIB) score after 12 weeks of treatment (at Week 13).  


 
 
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Name of Company:  
Neurotrope BioScience, Inc.
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
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 1:1:1 to one of three treatment arms: 20µg, 40µg or 
placebo for twelve weeks.  Study drug is administered IV by continuous infusion.  The first 
two doses of each active treatment arm will be a loading dose 20% higher than the assigned 
dose (24µg, 48µg) and will be administered one week apart.  Thereafter, the assigned dose of 
either 20µg, 40µg will commence with the third dose and be administered every other week.  
Subjects are scheduled to receive seven doses over 12 weeks. Subjects who drop out prior to 
completing the Week 7 visit will be replaced, up to a maximum of 15 subjects. 
 
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. 
 
Primary Safety End Points 
Treatment emergent AEs and SAEs 
 
Secondary Safety End Points 
 Vital signs, hematology, blood chemistry, PE including body weight 
 ECG parameters.  
 C-SSRS 
 
Primary Efficacy End Point 
Change from baseline in the SIB Scale Score at Week 13 
 
Secondary Efficacy End Points   
 Change from baseline in the SIB at Weeks 5 and 9 
 Change from baseline in Alzheimer Disease Cooperative Study Activities of Daily 
Living Inventory-Severe Impairment Version (ADCS-ADL-SIV) score at Weeks 5, 9 
and 13 
 Change from baseline in MMSE-2 score at Weeks 5, 9 and 13 
 Change from baseline in Neuropsychiatric Inventory (NPI) score at Weeks 5, 9 and 13 
 Clinical Global Impression of Improvement (CGI-I) at Weeks 5, 9 and 13 
Exploratory Pharmacokinetic and Pharmacodynamic End Points:  
 Determine a pharmacokinetic model for bryostatin plasma concentrations and 
summarize bryostatin exposure in plasma 


 
 
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Name of Company:  
Neurotrope BioScience, Inc.
Name of Study 
Medication:  
Bryostatin 1 
Name of Active Ingredient: 
Bryostatin 1 
 Peripheral blood mononuclear cell (PBMC) Protein Kinase C epsilon (PKCε) amount 
at various time points may be determined. 
Statistical Considerations:  
 
The primary statistical objective for efficacy is to estimate the effect of bryostatin on the 
mean change in the SIB after 12 weeks of treatment.  A linear model will be used for both 
estimation and significance testing.  This will be a mixed-model for repeated measures 
(MMRM) with fixed effects for treatment, baseline MMSE-2 stratum, scheduled visit (class 
variable) and scheduled visit by treatment interaction, plus a random effect for subject.  The 
baseline efficacy measurement (SIB for the primary) will be a covariate.  The primary 
contrasts will be the change from baseline in the SIB at Week 13 between each bryostatin 
group and the placebo group and between the combined (pooled) bryostatin dosing group and 
the placebo group.  Inferences will be based on the estimates of expected values (least 
squares means (LSM) by treatment by scheduled visit derived from the model. 
 
It is estimated that 150 subjects equally randomized among the three dosing groups (two 
doses of bryostatin and placebo administered over 12 weeks) will provide at least 80% 
power, assuming a true mean difference of at least 6.5 points in favor of the bryostatin groups 
(standardized effect size of 0.47), in a test between each bryostatin group and placebo in 
mean change from baseline in the SIB, (one-sided at α=0.10).  This assumes the standard 
deviation of change from baseline at Week 13 is 14 points.  This estimate allows that up to 
15% of randomized subjects will not provide information due to discontinuation.  The least 
significant difference for the test between the observed means under these conditions is 
estimated to be 3.9 points (effect size of 0.28). 
 
Efficacy analyses will be conducted according to randomized groups.  The full analysis set, 
consistent with the intention-to-treat principles, will be defined as all randomized subjects 
who received at least one dose of randomized study medication and who had at least one 
post-baseline 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. 
 
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  


 
 
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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 
5. Patients must be able to perform at least one item on the SIB   
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 drugs approved for treatment of Alzheimer’s disease (e.g. cholinesterase 
inhibitors, memantine), 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 on neuroleptic medications must be on a stable dose for ≥4 weeks (dose 
adjustments will be permitted) 
11.  Females participating in the study must meet one the following criteria: 
a. Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal 
ligation) for at least 6 months or postmenopausal (postmenopausal females 
must have no menstrual bleeding for at least 1 year) or 
b.  If not postmenopausal, agree to use a double method of contraception, one of 
which is a barrier method (e.g., intrauterine device plus condom, spermicidal 
gel plus condom) 30 days prior to dosing until 30 days after last dose and have 
negative human chorionic gonadotropin (β-hCG) test for pregnancy at 
screening 
12. 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  
13. 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 


 
 
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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  
5. Creatinine clearance (CL) of <45ml/min  
6. Poorly controlled diabetes, at the discretion of the Principal Investigator  
7. Use of vitamin E > 400 International Units (IU) per day within 14 days prior to screening 
8. Use of valproic acid within 14 days prior to screening  
9. Use of an active Alzheimer’s vaccine within 2 years prior to screening 
10. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening 
11. Any medical or psychiatric condition that is likely to require initiation of additional 
medication or surgical intervention during the course of the study 
12. Any screening laboratory values outside the reference ranges that are deemed clinically 
significant by the PI 
13. Use of an investigational drug within 30 days prior to screening  
14. 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 
15. 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 
16. Diagnosis of alcohol or drug abuse within the last 2 years  
17. 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. 
18. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per 
central reader) 
19. 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  
20. Known to be seropositive for human immunodeficiency virus (HIV)  


 
 
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21. Known to be seropositive for Hepatitis B or C 
22. AST or ALT >3x upper limit of normal (ULN) and total bilirubin >2x ULN or 
International Normalized Ratio (INR) >1.5 
23. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the 
study drug 
24. Any other concurrent medical condition, which in the opinion of the PI makes the subject 
unsuitable for the clinical study 


 
 
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Table of Contents 
SPONSOR’S SIGNATURE PAGE ..............................................................................................2 
STUDY CONTACT INFORMATION ......................................................................................44 
STUDY ADMINISTRATIVE STRUCTURE ...........................................................................55 
PROTOCOL SYNOPSIS ............................................................................................................66 
LIST OFABREVIATIONS .....................................................................................................1515 
1 
INTRODUCTION........................................................................................................1818 
1.0 
Alzheimer’s disease .......................................................................................................1818 
1.1 
Rationale for the use of bryostatin in the treatment of AD ............................................1919 
1.2 
Pharmacokinetics, Toxicology and Drug Metabolism in Animals ................................1919 
1.3 
Genotoxicity ...................................................................................................................2020 
2 
CLINICAL TRIAL DATA..........................................................................................2020 
2.0 
Oncology Data ...............................................................................................................2020 
2.1 
Alzheimer’s disease data................................................................................................2121 
2.1.1 
Study NTRP101-201 ................................................................................................2121 
3 
STUDY OBJECTIVES AND HYPOTHESIS ...........................................................2222 
3.0 
Objectives ......................................................................................................................2222 
3.0.1 
Primary objective: ....................................................................................................2222 
3.0.2 
Secondary Objectives...............................................................................................2323 
3.0.3 
Exploratory Objectives: ...........................................................................................2323 
3.1 
Hypothesis......................................................................................................................2323 
4 
INVESTIGATIONAL PLAN .....................................................................................2323 
4.0 
Overview of Study Design .............................................................................................2323 
4.1 
Dose Rationale ...............................................................................................................2424 
4.2 
Risk/Benefit ...................................................................................................................2525 
4.3 
Study Endpoints .............................................................................................................2626 
4.3.1 
Primary Safety End Points .......................................................................................2626 
4.3.2 
Secondary Safety End Points ...................................................................................2626 
4.3.3 
Primary Efficacy End Point .....................................................................................2626 
4.3.4 
Secondary Efficacy End Points ................................................................................2626 
4.3.5 
Exploratory Pharmacokinetic and Pharmacodynamic End Points: ..........................2727 
4.4 
Study Population ............................................................................................................2727 
4.4.1 
Inclusion Criteria .....................................................................................................2727 
4.4.2 
Exclusion Criteria ....................................................................................................2828 
5 
PRODUCTS USED IN THIS STUDY .......................................................................2929 
5.0 
Bryostatin .......................................................................................................................2929 
5.1 
Placebo ...........................................................................................................................3030 
5.2 
Packaging and Labeling of Study Drug Kits .................................................................3030 
5.3 
Storage and Preparation of Study Drug .........................................................................3030 
5.4 
Study Drug Accountability and Disposal ......................................................................3131 
5.5 
Randomization ...............................................................................................................3131 
5.6 
Blinding..........................................................................................................................3232 
5.7 
Study Drug Administration ............................................................................................3232 


 
 
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6 
STUDY PROCEDURES AND ASSESSMENTS ......................................................3232 
6.0 
Table 1 Schedule of Activities .......................................................................................3333 
6.1 
Assessments ...................................................................................................................3535 
6.1.1 
Safety .......................................................................................................................3535 
6.1.2 
Efficacy / Psychometric Assessments ......................................................................3737 
6.1.3 
Pharmacokinetic and Pharmacodynamic Assessments ............................................3838 
6.2 
Visit Procedures .............................................................................................................3838 
6.2.1 
Screening and Randomization (Days -28 to -2) .......................................................3838 
6.2.2 
Week 0 (Day 0 Dose 1) ............................................................................................3939 
6.2.3 
Week 1 (Day 7 (±2 days) Dose 2) ...........................................................................4040 
6.2.4 
Week 2 (Day 14 (±2 days) No dose) .......................................................................4040 
6.2.5 
Week3 (Day 21 (±2 days)/ Dose 3) .........................................................................4040 
6.2.6 
Week 5 (Day 35 (±2 days)/ Dose 4) ........................................................................4141 
6.2.7 
Week 7 (Day 49 (±2 days)/ Dose 5) ........................................................................4141 
6.2.8 
Week 9 (Day 63 (±2 days)/ Dose 6) ........................................................................4141 
6.2.9 
Week 11 (Day 77(±2 days)/ Dose 7) .......................................................................4242 
6.2.10 
Week 13 (Day 91 (±2 days) .....................................................................................4242 
6.2.11 
30-day Follow-up Visit ............................................................................................4343 
6.3 
Concomitant Medications ..............................................................................................4343 
6.3.1 
Medications for AD .................................................................................................4343 
6.3.2 
Concomitant Medications for Management of Myalgia ..........................................4444 
6.3.3 
Prohibited Medications ............................................................................................4444 
7 
ADVERSE EVENTS AND OTHER SAFETY EVALUATIONS ...........................4545 
7.0 
Definition of Adverse Events.........................................................................................4545 
7.1 
Adverse Event of Special Interest - Myalgia .................................................................4545 
7.2 
Definition of Serious Adverse Event .............................................................................4545 
7.3 
Assessment of Intensity .................................................................................................4646 
7.4 
Relationship to Study Drug ............................................................................................4646 
7.5 
Table 2 Relationship of AE to Study Drug or Trial-Related Procedures ......................4747 
7.5.1 
Unexpected Adverse Event ......................................................................................4747 
7.6 
Reporting Adverse Events .............................................................................................4747 
7.6.1 
SAE reports ..............................................................................................................4848 
7.6.2 
Reporting to Regulatory Authorities ........................................................................4949 
7.7 
Criteria for Withdrawal of Subjects ...............................................................................4949 
7.8 
Criteria for Permanent Discontinuation of Study Drug .................................................4949 
7.9 
Study discontinuation.....................................................................................................5050 
8 
INDEPENDENT DATA AND SAFETY MONITORING BOARD (DSMB) ........5050 
9 
DATA ANALYSIS / STATISTICAL METHODS ...................................................5050 
9.0 
Sample Size Determination............................................................................................5151 
9.1 
Demographics, Baseline Characteristics and Disposition .............................................5151 
9.2 
Safety Analysis ..............................................................................................................5151 
9.3 
Efficacy Analysis ...........................................................................................................5252 
9.3.1 
Analysis of Primary Endpoint ..................................................................................5252 
9.3.2 
Analysis of Secondary Endpoints ............................................................................5252 
9.4 
Pharmacokinetics ...........................................................................................................5353 
9.5 
DSMB Safety Assessments............................................................................................5353 


 
 
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10 
DATA MONITORING ................................................................................................5353 
10.0 
Source Documentation ...................................................................................................5353 
10.1 
Study Documentation and Record Retention .................................................................5454 
10.2 
Site Monitoring ..............................................................................................................5454 
10.3 
Quality Assurance and Quality Control .........................................................................5555 
10.4 
Audits and Inspections ...................................................................................................5555 
11 
ETHICS ........................................................................................................................5555 
11.0 
Institutional Review Board ............................................................................................5555 
11.1 
Ethical Conduct of the Study .........................................................................................5656 
11.2 
Written Informed Consent .............................................................................................5656 
12 
STUDY MANAGEMENT ...........................................................................................5656 
12.0 
Data Collection and management ..................................................................................5656 
12.1 
Data Quality Control ......................................................................................................5656 
12.2 
Data Management and Data Storage ..............................................................................5757 
12.3 
Inspection of Records ....................................................................................................5757 
12.4 
Retention of Records......................................................................................................5757 
12.5 
Confidentiality ...............................................................................................................5858 
12.6 
Protocol Amendments ....................................................................................................5858 
12.7 
Protocol Deviations ........................................................................................................5858 
12.8 
Data Corrections ............................................................................................................5858 
12.9 
Insurance ........................................................................................................................5959 
13 
PUBLICATION AND DISCLOSURE POLICY ......................................................5959 
14 
APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS ....................6060 
15 
APPENDIX 2  LIST OF REFERENCES ..................................................................6565 
16  
APPENDIX 3  SUMMARY OF CHANGES  
 
 
 
 
 
 
 
 
 
  66 
 
 
 
 
 


 
 
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LIST OFABREVIATIONS  
Abbreviation 
Definition 
 
Aβ 
Beta-amyloid  
AD 
Alzheimer’s Disease  
ADCS-ADL-SIV 
Alzheimer’s Disease Cooperative Study – Activities of Daily Living - 
Severe Impairment Version 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase  
ALT 
Alanine Amino Transferase 
APP 
Amyloid Precursor Protein 
AST 
Aspartate Amino Transferase 
Aβ1-42 
Beta-Amyloid 1-42 
ARIA 
Amyloid Related Imaging Abnormalities 
βAPP 
Beta-amyloid Precursor Protein  
β-hCG  
Human chorionic gonadotropin 
BDNF 
Brain-derived Neurotrophic Factor  
BUN 
Blood Urea Nitrogen  
CBC 
Complete Blood Count 
C-CASA 
Columbia-Classification Algorithm of Suicide Assessment 
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 
ERB 
Ethical Review Board  
FAS 
Full Analysis Set  


 
 
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Abbreviation 
Definition 
 
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 
IwRS 
Interactive Web Response System 
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 
PET 
Tween 80 (polysorbate 80)  
PI 
Principal Investigator 


 
 
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Abbreviation 
Definition 
 
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.1313  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 
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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 1414, 1313, 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 the ethanol/saline or the polyethylene glycol, 
ethanol, and Tween 80 (polysorbate 80) (PET) diluent.  LD50 range 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.  There were 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. 
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. 


 
 
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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 was evaluated using the bacterial reverse mutation assay (i.e., the Ames test), no positive 
responses were observed.  Bryostatin 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 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.  
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. 


 
 
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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 NTRP101-201  
This was a randomized, double-blind, Placebo-controlled safety study of a single dose of bryostatin in 
subjects with mild to moderate AD (MMSE: 14-26).  Subjects were randomized 2:1 to receive bryostatin 
25µg/m2 or Placebo.  The primary objective was to evaluate the safety and tolerability of bryostatin by 
the incidence of AEs and SAEs.  Secondary safety endpoints included assessment of physical 
examination, hematology including complete blood count (CBC) and platelet count, coagulation 
parameters, serum chemistries, ECG, urinalysis and vital signs. 
The primary efficacy endpoint was a composite end point of change from baseline in the Hopkins 
Verbal Learning Test-Revised (HVLT-R) delayed recall and Repeatable Battery of Assessments for 
Neuropsychological Status (RBANS) figure recall at 48 hours post study drug infusion. 
The study included single dose PK, and measurement of PKCε in peripheral blood mononuclear cells 
(PBMCs) as a potential biomarker.  
 
2.1.1.1 Results 
2.1.1.1.1 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. 
 
2.1.1.1.2 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. 
2.1.1.1.3 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 


 
 
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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. 
2.1.1.1.4 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 observed to be high (~ 40 L/h), consistent 
across the individual administered doses, and did not appear to be related to body weight, BSA, or sex.  
The bryostatin pharmacokinetic parameters were observed to have low to moderate intersubject 
variability. 
2.1.1.1.5 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. 
2.1.1.1.6 Conclusions 
This is 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 
Objectives 
3.0.1 Primary objective: 
 To evaluate the safety and tolerability of bryostatin for the treatment of moderately severe to 
severe Alzheimer’s disease  


 
 
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3.0.2 Secondary Objectives  
 To evaluate the efficacy of bryostatin in the treatment of moderately severe to severe 
Alzheimer’s disease  
3.0.3 Exploratory Objectives:  
To characterize the pharmacokinetics of bryostatin in subjects with AD following administration of 20 or 
40µg of bryostatin administered as a 45 minute IV infusion over 12 weeks.  
To characterize the pharmacodynamics of bryostatin in subjects with AD following administration of 20 
or 40µg of bryostatin administered as a 45 minute IV infusion over 12 weeks of treatment. 
3.1 
Hypothesis  
Treatment with bryostatin will result in improvement of cognitive function as measured by improvement 
on performance on the SIB measured after 12 weeks of treatment compared to placebo.  The primary 
efficacy endpoint will be tested against the null hypothesis: the change from baseline at Week 13 (after 
12 weeks of treatment) of the SIB score in the  bryostatin arms is equal to or less than the change from 
baseline of the SIB score in the placebo arm.  The alternative hypothesis is: the change from baseline at 
Week 13 of the SIB score due to bryostatin is greater than the change from baseline of the SIB score due 
to placebo.  
The null hypothesis will be rejected at a significance level of α (1-sided) = 0.10.  This analysis will be a 
test of superiority and only an improvement in the SIB score is of interest.  The analysis will be 
conducted using a mixed model for repeated measures (MMRM).  Analyses will be performed on each 
bryostatin dosing group vs. placebo and on the “pooled” bryostatin dosing group vs. placebo. 
4 INVESTIGATIONAL PLAN 
4.0 
Overview of Study Design   
This is a randomized double-blind placebo-controlled exploratory study comparing different doses of 
bryostatin for the treatment of moderately severe to severe Alzheimer’s disease.  The study is 15 weeks 
in duration, including a 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 1:1:1 to one of three 
treatment arms: 20µg, 40µg or placebo for 12 weeks of treatment (see Figure 1).  Study drug is 
administered IV by continuous infusion. The first two doses of each active treatment arm will be a 
loading dose 20% higher than the assigned dose (24µg, 48µg) and will be administered one week apart.  
The assigned dose of either 20µg or 40µg will commence with the third dose two weeks after the second 
loading dose and be administered every other week thereafter.  Subjects are scheduled to receive seven 
doses over 12 weeks.  Subjects who drop out prior to completing the Week 7 visit will be replaced, up to 
a maximum of 15 subjects.  Safety and efficacy assessments will be done as indicated on the Schedule 
of Activities (Table 1).  
 
 


 
 
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Figure 1:  Study Design 
 
 
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.  It is unclear where the inflection point for 
downregulation occurs, thus this study is designed to explore two doses of bryostatin at fixed dose levels 
and frequency that is thought to initiate and maintain activation of PKCε without downregulation.  
The dosing regimen is based on existing human oncology data and the recently completed phase 2a PK 
and safety study and PKCε levels in peripheral monocytes that were measured after treatment with 
bryostatin in both programs. 
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.  In the oncology studies where subjects 
received 75µg/m2 to 125µg/m2 of bryostatin over a 72-hour infusion, PKC levels were initially 
upregulated, but within 2-24 hours after start of the infusion, levels were down regulated for the 
remainder of the 72 hour of infusion.  This was not seen in the Phase 2a safety study where AD subjects 
received a single 25µg/m2 dose of bryostatin. 
Preliminary assessment of PKCε total concentration in AD subjects (Phase 2a safety study) who 
received bryostatin as a single 25µg/m2 dose demonstrated an increase in PKCε total protein. There were 


 
 
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no reports of myalgia in that study suggesting there was no down regulation.  Thus the activation of 
PKCε can be achieved with a dose of 25µg/m2.   
The phase 2a PK data demonstrated that total drug CL was high (~ 40 L/h), was consistent across the 
individual administered doses, and did not appear to be related to body weight, BSA, or sex.  In 
addition, bryostatin pharmacokinetic parameters were observed to have low to moderate inter-subject 
variability.  Based on these findings, a fixed dose regime is being used in this protocol.  Using 1.73 m2 
as standard body surface area, a 25µg/m2 dose translates to a fixed dose of 43.25μg.  To explore doses 
that can activate PKCε and not decrease the activity or concentration of the enzyme when repeated over 
time, doses of 40µg and 20µg will be explored.  The fixed doses used in this study will provide 
bryostatin exposures in plasma that are similar to or lower than exposures associated with a bryostatin 
dose of 25 g/m2.  In addition, fixed dosing will reduce the chance of dosing errors inherent in weight or 
body surface area dosing paradigms. 
Dosing will begin with two initial loading doses at one week intervals that are 20% higher (48μg and 
24μg respectively) than the maintenance doses to assure enzyme activation. Dosing will then continue 
every other week as noted in Figure 1. 
4.2 
Risk/Benefit 
In Study NTRP101-201, a Phase 2a safety study, which included nine Alzheimer’s disease subjects, six 
subjects received bryostatin.  There were no safety signals identified following a single IV infusion of 
25µg/m2 of bryostatin; there were no SAES, and AEs were mild and self-limited.  There were no 
laboratory or cardiac changes noted following treatment.  
Multiple phase 1 and phase 2 oncology studies were conducted under NCI’s IND for bryostatin using 
multiple dose regimens across a wide range of doses, as low as 5µg/m2 up to 180µg/m2 administered as 
infusions ranging from 1 to 72 hours duration.  The only dose limiting toxicity that was observed was 
myalgia.  The myalgia generally involved thigh, calf and ocular muscles.  The myalgia appeared in 
incidence and severity to be related to both administered dose and cumulative dose.  
The etiology of the myalgia is not clear.  No increase in muscle enzymes was found in those subjects in 
whom it was studied.  Electromyography (EMG) was abnormal in one subject who received 65µg/m2, 
suggesting a patchy myositis; and MRI in another subject was normal.  Almost all oncology studies 
were performed at higher doses than are planned in this protocol, and in some cases the oncology 
subjects were dosed at a higher frequency, including weekly for 3 weeks with one week off.  The doses 
planned in this study, 20µg and 40µg,are generally below those administered in the oncology studies.  
Myalgia was self-limited lasting hours to days, depending on severity.  The pain was relieved by over 
the counter analgesics such as acetaminophen.  To protect subject’s safety, myalgia is defined as an 
adverse event of special interest and a Data Safety Monitoring Board (DSMB) will review all safety data 
as described in Section 8 of this protocol with special attention to this dose limiting toxicity. 
Headache and infusion reactions that include dyspnea, fever, flushing, hypotension, and bradycardia 
have been reported in the oncology studies, and as noted in one study lasted only 5-10 minutes.  In the 
very early oncology studies, using a different formulation (60% ethanol/40% saline), phlebitis was 
reported at the injection site. It has also been reported across some studies with the present PET diluent. 


 
 
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Subjects will be monitored for infusion reactions and treated as needed.  Pretreatment with 
antihistamines or steroids is not deemed necessary at this time but can be implemented if the need arises. 
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 different 
mechanism of action than antibodies directed at amyloid, but in the transgenic mouse model of AD 
treated with bryostatin a decrease of Aβ deposition was observed.  Given the limited bryostatin 
experience in AD, the potential for ARIA and associated clinical events cannot be excluded.   
In the event that a subject develops findings suggestive of vasogenic edema or microhemorrhage, 
evaluation should include an MRI scan performed in accordance with Sperling 201116 including 2D T2*  
gradient refocused echo (GRE) for the detection of micro-hemorrhages and T2 Fluid Attenuated 
Inversion Recovery (FLAIR) for the detection of edema.  Should evidence of edema or micro-
hemorrhage be observed in association with clinical symptoms, study drug should be discontinued.  
ARIA cases have often resolved despite continued study drug, and no specific treatments for ARIA have 
been confirmed as necessary or useful, but intravenous corticosteroids may be considered in the event of 
severe symptoms and/or severe edema. 
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 doses in this protocol outweigh 
the risks. 
4.3 
Study Endpoints 
4.3.1 Primary Safety End Points 
Treatment emergent AEs and SAEs  
4.3.2 Secondary Safety End Points 
1. Vital signs, hematology, blood chemistry, and physical examination including body weight   
2. ECG parameters  
3. C-SSRS 
4.3.3 Primary Efficacy End Point 
1. Change from baseline in the SIB at Week 13 
4.3.4 Secondary Efficacy End Points   
1. Change from baseline in the SIB at Weeks 5 and 9 


 
 
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2. Change from baseline in ADCS-ADL-SIV score at Weeks 5, 9 and 13 
3. Change from baseline in MMSE-2 score at Weeks 5, 9 and 13 
4. Change from baseline in NPI score at Weeks 5, 9 and 13 
5. CGI-I at Weeks 5, 9 and 13 
4.3.5 Exploratory Pharmacokinetic and Pharmacodynamic End Points:  
1. Cmax, Tmax, AUClast, AUCinf, λz, T1/2, CL, Vz 
2. Peripheral blood mononuclear cell PKCε amount may be assessed at various time points 
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 dementia11.  The diagnosis must be confirmed at the time of the screening visit 
4. MMSE-2 score of 4-15 inclusive 
5. Patients must be able to perform at least one item on the SIB   
6. Neuroimaging (CT or 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 their 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 drugs approved for treatment of Alzheimer’s disease (e.g. cholinesterase inhibitors, 
memantine), must be on a stable dose for at least 3 months prior to entry into study and 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 on neuroleptic medications must be on a stable dose for ≥4 weeks (dose adjustments 
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11. Females participating in the study must meet one the following criteria: 
a. Surgically sterilized (e.g., hysterectomy, bilateral oophorectomy or tubal ligation) for at 
least 6 months or postmenopausal (postmenopausal females must have no menstrual 
bleeding for at least 1 year) or 
b. If not postmenopausal, agree to use a double method of contraception, one of which is a 
barrier method (e.g., intrauterine device plus condom, spermicidal gel plus condom) 30 
days prior to dosing until 30 days after last dose and have negative β-hCG test for 
pregnancy at screening 
12. 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  
13. 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 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  
5. Creatinine CL of <45ml/min 
6. Poorly controlled diabetes, at the discretion of the Principal Investigator  
7. Use of vitamin E > 400 IU per day within 14 days prior to screening 
8. Use of valproic acid within 14 days prior to screening  
9. Use of an active Alzheimer’s vaccine within 2 years prior to screening 
10. Use of a monoclonal antibody for treatment of AD within 1 year prior to screening 
11. Any medical or psychiatric condition that is likely to require initiation of additional medication 
or surgical intervention during the course of the study 
12. Any screening laboratory values outside the reference ranges that are deemed clinically 
significant by the PI 
13. Use of an investigational drug within 30 days prior to screening  


 
 
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14. Suicidality defined as active suicidal thoughts during the 6 months prior to the screening or at 
Baseline [Type 4 or 5 on C-SSRS scale], or history of suicide attempt in previous 2 years, or at 
serious suicide risk in PI’s judgment 
15. Major psychiatric illness such as current major depression according to Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition, current or past diagnosis of bipolar 
disorder, schizophrenia, or any other psychiatric disorder that might interfere with the 
assessments of safety or efficacy at the discretion of the PI 
16. Diagnosis of alcohol or drug abuse within the last 2 years  
17. 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. 
18. History of prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per central 
reader) 
19. 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].  History of cancer: the subject should be clear 
of cancer for at least 2 years prior to screening 
20. Known to be seropositive for human immunodeficiency virus (HIV)  
21. Known to be seropositive for Hepatitis B or C 
22. Aspartate Amino Transferase (AST) or Alanine Amino Transferase (ALT) >3x ULN and total 
bilirubin >2x ULN or INR >1.5 
23. Prior exposure to bryostatin, or known sensitivity (allergy) to bryostatin or any ingredient in the 
study drug 
24. Any other concurrent medical condition, which in the opinion of the PI makes the subject 
unsuitable for the clinical study.  
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 with CL<60ml/min should be referred for follow-up by their primary care 
provider. 
 
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 each vial of 


 
 
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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 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 and assigned to a subject via the 
Interactive Web Response System (IwRS), 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 label will contain the following information: 
1. Bryostatin or Placebo for Infusion Kit  
2. Kit number 
3. Store refrigerated at 2-8°C. 
4. A description of kit contents 
5. Caution: Investigational New Drug - Limited by Federal (US) Law to Investigational Use 
Only 
6. Sponsor’s manufacturer 
5.3 
Storage and Preparation of Study Drug 
The study drug kits will be stored under refrigeration (2-8°C) in a refrigerator, refrigerated cabinet or 
other refrigerated enclosure, which is securely locked and temperature monitored.  Access to the stored 
study drug kits will be restricted to the investigational site pharmacy or designated unblinded staff 
member.   
Study drug will be prepared and dispensed for administration by a qualified, unblinded 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.  The 
individual designated to prepare the study drug may not participate in any study subject safety or 
efficacy evaluations. 
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.  


 
 
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Study drug should be reconstituted with 1mL of PET diluent (resulting in 50μg bryostatin per mL or 
0.0μg bryostatin per mL). After swirling the vial to completely dissolve the contents, the resulting 
solution must be diluted immediately with 9mL of 0.9% sodium chloride (NS) injection, United States 
Pharmacopeia (USP).  The necessary volume of this solution to achieve the assigned dose for the subject 
should then be added to an IV infusion bag containing 50 mL of normal saline.  Once the infusion bag is 
filled, the 45-minute infusion must be completed within 3 hours. 
The infusion system (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 recommended, as plasticizer from the PVC is leached and there is some limited 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 (i.e., as a 45 minute (±5 min) IV infusion) 
 
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 
after drug accountability has been verified by the monitor.  If destruction on site is not possible, study 
medication should be retained and returned to BioConvergence 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, the subject will be randomized via IwRS. 
Instructions for use of the IwRS system are provided in the IwRS Manual.  A randomization number 
will be assigned, as well as the concentration (20µg or 40µg) of study drug to be administered, 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 unblinded individual who will be 
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member.  The study drug kit will not identify the vial containing study drug as either placebo or 
bryostatin.   
5.6 
Blinding 
All subjects, PIs, and investigational clinical site personnel, with the exception of the individual 
responsible for study drug preparation, will be blinded to dose assignment.  The individual responsible 
for preparation of study drug for infusion is not permitted to perform any safety or efficacy assessments 
and must maintain confidentiality of all dose assignments. 
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 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 (See 
Figure 1 Study Design).  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 final 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 
 
 
 
 
 
 
Week 
Screening and 
Randomization    
0 
1 
2 
3 
5    
7 
9   
11 
13    
30-day 
Follow-
up/ET  
Day (±2 days) 
 (Days -28 to -2) 
0 
7 
14 
21 
35 
49 
63 
77 
91 
Dose 
 
 
1 
2 
3 
4 
5 
6 
7 
  
  
Screening  
 Rand
  
  
  
  
  
  
  
  
  
  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Neuroimaging 
X# 
 
 
 
 
 
 
 
 
 
 
 
Rosen-modified 
Hachinski Scale 
X 
 
 
 
 
 
 
 
 
 
 
 
SIB 
X∆ 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
MMSE-2 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
ADCS-ADL-SIVb 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
X 
NPI 
X 
 
 
 
 
 
X* 
 
X* 
 
X 
 
CGI-I 
 
 
 
 
 
 
X* 
 
X* 
 
X 
 
CSSRS 
X 
 
 
 
X 
 
 
X* 
 
 
X 
 
Labs^^ 
X 
 
 
 
X 
 
 
X* 
 
 
X 
X 
ECG 
X (x3) 
 
 
 
X 
 
 
X 
 
 
X 
 
PE 
X* 
 
 
 
 
 
 
X*+ 
 
 
X 
X+ 
Vitals 
X 
 
Xc 
Xc 
X 
Xc 
Xc 
Xc 
Xc 
Xc 
X 
X 
Randomization 
 
Xa 
 
 
 
 
 
 
 
 
 
 
Confirm Eligibility 
 
X 
 
 
 
 
 
 
 
 
 
 
Study Drug Dosing 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
 
PKCɛ 
 
 
X^ 
 
 
X^ 
 
 
 
X^ 
 
 
Bryostatin levels 
 
 
X∞ 
 
 
X∞ 
 
X∞ 
 
X∞ 
 
 
AE 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conmeds 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


 
 
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∆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, ^PKCε samples prior to dose, 
at the end of infusion, and 60(±5) minutes after end of infusion (at selected sites);  ∞Bryostatin level samples prior to dosing, 15-20 
minutes after start of infusion, at end of infusion (+5 minutes time window allowed), 15(±5) min, 30(±5)min, 45(±5) min, 60(±5) min 
and 120 (±10) min after end of infusion;  # CT scan if imaging not performed within last 2 years or if subject has had significant 
worsening over last 12 months;  ^^Labs: CBC including differential, coagulation, clinical chemistry, TSH, CPK at screening and 
event of myalgia, βhCG if indicated; B12, T-3 and T-4 if TSH abnormal, Hb A1C if clinically indicated;  + abbreviated physical 
examination;  a  Randomization after initial screening procedures indicate eligibility;  b The ADCS-ADL-SIV 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 (supine) prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the infusion, before and after drug 
administration.


 
 
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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 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-SIV 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.  The tests 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-SIV 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 range from 0-54 with lower 
scores indicating greater functional impairment.  The ADCS-ADL-Severe 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 12 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 0-144 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. 
6.1.3 Pharmacokinetic and Pharmacodynamic Assessments 
Selected sites will draw blood samples for pharmacokinetics at the time of doses 1, 3, 5, and 7.  
Samples will be drawn prior to dosing, at 15-20 minutes after the start of infusion, at the end of 
infusion (+5minute window), 15 minutes (±5minutes), 30 minutes (±5minutes), and 
45(±5minutes) 60 minutes (±5minutes),  and 120 minutes 120 (±10) after the end of infusion.  If 
for any reason samples cannot be obtained for a dose as scheduled, they may be drawn at the 
time of the next scheduled dose.  
In addition, selected sites will collect blood samples for assessment of PKCε concentration prior 
to the infusion, at the end of infusion (+5minute window) and 60 minutes after completion of 
infusion(±5minutes).) for doses 1, 3, and 7., respectively.  
Instructions for sample preparation, handling and shipment are provided in the study Laboratory 
Manual. 
6.2 
Visit Procedures 
6.2.1 Screening and Randomization (Days -28 to -2) 
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).   


 
 
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The following procedures should be performed first to avoid unnecessary procedures for 
ineligible subjects:  
 Collect subject demographic data  
 Review of medical history  
 Assessment of neuroimaging (CT or MRI) 
 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 SIB score obtained closest to the day of 
dosing should be entered as the baseline value. 
 NPI 
 ADSC-ADL-SIV 
 Columbia Suicide Severity Rating Scale (C-SSRS) 
 Blood samples for routine safety including hematology, PT, PTT, INR and 
serum-chemistry, CPK, TSH (T-3 and T-4 if indicated),  and β-hCG, if indicated 
 12-lead ECG (x3) 
 Complete physical examination  
 Vital signs 
 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, and   
CSSRS by the Worldwide Clinical Trials’ Clinical Assessment Technologies (CAT) 
group.  
 
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.  


 
 
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A final assessment of the inclusion/exclusion criteria, including any changes in medications or 
health status will be done before dosing to confirm the subject’s eligibility.   
 The following procedures will be done on Day 0: 
 Dosing by IV infusion will be done according to the procedures outlined in Section 5.7. 
 Vital signs prior to infusion, then at 30(±5), 60(±5) and 90(±5) minutes from start of the 
infusion 
 At selected sites, blood sample to measure bryostatin levels (prior to dosing, 15-20 
minutes after start of infusion, at end of infusion, 15, 30, 45, 60 minutes (±5 minutes, 
respectively) and 120 (±10) minutes after end of infusion. and PKCɛ assay (prior to dose, 
at the end of infusion, and 60 (±5) minutes after end of infusion) will be drawn and 
processed as described in the Laboratory Manual. 
 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 
 At selected sites, blood sample to measure bryostatin levels (prior to dosing, 15-20 
minutes after start of infusion, at end of infusion, 15, 30, 45, 60 minutes (±5 minutes, 
respectively) and 120 (±10) minutes after end of infusion and PKCε assay (prior to dose, 
at the end of infusion, and 60 (±5) minutes after end of infusion) will be drawn and 
processed as described in the Laboratory Manual. 
 
Dosing by IV infusion 


 
 
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 
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-SIV 
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 
6.2.7 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 
 At selected sites, blood sample to measure bryostatin levels (prior to dosing, 15-20 
minutes after start of infusion, at end of infusion, 15, 30, 45, 60 minutes (±5 minutes, 
respectively) and 120 (±10) minutes after end of infusion) as described in the Laboratory 
Manual 
 Dosing by IV infusion 
 AEs and concomitant medications 
6.2.8 Week 9 (Day 63 (±2 days)/ Dose 6) 
 Prior to dosing:  
o SIB  


 
 
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o MMSE-2 
o ADCS-ADL-SIV 
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 
 At selected sites, blood sample to measure bryostatin levels (prior to dosing, 15-20 
minutes after start of infusion, at end of infusion, 15, 30, 45, 60 minutes (±5 minutes, 
respectively) and 120 (±10) minutes after end of infusion) and PKCɛ assay (prior to 
dose, at the end of infusion, and 60 (±5) minutes after end of infusion) will be drawn 
and processed as described in the Laboratory Manual. 
 
Dosing by IV infusion 
 
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-SIV 
 NPI 
 CGI-I 
 CSSRS 
 Blood samples for routine safety  
 12-lead ECG 
 PE 


 
 
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 Vital signs  
 AEs  
 Concomitant medications 
6.2.11 30-day Follow-up Visit 
For subjects who have completed or withdrawn from the study, a final follow-up visit will take 
place 30 days after the last dose of study drug. The following will be performed: 
 SIB 
 MMSE-2 
 ADCS-ADL-SIV 
 Blood samples for routine safety  
 Abbreviated PE 
 Vitals 
 AEs and concomitant medications 
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 may be enrolled in the study.  
The subject must be on a stable dose for at least 3 months prior to entry into 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.  


 
 
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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 is permitted, however, due to the theoretical consideration that it may 
inhibit PKC, it should be used sparingly. 
6.3.3 Prohibited Medications  
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, MRI 
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:  
1. Hospitalization solely for a diagnostic purpose, even if related to an AE,  
2. Elective hospitalization for an intervention planned before the subject enrollment in the 
study  
3. 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. 
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. 


 
 
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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:  
 severe injection/infusion site reactions (ulceration or necrosis that is severe; operative 
intervention indicated) 
 systemic hypersensitivity reactions 
 myalgia  


 
 
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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 
 if the PI believes that discontinuing treatment is in the best interest of the subject 


 
 
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7.9 
Study discontinuation 
Neurotrope BioScience, Inc. 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 BioScience, Inc. 
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 Bioscience, Inc. or designee. 
  
8 INDEPENDENT DATA AND SAFETY MONITORING BOARD (DSMB) 
Since there is limited exposure in this population and since the study population is largely elderly 
and potentially fragile, an independent safety monitoring board will be formed.  The roles and 
responsibilities of the DSMB will be detailed in the DSMB Charter.  The DSMB will have 
access to unblinded safety data and will conduct review of these data at regular intervals during 
the study.  The DSMB may also conduct ad hoc safety reviews at their own request or at the 
request of the Sponsor. 
The first safety analysis will be performed when 30 subjects have received four doses of study 
drug, followed by additional safety analyses when 60 and 90 subjects have received 4 doses.  
The safety analyses will be performed by an independent unblinded statistician.  Tables and 
listings will be provided according to the procedures specified in the DSMB Charter.  The 
DSMB will advise the sponsor of any safety issues. Any recommendations made by the DSMB 
to alter the conduct of the study will be forwarded to the Sponsor for appropriate action. 
 
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. 
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 and secondary endpoints will be conducted on data 
collected through Week 13.  


 
 
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9.0 
Sample Size Determination 
Since the primary objective of the study is to obtain safety and tolerability data for the 
administration of multiple doses of bryostatin, the planned sample size is based largely on 
feasibility.  However, the following is an assessment of power for the primary analyses of the 
primary efficacy endpoint, estimation of the effect of bryostatin on the mean change from 
baseline in the SIB at Week 13. 
It is estimated that 150 subjects equally randomized among the three dosing groups (two doses of 
bryostatin and placebo) will provide at least 80% power, assuming a true mean difference of at 
least 6.5 points in favor of the bryostatin groups (standardized effect size of 0.47), in a test 
between each bryostatin group and placebo in mean change from baseline in the SIB, (one-sided 
at α=0.10).  This assumes the standard deviation of change from baseline at Week 13 is 14 
points.  This estimate allows that up to 15% of randomized subjects will not provide information 
due to discontinuation.  The least significant difference for the test between the observed means 
under these conditions is estimated to be 3.9 points (standardized effect size of 0.28). Analysis 
Sets (Populations) 
The Safety Analysis Set (SA) 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 intention-to-treat 
(ITT) 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. 
9.1 
Demographics, Baseline Characteristics and Disposition 
Demographics will include age, sex, race, ethnicity, height, and body weight and will be 
summarized by treatment group using descriptive statistics for both the SA 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 SA 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 
Safety Analysis 
The SA population will be used for all safety analyses with treatment group determined by the 
treatment actually received. AEs, safety laboratory, ECGs, physical exam and vital signs data 
will be presented in tabular format and summarized descriptively by treatment group.  No formal 
hypothesis testing will be carried out on these safety assessments.  Incidence and severity of AEs 
will be summarized by treatment dose using System Organ Class (SOC).  AEs will be coded 
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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. 
9.3 
Efficacy Analysis 
The FAS population will be used for efficacy analyses.  In further keeping with ITT principles, 
analyses will be conducted according to randomized groups regardless of treatment actually 
received.  Analyses will be performed on each dosing group vs. placebo and on the “pooled” 
dosing group vs. placebo. 
Descriptive statistics by visit and randomized treatment group will be provided for all efficacy 
data.  Efficacy evaluations will include inferential analyses and estimation at each visit for the 
change from baseline in the SIB (primary endpoint), ADCS-ADL-Severe, MMSE-2 and NPI, 
and the value at each visit for the CGI-I.  The primary analysis will test the hypothesis that there 
is a beneficial effect of each bryostatin dose group or the combined (pooled) bryostatin group 
compared to placebo on the change from baseline in the SIB at the Week 13 visit.  The 
secondary efficacy endpoints will be analyzed in all 3 groups (i.e., each dose separately and 
pooled vs. placebo); p-values and confidence intervals will be reported and used to assist in 
interpretations of the results. 
All statistical tests will be one-sided and use α = 0.10 unless otherwise stated.  LSM and two-
sided 80% confidence intervals will be provided for treatment group differences and estimated 
endpoint values by visit.   No multiplicity adjustments will be made.   Estimates of effect with 
confidence intervals and p-values comparing each dose of bryostatin to placebo and the pooled 
bryostatin group to placebo will be provided for all endpoints. 
9.3.1 Analysis of Primary Endpoint 
The primary statistical objective for efficacy is to estimate the effect of bryostatin on the mean 
change in the SIB at Week 13.  A linear model will be used for both estimation and significance 
testing for the primary endpoint.  This will be a Mixed Model for Repeated Measures (MMRM) 
with fixed effects for treatment, baseline MMSE-2 stratum, scheduled visit (nominal) and 
scheduled visit by treatment interaction, plus a random effect for subject.  The baseline SIB 
measurement will be a covariate.  The primary contrast will be the change from baseline in the 
SIB at Week 13 between each bryostatin group and the placebo group.  Inferences will be based 
on the model estimates of expected values for the treatment by visit interaction.  
Secondary analyses of the primary endpoint will include analyses at the other scheduled visits 
(Weeks 5 and 9). 
9.3.2 Analysis of Secondary Endpoints 
The ADCS-ADL-SIV, MMSE-2, and NPI secondary endpoints will be analyzed using the 
statistical model used in the analysis of the SIB.  The model for the CGI-I will differ in that there 
is no baseline value used as a covariate in this global assess of change.  These analyses will use 
the statistical models to generate point estimates, confidence intervals and p-values and will be 


 
 
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used to support the results of the primary endpoint analysis in addressing the primary efficacy 
objective. 
9.4 
Pharmacokinetics 
Plasma samples will be analyzed for bryostatin concentrations using a validated assay.  A 
separate Pharmacokinetic Analysis Plan (PAP) will be developed prior to the pharmacokinetic 
analysis that will describe methods to be used, as well as the tables, figures, and listings that will 
be generated as part of this analysis.  
Plasma samples may be analyzed to determine PKCɛ amount in PBMCs.  Dose-response 
relationships may be examined, as well as possible exposure-response relationships. 
9.5 
DSMB Safety Assessments 
Unblinded summaries and listings of safety data will be provided to the Independent DSMB as 
described in Section 7. Details for these will be described further in the DSMB Charter and the 
Interim Analysis Plan (IAP).  Analyses will be performed by an independent unblinded 
statistician so that study investigators and other sponsor personal (and contractors) involved in 
study monitoring, data processing and other aspect of the study remain blinded.   
 
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.   
 


 
 
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10.1 
 Study Documentation and Record Retention 
The PI, or designees, must enter all results collected during the clinical study into eCRFs.  eCRF 
completion guidelines will be reviewed with clinical site personnel at the PI’s Meeting and site 
initiation visits.  PIs are responsible for approval of all entered or corrected data.  The PI, or 
designees, must review and approve the data before database lock, or before any scheduled 
interim analyses, as required by the sponsor. 
The medical records (source documents) upon which the eCRFs are based must be kept at the 
clinical site for at least a period of 2 years following the date a marketing application is approved 
for the drug for the indication for which it is being investigated; or, if no application is to be filed 
or if the application is not approved for such indication, until 2 years after the investigation is 
discontinued and the FDA is notified.  Neurotrope BioScience, Inc. 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 BioScience, Inc. 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 BioScience, Inc., 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 BioScience, Inc., or its representatives.  
This will be documented in a clinical study agreement between Neurotrope BioScience, 
Inc. and the PI. 
During the study, a monitor from Neurotrope BioScience, Inc., 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). 


 
 
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 Record and report any protocol deviations not previously sent to Neurotrope BioScience, 
Inc  
 Confirm AEs and SAEs have been properly documented on CRFs and confirm any SAEs 
have been reported and those SAEs that met criteria for reporting have been forwarded to 
the EC/IRB/ Independent Ethics Committee (IEC). 
The monitor will be 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 
BioScience, Inc. or its representative may conduct a quality assurance audit. 
10.4 
 Audits and Inspections 
Authorized representatives of, Neurotrope Bioscience, Inc., 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 BioScience, Inc. 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 BioScience, 
Inc. 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 BioScience, Inc. 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. 


 
 
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Progress reports will be provided to the IRB according to local regulations and guidelines. 
11.1 
 Ethical Conduct of the Study 
The conduct of this study will be consistent with ICH Guidance E6, GCP, and U.S. federal 
regulatory requirements, as applicable.  This study will be conducted in accordance with 
applicable local law(s) and regulation(s) and the principles of protection of healthy human 
subjects participating in clinical medical research that have their origin in the Declaration of 
Helsinki. The PI must agree to the direct access to source documents and inspection of clinical 
study-related records by the regulatory authority/Neurotrope BioScience 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 
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or designee.  The eCRF data for each subject will be reviewed against source documents at the 
study sites by the investigational site study monitor. 
The PI and investigational site will allow study related quality control monitoring and audits, 
EC/IRB/IEC review, and/or regulatory inspection and will cooperate in providing direct access 
to source data and documentation. 
12.2 
 Data Management and Data Storage 
Study procedures will be documented on source documents that will be retained at the site(s).  
An Electronic Data Capture (EDC) system will produce eCRFs that will be used to collect 
assessment data for this study.  All study data entered into the eCRF will be compliant with 
regulatory requirements and 21CFR part 11.  The system will allow differing levels of access and 
will accommodate roles for the PI, Medical Monitor, CRO, and Sponsor.  All data changes made 
within the system will be subjected to an audit trail.  In compliance with GCP, source 
documentation supporting the eCRF data should indicate the subject’s participation in the study 
and should clearly document the dates and details of study procedures, AEs, and subject status.  
The eCRFs will identify study subjects with unique identifiers.  Data are recorded from the 
source documents, directly onto the eCRF at the site.   
Electronic CRF data items will undergo quality control standards of operation.  Unresolved 
errors, omissions, or requests for clarification will trigger a query to the Investigational Site for 
resolution via electronic queries.  The database will be corrected for completeness and accuracy.  
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 BioScience, 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 BioScience, Inc., or designee.  No study 


 
 
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documentation should be destroyed or moved to a new location without prior written approval by 
Neurotrope BioScience, Inc.  
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 BioScience, Inc. 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. 


 
 
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12.9 
 Insurance 
The Sponsor has taken out a liability insurance policy, which covers the liability of PIs.  This 
policy is in accordance with local laws and requirements.  
The Sponsor’s insurance does not relieve the PI or the collaborators of any obligation to maintain 
their own liability insurance policy as required by the applicable law. 
13 PUBLICATION AND DISCLOSURE POLICY 
Study findings are an integral part of the overall commercialization plan for this investigational 
compound. To this end, the contents of this protocol and any amendments and results obtained 
during the study shall be kept confidential by the investigator, the investigator’s staff, and the 
IRB/IEC, and shall not be disclosed in whole or in part to others, or used for any purpose other 
than reviewing or performing the study, without the review and prior written consent of the 
Sponsor. These obligations of confidentiality and non-use shall in no way diminish such 
obligations as set forth in either the Confidentiality Agreement or Clinical Trial Agreement 
executed between the Sponsor/CRO and the institution/investigator. All persons assisting in the 
performance of this study must be bound by the obligations of confidentiality and non-use set 
forth in either the Confidentiality Agreement or Clinical Trial Agreement executed between the 
institution/investigator and the Sponsor/CRO.  Additionally, the publication plan of the Sponsor, 
considering, among other items, proprietary patent issues and competitive strategic goals, must 
be complied with prior to the public disclosure of any aspect of this study by abstract, verbal 
presentation, invited lecture, journal article, or journal letter. Matters regarding authorship and 
the order of authorship on publications reporting the results of single study findings are covered 
in a separate agreement. 
 


 
 
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14 APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS 
Drugs Allowed (Y) and Not Allowed (N) as Concomitant medications in this study. 
 
Drug Class 
                 Usage 
(p.r.n.)      Chronic Use 
 
Restrictions 
 
Analgesics 
(Y)  
(Y) 
Only non-opioid containing 
analgesics can be administered 
chronically. Use of 
acetaminophen is permitted, 
however, due to the possibility 
that it may inhibit PKC, it 
should be used sparingly. 
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 of 
a clinic visit.  
 
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. 
 
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 
 


 
 
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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 
 
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, 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 
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 


 
 
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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 
 
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 
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) Reminyl 
(galantamine), and memantine  


 
 
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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 
 
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 
(docusate sodium) are allowed. 
 
Muscle relaxants 
(N) 
(N) 
 
 
Psychotropic drugs 
not otherwise 
specified (including 
herbal products) 
(N) 
(N) 
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 
 
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 notallowed; Dose must 
be stable for at least one 
month prior to Screening. 
 
Vaccines for AD 
N 
N 
Patients treated with active 
vaccine against amyloid/tau 
within 2 years are not allowed.  
 
 
 
 


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


 
 
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14 Schroot LM, Jackson K, Yi P et al. 2015. Acute oral Bryostatin-1 administration improves 
learning deficits in the APP/PS1 transgenic mouse model of Alzheimer’s disease. Current 
Alzheimer Research 12: 222-31. 
15 Etcheberrigaray R, Tan M, Dewachter I et al. 2004. Therapeutic effects of PKC activation in 
Alzheimer’s disease transgenic mice. PNAS: 101 (30): 11141-11146. 
 
16 Sperling RA, Jack CR, Black SE, Frosch MP, Greenberg SM, Hyman BT, Scheltens P, 
Carrillo MC, Thies Martin W, Bednar MM, Black RS, Brashear HR, Grundman M, Siemers ER, 
Feldman HH, Schindler RJ. 2011.  Amyloid-related imaging abnormalities in amyloid-modifying 
therapeutic studies: recommendations from the Alzheimer's Association Research Roundtable 
Workgroup. Alzheimer's & dementia  : 7(4), 367–85. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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16 APPENDIX 3 – SUMMARY OF CHANGES   
16.1 
Version 2.0,  20 January 2016 
Spelling, grammar and syntax corrections have been made throughout the document for clarity 
and correctness. In addition, the following changes and corrections were made. 
Study Administrative Structure: 
Study Medical Monitor/Emergency Contact Information has been updated to list Idil Cavus, 
MD PhD as medical monitor. 
Central Laboratory has been changed to ACM Global 
eResearchTechnology, Inc. (ERT) has been added as the central ECG vendor 
Pharmacokinetic and Pharmacodynamic Plasma Sample Analysis Laboratory locations have 
been updated. 
Protocol Synopsis and Section 4.4.2, Exclusion Criteria: 
Exclusion 5 has been modified from poorly controlled diabetes, with a hemoglobin A1c of 
8.5% or greater to poorly controlled diabetes, at the discretion of the Principal Investigator.  
This change was implemented to remove the perceived but unintended requirement to test 
hemoglobin A1c for all subjects during screening. Investigators may elect to test subjects 
suspected of having poorly controlled diabetes, but the test is intended to be done at the 
investigator’s discretion based on medical history or clinical assessment. 
Exclusion 6 has been modified from Creatinine CL of <60ml/min to Creatinine CL of 
<45ml/min.  The rationale for this change is as follows: 
The lower exclusionary CL of <45 mL/min is based on the National Kidney Foundation 
(NKF) guideline and recommendations, as well as on the extensive experience with 
bryostatin in oncology patients (absence of renal complications).   
CL is measured using the Cockcroft-Gault (C-G) equation, which takes into account the age 
and gender of the patients. According to the National Kidney Foundation (NKF), almost 75% 
of individuals = or >70 years old may have GFR <90 mL/min/1.73 m2, and almost 25% may 
have GFR <60 mL/min/1.73 m2.  (NKF Guideline pg 263).   
Since single measures of GFR can fluctuate and is influenced by hydration, diet, medications, 
etc., the NKF in their recent US commentary recommends follow up of patients based on 
their renal function, together with other risk factors such as hypertension, diabetes etc. 
(https://www.kidney.org/professionals/guidelines/guidelines_commentaries). Therefore, for 
patients who have CL<60, the PI should refer patients to their primary care provider for 
appropriate follow-up.   
The NKF endorses the new distinction between chronic kidney disease (CKD) stage 3a (GFR 
of 45-59 mL/min/1.73 m2) and 3b (GFR of 30-44 mL/min/1.73 m2) in the updated guideline. 
As reviewed in the guideline, the risks of mortality and other outcomes vary greatly between 


 
 
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these groups. Consistent with this, in their 2014 guideline severe dose restrictions of certain 
meds are recommended only for patients with CL <30.  
Exclusion 7 has been corrected to exclude subjects using > 400 International Units of 
vitamin E. The previous version specified ≥ 400 International Units in some areas of the 
document, which was incorrect. A corresponding correction was made to Section 17, 
Appendix 1, Restricted Concomitant Medications.  
Exclusion 17 has been modified to clarify if and when laboratory tests should be done to rule 
out 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.    
Exclusion 18 has been clarified to define the established cut-off for QTc: History of 
prolonged QT or prolonged QT on screening ECG (QTcB or QTcF >499 per central reader).  
 
The following text has been added to Section 4.4.2 regarding re-screening and expected follow-
up: 
“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 with CL<60ml/min should be referred for follow-
up by their primary care provider.” List of Abbreviations, and Sections 5.3, 5.6 and 8.2.10 
The term Interactive Response Technology (IRT) has been replaced with Interactive Web 
Response System (IwRS), which is the specific system used in this study. 
Section 2.1 
Numbers of patients treated in oncology trials have been updated. 
Section 5.3 
Text describing packaging and labeling of Study Drug kits has been updated. 
Section 5.4 
Text describing storage and preparation of Study Drug has been clarified. A time window of 3 
hours has been specified for completion of the 45-minute infusion after the IV bag containing 
Study Drug has been prepared. 
Section 5.5 
The following text has been deleted to conform to standard operating procedures which apply to 
disposal of biohazardous waste at some investigational sites. Used infusion bags and tubing will 
be disposed of following site standard procedures. 


 
 
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Deleted text:  After the infusion has been completed, the used infusion bag should be returned to 
the pharmacist or individual designated as responsible for study drug and retained for drug 
accountability. 
Section 8 Table 2 Schedule of Activities, Section 8.2.1 Screening and Randomization 
Language has been modified to permit all screening assessments to be performed on the same 
day if practical. The Schedule of Activities Table has been adjusted to reflect this change.  The 
new text in Section 8.2.1 reads: 
The following may be performed on the same day or on another day within the 21– 
day (+ 2 days) screening window: 
 Severe Impairment Battery (SIB) 
 Alzheimer Disease Cooperative Study Activities of Daily Living Inventory-
Severe Impairment Version (ADCS-ADL-SIV)  
 Neuropsychiatric Inventory (NPI) 
The SIB, ADCS-ADL-SIV, and NPI may be administered at any time within the 21-
day (+2) screening window, including the screening (first) day, allowing all 
procedures to be completed on the same day if practical.  
If the SIB and MMSE-2 are performed on the same day, the SIB should be 
performed first, followed by the MMSE-2. 
If the subject has had no intervening medical issues or changes in medications 
between the date the SIB is performed and Day 0, dosing may proceed as scheduled 
without repeating scale assessments.  
If changes in the subject’s health or mental status occur during this period, including 
changes in medication affecting the mental status, the Medical Monitor should be 
notified. In this case, the subjects will need to have the SIB, MMSE-2, C-SSRS, 
ADCS-ADL-SIV, NPI repeated before they can be randomized. The site will need to 
continue to ensure eligibility requirements are met per the protocol regarding these 
scales.  
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, and CSSRS by the Worldwide Clinical Trials’ Clinical Analytics, 
Training, and Surveillance (CATS) group. 
 
Section 17, Appendix 1, Restricted Concomitant Medications 
Multiple changes were made to the table of restricted medications, removing medications 
that have minimal effect on cognitive performance and testing.  There are no known 
drug/drug interactions with bryostatin. 


 
 
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16.2  Summary of Changes, Version 3.0 15 July 2016 
Except as noted, section numbers refer to the amended protocol section numbering. 
Global changes:  
The document version and date have been updated. 
A number of grammatical corrections and clarifications were made to the text, which do not 
change the content. These have not been individually described in the summary of changes. 
Title Page 
Planned  LPLV has been changed to February 2017. 
Study Contact Information 
Paula T. Trzepacz, MD has replaced Warren W. Wasiewski, MD as Chief Medical Officer. 
Protocol Synopsis 
Study duration has been changed to approximately 14 months. 
Study Design 
Two doses of bryostatin, 20µg or 40µg, will be compared to placebo. Study subjects will 
receive a total of 7 doses of study drug over 12 weeks of treatment, followed by safety and 
efficacy assessments at Week 13 and a final study visit at Week 15.  There will be no 
second randomization for additional treatment for those in the active drug arms nor will 
those in the placebo arm be randomized a second time to receive either 10 µg of bryostatin 
or continued treatment with placebo.  
Text describing the second randomization and second 12 weeks of treatment has been 
deleted. 
Secondary Efficacy Endpoints (as described in Study Synopsis and Section 4.2.4) 
The timepoints at which secondary efficacy endpoints will be assessed has been specified as 
follows: 
 Change from baseline in the SIB at Weeks 5 and 9 
 Change from baseline in Alzheimer Disease Cooperative Study Activities of Daily Living 
Inventory-Severe Impairment Version (ADCS-ADL-SIV) score at Weeks 5, 9 and 13 
 Change from baseline in MMSE-2 score at Weeks 5, 9 and 13 
 Change from baseline in Neuropsychiatric Inventory (NPI) score at Weeks 5, 9 and 13 
 Clinical Global Impression of Improvement (CGI-I) at Weeks 5, 9 and 13 
Exploratory Pharmacokinetic and Pharmacodynamic Endpoints 


 
 
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Peripheral blood mononuclear cells will be tested for PKCɛ concentration but not for 
activity as previously stated. 
Statistical Considerations  
(text in Protocol Synopsis and Section 11.0 have been revised as follows) 
The primary contrasts will be the change from baseline in the SIB at Week 13 between each   
bryostatin group and the placebo group. These will be conducted sequentially, first for the 
bryostatin 40µg group, and if significant (at 1-sided level of 0.10), for the 20µg bryostatin 
group. The Bryostatin treatment groups will not be pooled. 
To provide at least 80% power, it is assumed that a true mean difference of at least 6.5 (not 
5.6) points in favor of the bryostatin groups (standardized effect size of 0.47, not 0.40) will 
be observed, in a test between each bryostatin group and placebo in mean change from 
baseline in the SIB (one-sided at α=0.10). The least significant difference for the test 
between the observed means under these conditions is estimated to be 3.9 points (not 3.4), 
(effect size of 0.28 not 0.24). 
Protocol Synopsis and Sections 4.3.1 and 4.3.2: Eligibility criteria  
Inclusion #4 has been clarified to state that the MMSE-2 range of 4-15 is inclusive. 
Inclusion #9 has been modified to allow a change in concomitant drugs for treatment of 
Alzheimer’s disease under specific conditions. The text now reads: If taking drugs approved for 
treatment of Alzheimer’s disease (e.g. cholinesterase inhibitors, memantine), must be on a stable 
dose for at least 3 months prior to entry into study and 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 
Inclusion #11b has been rephrased as follows to specify use of contraceptives 30 days prior to 
dosing: 
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. 
Inclusion #12 has been modified to correspond with the change in Inclusion #11b: 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  
Exclusion criteria #5 and #6: The numbering of these criteria have been corrected in the 
Protocol Synopsis to match the order in which they occur in Section 4.3.2. 
Exclusion #19 has been modified to address history of cancer. The text now reads: 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].  History of cancer: the subject should be clear of 
cancer for at least 2 years prior to screening. 


 
 
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Section 3.0.3 
References to the second 12 weeks of the study have been deleted. 
Section 3.1  Hypothesis 
The null hypothesis will be rejected at a significance level of α (1-sided) = 0.10.  This analysis 
will be a test of superiority and only an improvement in the SIB score is of interest.  The analysis 
will be conducted using a mixed model for repeated measures (MMRM). For this formal 
inferential testing, the bryostatin 40µg group will first be compared to the placebo group; if the 
null hypothesis is rejected, the bryostatin 20µg group will be then compared to the placebo 
group. 
Section 4.0 
Text describing the second randomization and details regarding dosing assignments in the second 
12 weeks of the study have been deleted. 
Figure 1: Study Design has been inserted. 
Sections 4.2.5, 8.0.3 and 12.5 Pharmacokinetics 
Peripheral blood mononuclear cells will be tested for PKCɛ concentration but not for activity as 
previously stated. 
Section 5.5 
Text referring to the second randomization has been deleted. 
Section 5.7 
Table 1: Dosing Schedule has been deleted. It has been replaced by Figure 1 in Section 4.0. 
Remaining tables in the document have been renumbered accordingly. 
Section 6 
Reference to the second randomization has been deleted. 
Section 6.2.1 Screening and Randomization 
The screening period has been expanded to approximately 4 weeks to accommodate scheduling 
of imaging procedures. The SIB performed in screening must be done within 3 weeks before 
dosing, therefore if the screening period exceeds 3 weeks, the SIB should be repeated on the day 
of the first dose, prior to dose administration. The SIB score obtained closest to the day of dosing 
should be entered as the baseline value. 
Section 6, Table 1 Schedule of Activities 


 
 
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The screening period has been expanded from 21 days to 28 days (4 weeks). This has been done 
to accommodate scheduling of imaging procedures, if needed. If the screening SIB is done more 
than 3 weeks before the date of the first dose, the SIB should be repeated on the day of dosing, 
prior to dose administration. The SIB value obtained on the day of dosing should be entered as 
the baseline SIB value. 
Lab tests at screening will include TSH, and if indicated by abnormal TSH results, T-3 and T-4 
will automatically be tested by the central lab. 
Vital signs will be measured while the subject is in a supine position (previously unspecified). 
A 5-minute time window has been added to Bryostatin level sample times, and vital sign 
measurements. This time window is also inserted in Sections 8.1.2 through 8.1.9, which describe 
study visit procedures. 
Section 6.0.1.1 Laboratory 
TSH has been added at screening, and T-3 and T-4 will be done if TSH result is abnormal. 
Section 6.0.3 Pharmacokinetic and Pharmacodynamic Assessments 
References to testing at doses 9, 12, and 14 have been deleted. A five-minute window has been 
provided for scheduled blood sampling. 
Section 6.1.1 Screening and Randomization 
Screening procedures and randomization will take place within an approximate 4-week period 
prior to first dose administration (Days -28 to -2).  The previous screening period was 21 days. 
TSH has been added to screening lab tests, with follow-up testing of T-3 and T-4 if 
TSH is abnormal. 
Regarding changes in the subject’s health or mental status that occur during the 
screening and randomization period, including changes in medication affecting the 
mental status, the following text has been revised to provide a case by case assessment 
of subject eligibility:  
Old text: In this case, the subjects will need to have the SIB, MMSE-2, C-SSRS, 
ADCS-ADL-SIV, NPI repeated before they can be randomized. 
New text: The Medical Monitor will advise the PI regarding any assessments that 
should be repeated to ensure eligibility requirements are met. 
Section 6.1.10 Week 13 Day 91 (+/-2 days) 
The following text has been deleted because no further dosing will occur: 
Each subject will begin the newly assigned dose regimen at this visit, therefore, AEs  
will be collected prior to the infusion that reflect previous dosing and again after 
dosing.  


 
 
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Text describing the timing of vital sign measurements during infusion has also been 
deleted. 
Sections  7.1.12 through 8.1.19 (section numbers from Version 2) 
Sections referring to study visits in the second dosing period have been deleted. 
Sections 8 and 9.5  
References to efficacy data have been deleted. The DSMB will not review efficacy data. 
Section 9 Data Analysis / Statistical Methods 
The following text has been deleted, since it refers to the second dosing period: 
The study will be conducted and analyzed in two parts.  In the first part subjects will be 
randomized in equal numbers to one of two doses of bryostatin and Placebo and assessments will 
be scheduled during and after the first 12 weeks of treatment.  After 12 weeks of treatment 
subjects in each dose group will be randomly assigned in equal numbers to either continue on 
their original treatment or begin a new dose of bryostatin. 
Section 9.3 Efficacy Analysis 
All statistical tests will be one-sided and use α = 0.10 unless otherwise stated.  LSM and two-
sided 80% confidence intervals will be provided for treatment group differences and estimated 
endpoint values by visit. The following hierarchal procedure will be used for the formal 
inferential testing of the change from baseline in the SIB at Week 13: first the bryostatin 40µg 
group will be compared to the placebo group; if the null hypothesis is rejected, the bryostatin 
20µg group will be then compared to the placebo group. Other than using the above stepwise 
inferential testing procedure for formal testing of the primary contrasts, no multiplicity 
adjustments will be made for analysis of the secondary endpoints. Whether or not the formal 
inferential testing yields rejection of the null hypothesis, estimates of effect with confidence 
intervals and p-values comparing each dose of bryostatin to placebo will be provided for all 
endpoints. 
Section 9.3.1 
The primary contrast will be the change from baseline in the SIB at Week 13 between each 
bryostatin group and the placebo group, using the hierarchical procedure described above for the 
formal hypothesis testing. 
Section 9.3.2 
The ADCS-ADL-SIV, MMSE-2, and NPI secondary endpoints will be analyzed using the 
statistical model used in the analysis of the SIB.   
Section 12.7  Primary Efficacy Analysis (as numbered in version 2.0 of the protocol) has been 
deleted. 


 
 
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The following text has been deleted since the study will not be ongoing at the time of data 
analysis. 
The primary analyses of the safety and efficacy endpoints is to be based on the data through the 
Week 13 visit.  A complete unblinded analysis of the safety and efficacy data will be conducted 
on all data for the study.  This will be conducted after all subjects have completed the Week 13 
visit (or have discontinued), all data has been collected, checked and is final, and the database for  
the study has been locked.   
Measures will be taken to prevent unblinding of individual study subjects and their data until 
completion of the study and final database lock.    
The unblinded summaries from this analysis (data through Week 13) will be provided to the 
sponsor for the purpose of informing decisions about future development of bryostatin.  The 
sponsor may also make public announcements regarding the study’s meeting its primary safety 
and efficacy endpoints. 
Since the study will be ongoing at the time of this analysis, the individual treatment assignment 
for all subjects should remain blinded.   
16.3 Summary of Changes, Version 4.0  1 March 2017 
Global changes:  
The document version and date have been updated. 
Study Contact Information 
Kenneth Gorelick, MD has replaced Paula T. Trzepacz, MD as Acting Chief Medical Officer. 
Protocol Synopsis 
Exploratory Pharmacokinetic and Pharmacodynamic End Points: a population pharmacokinetic 
model will not be used to summarize bryostatin exposure in plasma. 
 
Peripheral blood mononuclear cell (PBMC) Protein Kinase C epsilon (PKCε) amount at various 
time points may be determined. 
 
Statistical Considerations: The primary contrasts will be the change from baseline in the SIB at 
Week 13 between each bryostatin group and the placebo group and between the combined 
(pooled) bryostatin dosing group and the placebo group.   
Section 3.1 Hypothesis 
Analyses will be performed on each bryostatin dosing group vs. placebo and on the “pooled” 
bryostatin dosing group vs. placebo. A stepwise hierarchal testing procedure will not be 
followed. 
Section 4.3.5 Exploratory Pharmacokinetic and Pharmacodynamic End Points  


 
 
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Peripheral blood mononuclear cell PKCε amount may be assessed   at various time points. 
Section 9.3 Efficacy Analysis  
Analyses will be performed on each dosing group vs. placebo and on the “pooled” dosing group 
vs. placebo. 
The primary analysis will test the hypothesis that there is a beneficial effect of each bryostatin 
dose group or the combined (pooled) bryostatin group compared to placebo on the change from 
baseline in the SIB at the Week 13 visit. 
The secondary efficacy endpoints will be analyzed in all 3 groups (i.e., each dose separately and 
pooled vs. placebo); p-values and confidence intervals will be reported and used to assist in 
interpretations of the results. 
A hierarchal procedure will not be used for the formal inferential testing of the change from 
baseline in the SIB at Week 13. 
Estimates of effect with confidence intervals and p-values comparing each dose of bryostatin to 
placebo and the pooled bryostatin group to placebo will be provided for all endpoints. 
Section 9.4  Pharmacokinetics 
A population pharmacokinetic model will not be used.  
Plasma samples may be analyzed to determine PKCɛ concentrations in PBMCs.  Dose-response 
relationships may be examined, as well as possible exposure-response relationships. 

SAP_001.pdf: 
 
 
Neurotrope BioScience 
 
NTRP101-202 
 
Statistical Analysis Plan 
 
Version Final 
 
Issue Date 17-Mar-2017 
 
Template: WCT-TP-ST-005-005 
 
Page 1 of 46 
Effective Date: 15-Apr-2016 
 
Confidential 
 
 
 
Statistical Analysis Plan 
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 
 
Protocol Number: NTRP101-202 
 
Version Final 
Issue Date: 17-Mar-2017 
Author: Shuhua Qi, MSc 
 
Previous Versions 
  
 
 


 
 
Neurotrope BioScience 
 
NTRP101-202 
 
Statistical Analysis Plan 
 
Version Final 
 
Issue Date 17-Mar-2017 
 
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Page 2 of 46 
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Confidential 
 
SAP Amendments before database lock 
Version  
Issue Date 
Section 
Revision/Addition 
Rationale 
Final 
17Mar2017 6.10.2 
Updated SAS code 
Sponsor agreement 
Final   
14Mar2017 Page 1 
Updated protocol version 
Protocol amendment 4 
Final   
14Mar2017 6.10.2, 
6.10.4, 6.10.6 
1) Re-organizes.  
2) Added  following 
sentence in section 
6.10.6: 
The effects of center and 
treatment by center 
interaction will be 
explored using an 
analysis of covariance 
(ANCOVA) model as 
describe in section 6.10.4 
if data permit. Low 
enrolling centers may be 
pooled if appropriate. 
Stepwise covariates 
selection approach may 
be applied. These will 
explored as post hoc 
analyses. 
3) the followings were 
removed  
- Correlation of change in 
(SIB, ACDC-ADL, NPI, 
etc) with bryostatin Cmax 
and AUC   
- Correlation of change in 
(SIB ACDC-ADL, NPI, 
etc) with mean change in 
serum PKCepsilon levels  
Sponsor 
request/agreement 
Draft v4 
14Feb2017 
3.3 
Removed percent from 
baseline in SIB score 
 
Not in protocol 
 
 
6.1.4 
Removed PPS      
Sponsor request 


 
 
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Version Final 
 
Issue Date 17-Mar-2017 
 
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Confidential 
 
 
 
 
 
6.2.8.1 
Replaced by 
original/draft1 SAP 
wording for calculation 
of dose taken and 
percentage of planned 
dose taken 
 
The analysis can/will 
take place after 
unblinding per sponsor 
request 
 
 
6.10.1, 6.10.2  Revised primary analysis 
method 
Protocol amendment 
XXX 
 
 
6.10.3 
Sensitivity analysis was 
not planned 
 
Sponsor request 
 
 
6.10.4, 6.10.5 
and 6.10.6 
Revised/added 
exploratory analysis 
methods 
 
Sponsor request 
 
 
6.12.3 
Added vital BP based on 
CTCAE grade 
 
Sponsor request 
Draft v3 
02Feb2017 
6.11 
WCT PK group will 
proved summary 
table/listings for PKCε 
concentration 
 
WCT PK group 
agreement 
 
 
Last page 
Approval for 
implementation of 
Statistical Analysis Plan 
 
Draft v2 
27Dec2016  Cover page 
Changed author 
Transition,12Dec2016 
 
 
Original 
6.2.20, 6.11 
Removed section 6.2.20 
Calculation of Area under 
the Curve and section 
6.11 Pharmacokinetic 
Analyses 
A separate PK data 
analysis plan (PAP). 
 
 
 
 
2.8.1 
Revised Calculation of 
dose taken and 
percentage of planned 
dose taken 
 
 
Sponsor agreement 
 
 
6.12.2, 6.12.3 
& 6.12.3 
Added figures for Lab, 
vital signs and ECG 
 
Sponsor request 
  
 


 
 
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Statistical Analysis Plan 
 
Version Final 
 
Issue Date 17-Mar-2017 
 
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Confidential 
 
Table of Contents 
 
1 
INTRODUCTION ............................................................................................... 7 
2 
STUDY OBJECTIVES ....................................................................................... 7 
3 
ENDPOINTS ....................................................................................................... 8 
3.1 
Primary Endpoint ............................................................................................................ 8 
3.1.1 
Safety ........................................................................................................................ 8 
3.1.2 
Efficacy ..................................................................................................................... 8 
3.2 
Secondary Endpoints ...................................................................................................... 8 
3.2.1 
Safety ........................................................................................................................ 8 
3.2.2 
Efficacy ..................................................................................................................... 8 
4 
SAMPLE SIZE .................................................................................................... 9 
5 
RANDOMIZATION ........................................................................................... 9 
6 
PLANNED ANALYSES ..................................................................................... 9 
6.1 
Analysis Sets ................................................................................................................. 10 
6.1.1 
Enrolled Set ............................................................................................................. 10 
6.1.2 
Randomized Set ...................................................................................................... 10 
6.1.3 
Full Analysis Set ..................................................................................................... 10 
6.1.4 
Per-Protocol Set ...................................................................................................... 10 
6.1.5 
Safety Analysis Set ................................................................................................. 10 
6.2 
Derived Data ................................................................................................................. 10 
6.2.1 
Age .......................................................................................................................... 10 
6.2.2 
Screening................................................................................................................. 11 
6.2.3 
Baseline and Change from Baseline ....................................................................... 11 
6.2.4 
Duration/Study Day/Time ....................................................................................... 11 
6.2.5 
Conventions for Missing and Partial Dates ............................................................ 11 
6.2.6 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 11 
6.2.7 
Missing Diagnosis Dates......................................................................................... 12 
6.2.8 
Exposure to Study Drug .......................................................................................... 13 
6.2.9 
Inexact Values ......................................................................................................... 14 
6.2.10 
Study Period/Analysis Windows ............................................................................ 14 
6.2.11 
Diagnosis of AD ..................................................................................................... 15 


 
 
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6.2.12 
Severe Impairment Battery (SIB) ........................................................................... 15 
6.2.13 
Alzheimer Disease Cooperative Study Activities of Daily Living Inventory-Severe 
Impairment Version (ADCS-ADL-SIV) ............................................................................... 15 
6.2.14 
Mini Mental State Examination 2 (MMSE-2) ........................................................ 16 
6.2.15 
Neuropsychiatric Inventory (NPI) .......................................................................... 16 
6.2.16 
Clinical Global Impression of Improvement (CGI-I) ............................................. 17 
6.2.17 
Rosen-Modified Hachinski Scale ........................................................................... 17 
6.2.18 
Electrocardiogram Data .......................................................................................... 17 
6.2.19 
Columbia-Suicide Severity Rating Scale ................................................................ 18 
6.2.20 
Unscheduled Visits ................................................................................................. 18 
6.3 
Conventions .................................................................................................................. 19 
6.3.1 
Decimal Places ........................................................................................................ 20 
6.4 
Subject Disposition ....................................................................................................... 20 
6.5 
Protocol Deviations ....................................................................................................... 20 
6.6 
Baseline Comparability ................................................................................................. 21 
6.7 
Medical History ............................................................................................................ 21 
6.8 
Prior and Concomitant Medications ............................................................................. 21 
6.9 
Exposure to Study Drug/Treatment compliance ........................................................... 22 
6.10 
Efficacy Analyses ......................................................................................................... 22 
6.10.1 
Primary Endpoint .................................................................................................... 22 
6.10.2 
Primary Efficacy Analysis ...................................................................................... 23 
6.10.3 
Sensitivity Analysis ................................................................................................ 24 
6.10.4 
Exploratory Analysis .............................................................................................. 24 
6.10.5 
Secondary Endpoints .............................................................................................. 25 
6.10.6 
Exploratory Endpoints ............................................................................................ 25 
6.10.7 
Multiplicity ............................................................................................................. 25 
6.11 
Pharmacodynamic Analyses ......................................................................................... 26 
6.12 
Safety Analyses ............................................................................................................. 26 
6.12.1 
Adverse Events ....................................................................................................... 26 
6.12.2 
Laboratory Data ...................................................................................................... 27 
6.12.3 
Vital Signs ............................................................................................................... 29 
6.12.4 
Electrocardiogram Data .......................................................................................... 30 
6.12.5 
Physical Examination.............................................................................................. 30 
6.12.6 
Second Treatment Period Analyses ........................................................................ 31 


 
 
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Issue Date 17-Mar-2017 
 
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Confidential 
 
7 
INTERIM ANALYSIS ......................................................................................31 
8 
DATA SAFETY MONITORING BOARD ANALYSIS .................................31 
9 
CHANGES TO PLANNED PROTOCOL ANALYSIS ...................................31 
10 REFERENCES ..................................................................................................32 
11 LIST OF TABLES, FIGURES AND LISTINGS .............................................33 
 
 
 


 
 
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Confidential 
 
1 INTRODUCTION 
This document details the planned statistical analyses of non-pharmacokinetic (PK) data for 
Neurotrope BioScience , protocol “NTRP101-202” study titled “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”. 
The proposed analyses are based on the contents of the final version of the protocol (dated 17-
Apr-2015) and amendments 2.0, 3.0 and 4.0 (dated 20-Jan-2016, 15-Jul-2016 and 03-Mar-2017, 
respectively). 
This is a randomized double-blind placebo-controlled Phase 2 study comparing different doses of 
bryostatin for the treatment of moderately severe to severe Alzheimer’s disease (AD). The study 
was originally 28 weeks in duration, including two 12-week treatment phases where eligible 
subjects were randomized to 1 of 3 treatments (bryostatin 20µg, bryostatin 40µg or placebo) for 
the first 12 weeks of the study.   At the end of the 12 weeks, subjects in the 2 active treatment 
arms were to be randomized to continue on the initial dose or to receive an alternate dose 
(bryostatin 20µg or 40µg, depending on the initial bryostatin dose received) for an additional 12 
weeks and subjects in the placebo arm were to be randomized either to continue on placebo or to 
receive bryostatin 10µg for an additional 12 weeks.   Amended protocol version 3.0 (dated 15-
Jul-2016), dropped the second 12-week treatment phase from the study design.  This study is 
now 15 weeks in duration, including a safety and efficacy evaluation 30 days after the last dose 
of study drug.   
Details of the proposed PK analysis will be covered by WCT Bioanalytical Sciences Group prior 
to the pharmacokinetic analysis in a separate PK data analysis plan (PAP). The PAP will 
describe the analysis population the modeling methods and possible covariates that will be 
examined, as well as the tables, figures, and listings.  
2 STUDY OBJECTIVES 
 Primary objective:  
 To evaluate the safety and tolerability of bryostatin 1 (hereafter referred to as bryostatin) 
for the treatment of moderately severe to severe AD. 
Secondary objective:  
 To evaluate the efficacy of bryostatin in the treatment of moderately severe to severe AD.  
Exploratory objectives:  


 
 
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 To characterize the pharmacokinetics (PK) of bryostatin in subjects with AD following 
administration of 20 or 40µg of bryostatin administered as a 45 minute intravenous (IV) 
infusion over 12 weeks of treatment.  
 To characterize the pharmacodynamics of bryostatin in subjects with AD following 
administration of 20 or 40µg of bryostatin administered as a 45 minute IV infusion over 
12 weeks of treatment. 
 
3 ENDPOINTS 
3.1 Primary Endpoint 
3.1.1 
Safety 
 Treatment emergent AEs (TEAEs) 
 Treatment emergent SAEs 
3.1.2 
Efficacy  
 Change from baseline in the Severe Impairment Battery (SIB) score at Week 13  
3.2 Secondary Endpoints 
3.2.1 
Safety 
 Vital signs    
 Hematology 
 Blood chemistry 
 Physical examination (PE) including body weight 
 Electrocardiogram (ECG) parameters  
 Columbia-Suicide Severity Rating Scale C-SSRS 
3.2.2 
Efficacy 
 Change from baseline in the SIB at Weeks 5 and 9 
 Change from baseline in Alzheimer Disease Cooperative Study Activities of Daily Living 
Inventory-Severe Impairment Version (ADCS-ADL-SIV) score at Weeks 5, 9, and 13 
 Change from baseline in Mini-Mental State Examination (MMSE)-2 score at Weeks 5, 9, 
and 13 
 Change from baseline in Neuropsychiatric Inventory (NPI) score at Weeks 5, 9, and 13 


 
 
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 Clinical Global Impression of Improvement (CGI-I) at Weeks 5, 9, and 13 
4 SAMPLE SIZE 
Since the primary objective of the study is to obtain safety and tolerability data for the 
administration of multiple doses of bryostatin, the planned sample size is based largely on 
feasibility.  However, the following is an assessment of power for the primary analysis of primary 
efficacy endpoint, estimation of the effect of bryostatin on the mean change from baseline in the 
SIB at Week 13. 
It is estimated that 150 subjects equally randomized among the 3 dosing groups (2 doses of 
bryostatin and placebo) will provide at least 80% power, assuming a true mean difference of at 
least 6.5 points in favor of the bryostatin groups (standardized effect size of 0.47), in a test between 
each bryostatin group, and the polled bryostatin groups, and placebo in mean change from baseline 
in the SIB, (one-sided at α=0.10). This assumed the standard deviation of change from baseline at 
Week 13 is 14 points. This estimate allowed that up to 15% of randomized subjects would not 
provide information due to discontinuation. The least significant difference for the test between 
the observed means under these conditions was estimated to be 3.9 points (standardized effect size 
of 0.28).   
5 RANDOMIZATION 
Using a stratified randomization based on MMSE-2 score (4-9 vs. 10-15), eligible subjects were 
randomized 1:1:1 to 1 of 3 treatment arms: bryostatin 20µg, bryostatin 40µg or placebo. 
Prior to amendment 3, after 12 weeks of treatment, eligible subjects were randomized for an 
additional 12 treatment period.   Initial MMSE-2 scores were used for stratification. Subjects in 
the 20µg group were randomized 1:1 either to the same dose or to the 40µg dose.  Subjects in the 
40µg group were randomized 1:1 either to the same dose or to the 20µg dose.   Subjects in the 
placebo group were randomized 1:1 either to continue on placebo or to the bryostatin 10µg dose.   
6 PLANNED ANALYSES 
This study contained 2 double-blind treatment phases/periods until protocol amendment 3.0.  
Subjects that were in the second treatment period discontinued the study once protocol 
amendment 3.0 was approved.  The primary treatment period of interest is the initial treatment 
period and hereafter treatment period references this initial treatment period.  The second 
treatment period will be referred to as treatment period 2 and unless otherwise stated, these data 
will only be listed.  For full definition, see Section 6.2.10.2.   
No statistical analysis plan (SAP) prepared in advance of the data can be absolutely definitive 
and the final clinical study report (CSR) may contain additional tables or statistical tests if 


 
 
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warranted by the data obtained.  The justification for any such additional analyses will be fully 
documented in the final CSR.  
6.1 Analysis Sets 
Subjects excluded from the analysis sets and the reason for their exclusion will be listed in 
Appendix 16.2. 
6.1.1 
Enrolled Set 
The Enrolled Set (ES) includes all subjects screened or those who give informed consent and are 
allocated a subject number. Subjects who are rescreened and assigned a new subject number will 
be counted only once.   
6.1.2 
Randomized Set 
The Randomized Set (RS) consists of all subjects that are randomized.    
6.1.3 
Full Analysis Set 
The Full Analysis Set (FAS) used for efficacy analyses, consistent with the intent-to-treat (ITT) 
principles, is defined as all randomized subjects who receive at least 1 dose of study medication 
and who have at least 1 post-baseline efficacy assessment.  
6.1.4 
Per-Protocol Set 
A Per Protocol Analysis Set (PP) is not planned. Major protocol deviations will be summarized. 
A supportive data listing of protocol deviations (major/minor) will be provided. 
6.1.5 
Safety Analysis Set 
The Safety Analysis Set (SA) is defined as all randomized subjects who receive any study 
medication (either partial or completed infusions of Bryostatin or Placebo). For safety analysis 
subjects will be grouped on an as-treated basis. If subjects received different doses over the 
course of the study, they will be grouped according to the dose most often administered. In 
addition, all treated subjects will be grouped and compared to placebo subjects. 
6.2 Derived Data 
This section describes the derivations required for statistical analysis. Unless otherwise stated, 
variables derived in the source data will not be re-calculated. 
6.2.1 
Age 


 
 
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Age at screening will be calculated in SAS as 
age = floor ((intck('month',birthdate,date) - (day(date) < day(birthdate))) / 12);  
6.2.2 
Screening 
For each variable where a subject is re-screened, his/her latest non-missing value from the original 
or re-screening assessment will be taken for tabulation purposes. 
6.2.3 
Baseline and Change from Baseline 
Baseline is defined as the last non-missing value (either scheduled, unscheduled or repeat) before 
the subject receives first dose of study medication (Week 0).   
Change from baseline CHG=AVAL-BASE where AVAL is the post-baseline value, BASE is the 
baseline value. 
6.2.4 
Duration/Study Day/Time  
Study day will be calculated as the number of days from first dose of study medication (ie, for 
the analysis, the study day is relative to the first dose of study medication which will be deemed 
“Day 1”; note that this is a different definition than the one in Protocol NTRP-1010-202 V4, 
where the first dose of the study medication is given on Day 0). 
 date of event – date of first dose of study drug + 1, for events on or after first dose  
 date of event – date of first dose of study drug, for events before first dose.   
Duration (e.g., event duration/medication usage) = stop date-start date +1 
6.2.5 
Conventions for Missing and Partial Dates 
All rules explained below for partial/missing dates will be followed unless contradicted by any 
other data recorded on the electronic Case Report Form (eCRF). 
All dates presented in the individual subject listings will be as recorded on the eCRF (i.e., not 
completed as per the rules below). 
6.2.6 
Missing/Partial Start/Stop Date of Adverse Events and Concomitant Medications 
Partial or missing stop date will be imputed as follows: 
If the stop date is completely missing and the event has resolved or the subject has stopped 
taking the concomitant medication, the stop date will be imputed as the date of the subject’s last 
clinic visit in the study. 
 


 
 
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• 
If only the year is known, the stop date will be imputed as “31-Dec” of that year or as the 
date of the subject’s last clinic visit in the study if in the same year. 
• 
If the month and year are known, the stop date will be imputed as the last day of that 
month unless the stop date corresponds to the same month as the subject’s last clinic visit 
in which case the date of the subject’s last clinic visit in the study will be used instead. 
 
Missing start date will be imputed as follows: 
• 
If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the date of the first dose of study 
drug.  
• 
If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the subject’s screening date or the stop 
date of the event/concomitant medication whichever the earlier. 
 
Partial start date (year present, but month and day missing): 
• 
If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, and the year is the same as the year of first dosing the start date 
will be imputed as “01-Jan” of the same year or the date of the first dose of study drug 
whichever is later. If the year is different from the year of first dosing “01-Jan” will be 
used. 
• 
If the stop date occurs before the start of study drug, the start date of the 
event/concomitant medication will be imputed as the “01-Jan” of the same year. 
 
Partial start date (month and year present, but day missing): 
• 
If the stop date occurs on or after the start of study drug or the event/concomitant 
medication is ongoing, the start date will be imputed as the first day of the same month 
and year unless this partial start date is in same month as the first dose of study drug in 
which case the date of first dose of study drug will be used.  
• 
If the stop date occurs before the start of study drug, the start date will be imputed as the 
first day of the month and year of the partial stop date. 
 
Missing start/stop time of adverse events: 
• 
If the start time of the adverse event (AE) is missing, it will imputed only in the case 
where the start date of the AE corresponds to the date of the first dose of study drug. The 
time will be imputed as the same time as the first dose of study drug. In all other cases the 
time will not be imputed. 
• 
If the stop time of the adverse event is missing, it will be imputed as 23:59 for stop time. 
  
6.2.7 
Missing Diagnosis Dates   


 
 
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If the month and year are present but the day is missing, the diagnosis date will be set to the first 
day of the relevant month. If only the year is recorded the diagnosis date will be set as “01-Jan” 
for that year.  
6.2.8 
Exposure to Study Drug  
6.2.8.1  Calculation of dose taken and percentage of planned dose taken 
Per protocol, study drug (bryostatin or placebo sterile lyophilized powder in 10 ml vials) should 
be reconstituted with 1 mL of PET diluent (resulting in 50 μg bryostatin per mL or 0.0 μg 
bryostatin per mL). After swirling the vial to completely dissolve the contents, the resulting 
solution must be diluted immediately with 9 mL of 0.9% sodium chloride (NS) injection, United 
States Pharmacopeia (USP). The necessary volume of this solution to achieve the assigned dose 
for the subject should then be added to an IV infusion bag containing 50 mL of normal saline. 
Thus, the total volume of the infusion varies depending on the randomized treatment.   
After diluting the 1 mL PET solution with 9 mL of 0.9% sodium chloride (NS), the resulting 
solution will result in 5 μg bryostatin per mL or 0.0 μg bryostatin per mL. 
Subjects are supposed to receive a total of 7 doses with the first 2 doses being loading doses.  
The following table lists the total volume of 1 infusion for each treatment group. 
 
Dose 
1 infusion (total volume in mL)    
Placebo 
50 mL 
20 µg 
54 mL 
24 µg (loading dose) 
54.8 mL 
40 µg 
58 mL 
48 µg (loading dose) 
59.6 mL 
 
The following table details total planned doses in terms of planned volume for 7 doses for each 
randomized treatment group.  It also states the criteria to determine if a subject received at least 
80% of his/her planned dose.   
Dose 
Planned dose in terms of planned volume    80% planned dose 
Placebo 
350 mL 
280 mL 
20 µg 
379.6 mL 
303.7 mL 
40 µg 
409.2 mL 
327.4 mL 
 


 
 
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6.2.9 
Inexact Values 
In the case where a variable is recorded as “>x”, “≥x”, “<x” or “≤x”, then for analysis purposes a 
value of x will be taken, with x fulfilling the record of the variable. Where a range of values is 
quoted the midpoint of the range will be taken.  
6.2.10 
Study Period/Analysis Windows 
6.2.10.1 Pre-Treatment Period 
The Pre-Treatment Period is defined as the period of time between the subject signing the 
informed consent through immediately prior to the subject receiving the first dose of study 
medication.  
6.2.10.2 Treatment Period 
The primary treatment period of interest is the initial treatment period and will be referred to as 
treatment period.  The second treatment period will be referred to as treatment period 2. 
The treatment period starts on the day and time of first dose of study medication and ends on 
Week 13 Visit.  This is the primary treatment period of interest. 
For those subjects that were randomized for the second treatment period and had the first dose of 
second treatment period study medication on Week 13 visit, the treatment period ends prior to 
the infusion date and time for first dose of the second treatment period on Week 13 Visit.    
Hence any data collected prior to the infusion date and time on Week 13 Visit would be assigned 
to the initial treatment period.   The data collected after that date and time will be assigned to 
treatment period 2 unless otherwise stated.  For assessments at Week 13 where only date was 
collected and per protocol the assessments were pre-dose, these would be assigned to the initial 
treatment period. 
6.2.10.2.1 Early Termination efficacy assessments 
For analysis purposes, efficacy data collected from early termination (ET) visit will be assigned 
to the next scheduled visit.  This only pertains to ET visits that occur during the treatment period. 
Subjects who complete the treatment period but discontinue during the second treatment period 
are considered completers in the main treatment period analyses. 
6.2.10.2.2 30-Day Follow-Up Visit 
A follow-up visit should be scheduled 30 days after the last dose of study drug for all subjects 
that complete or are withdrawn from the study. 
 


 
 
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Follow-up visits will be assigned to the treatment period of the last dose of study drug taken by 
subject (and hence summarized under the treatment assigned for that treatment period.). 
 
For details regarding concomitant medications and AEs please see corresponding Sections 6.8 
and 6.12.1. 
6.2.11 
Diagnosis of AD 
Diagnosis of AD is collected in medical history.  Medical history is coded using MedDRA 
version 18.1. Years from Diagnosis of AD to Screening will be calculated based on preferred 
term for AD.  Terms to be pulled will be finalized prior to unblinding.   
6.2.12 
Severe Impairment Battery (SIB) 
The SIB is used to assess cognition in subjects with moderate and severe AD. There are forty 
questions that are divided into 9 subscales that include attention, language, orientation, memory, 
praxis, visuospatial ability, construction, social skills, and orienting head to name. Non-verbal 
responses are allowed, thus decreasing the need for language output. Most items have a point 
range of 0-2 except for item 19 and 24.  The point score range for SIB total score (sum of the 40 
items) is 0-100.  Lower scores indicate greater cognitive impairment. 
 
 Items 
Point range 
SIB Total Score 
All 
0-100 
Social interaction 
 1 (a,b,c) 
0-6 
Orientation 
3,5, 7 
0-6 
Visuospatial ability 
27,29,31,33 
0-8 
Construction 
35(a,b) 
0-4 
Language 
4 (a,b),6,8 (a,b), 9(a,b,c),11 
(a,b),13,15,17, 19(0-1 
value),20,22, 24 (0-1 
value),26,30 (a,b,c), 
34(a,b),40 
0-46 
Memory 
2, 10,14,25,28,32, 38  
0-14 
Praxis 
16,18,21,23 
0-8 
Attention 
12,36,37 
0-6 
Orienting to name 
39 
0-2 
 
6.2.13 
Alzheimer Disease Cooperative Study Activities of Daily Living Inventory-Severe 
Impairment Version (ADCS-ADL-SIV) 


 
 
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The ADCS-ADL-SIV is a 19-item functional assessment of the performance of activities of daily 
living for subjects with moderate to severe AD. Informants (Caregiver) 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.  The questionnaire is split into two types of 
questions, an initial question relating to whether a subject has completed a particular activity and 
then a follow on question which scores how much assistance the subject has required if they have 
performed that particular activity. Note if a caregiver responds to the question relating to whether 
the subject performed a particular activity as no or don’t know this will contribute a zero to the 
total score.  Total score (sum of the 19 items) range from 0-54 with lower scores indicating 
greater functional impairment.   
6.2.14 
Mini Mental State Examination 2 (MMSE-2) 
The standard version of the MMSE-2, with 2 alternate forms, is used in this study.  The MMSE-2 
is a brief, widely used test for assessing overall cognitive state. The MMSE-2 (sum of 11 items) 
measures selected aspects of cognition such as memory, orientation, attention, language, and 
praxis on a scale of 0-30. Lower scores indicate greater cognitive impairment.  
6.2.15 
Neuropsychiatric Inventory (NPI) 
The NPI is a behavior rating scale composed of a 12-item structured interview of the caregiver 
that is scored from 0 to 144 (the higher the score, the greater the psychiatric disturbance).  The 
NPI assesses 12 behavioral and psychological disturbances occurring in dementia patients: 
delusions, hallucinations, agitation/aggression, depression/dysphoria, anxiety, elation/euphoria, 
apathy/indifference, disinhibition, irritability, aberrant motor behavior, sleep and nighttime 
behavior disorders, and appetite and eating disorders.  Both the frequency and the severity of 
each behavior are determined.   
Scoring the NPI: 
Category 
Numeric values assigned 
 
 
Frequency is 
rated as: 
1 = Occasionally - less than once per week 
2 = Often - about once per week 
3 = Frequently - several times per week but less than every day 
4 = Very frequently - daily or essentially continuously present 
 
 


 
 
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Severity is rated 
as: 
1 = Mild - produces little distress in the patient 
2 = Moderate - more disturbing to the patient but can be redirected by the 
caregiver 
3 = Severe - very disturbing to the patient and difficult to redirect 
 
 
Caregiver 
Distress is rated 
as: 
0 = no distress 
1 = minimal 
2 = mild 
3 = moderate 
4 = moderately severe 
5 = very severe or extreme. 
Category 
Numeric values assigned 
 
 
 
The total score for each of the 12 domains is domain score = frequency x severity 
Thus, for each behavioral domain there are 4 scores: 
•  Frequency  
•  Severity  
•  Total (frequency x severity)  
•  Caregiver distress  
 
A total NPI score will be calculated by adding the total scores of the 12 domain scores together. 
The caregiver distress score is not included in the total NPI score. The total distress score is 
generated by adding together the scores of the 12 items of the NPI distress questions.  
6.2.16 
Clinical Global Impression of Improvement (CGI-I) 
The CGI-I is used to assess global change in the subject’s condition compared to baseline before 
treatment.  This is a 7-point scale ranging from (1) very much improved to (7) very much worse.  
A score of 0 means that the scale was not assessed and hence this value is not included in any 
summary/analysis unless stated otherwise. 
6.2.17 
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. 
6.2.18 
Electrocardiogram Data 


 
 
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For ECG data recorded on continuous scales, if more than 1 value is recorded at a time point, the 
mean value rounded to the integer will be presented. For overall interpretation if more than 1 
value is recorded, the most severe (worst case) of the respective readings will be taken. - 
 
6.2.19 
Columbia-Suicide Severity Rating Scale 
The following outcomes are C-SSRS categories and have binary responses (yes/no). The 
categories have been re-ordered from the actual scale to facilitate the definition of composite 
endpoints: 
Category 1  
Wish to be Dead 
Category 2  
Non-specific Active Suicidal Thoughts 
Category 3  
Active Suicidal Ideation with Any Methods (Not Plan) without 
Intent to Act 
Category 4 
Active Suicidal Ideation with Some Intent to Act, without Specific 
Plan 
Category 5 
Active Suicidal Ideation with Specific Plan and Intent 
Category 6 
Preparatory Acts or Behavior 
Category 7  
Aborted Attempt 
Category 8 
Interrupted Attempt 
Category 9 
Actual Attempt (non-fatal) 
Category 10 
Completed Suicide 
 
Suicidal Ideation since baseline – A “yes” answer at any time during double-blind treatment to 
any one of the 5 suicidal ideation questions (categories 1-5) on the C-SSRS. 
Suicidal Behavior since baseline – A “yes” answer at any time during double-blind treatment to 
any one of the 5 suicidal behavior questions (categories 6-10) on the C-SSRS. 
There will be no imputation of missing data for C-SSRS. 
6.2.20 
Unscheduled Visits 


 
 
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In general, only scheduled post-baseline laboratory and vital signs values will be tabulated. 
However, post-baseline repeat/unscheduled assessments could be included if an “any time, post-
baseline” summary is specified.  At minimum, these post-baseline assessments will be listed in 
the relevant appendices to the CSR.   
6.3 Conventions 
All data listings, summaries, figures and statistical analyses will be generated using SAS version 
9.3 or higher1. 
Summaries will be presented by treatment group or overall.  Treatment group labels will be 
displayed as follow:   
 
Placebo 
Bryostatin  
(20 µg) 
Bryostatin  
(40 µg) 
Bryostatin  
(20+40 µg) 
 
Overall columns are to be included within the table shells as follows: 
Demography 
Treatment and overall 
Baseline 
Treatment and overall 
Disposition 
Treatment and overall 
Efficacy 
Treatment 
PD 
Treatment 
AEs 
Treatment & overall 
Other safety 
Treatment 
 
Listings will be sorted in the following order: treatment group, subject, parameter, and visit 
unless otherwise stated.   
Continuous variables will be summarized by the number of non-missing observations, mean, 
median, standard deviation, and minimum and maximum. 
 
Categorical variables will be summarized by presenting the frequency and percent. Percentages 
will be based on the number of non-missing observations or the subject population unless 
otherwise specified. For each variable, all categories will be shown. Zero frequencies (but not the 
percent) within a category will be presented.   


 
 
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6.3.1 
Decimal Places 
Decimal places for derived data will be determined by the scale of measurement unless otherwise 
stated. No decimal places will be displayed if the smallest calculated value is ≥ 100; 1 decimal 
place will be displayed when the smallest value is within the interval (10, 100), with 10 being 
inclusive; 2 decimal places will be displayed when the smallest value is within (1, 10), with 1 
being inclusive; and so on for even smaller scales of measurement.  
For derived data where known in advance that the result will be an integer (e.g., day, month, 
year, number of days and total scores [for rating scales]) will be presented with zero decimal 
places unless otherwise stated.  
Means, medians, and percentiles will be displayed to one more decimal place than the data, 
dispersion statistics (e.g., standard deviation) will have 2 more decimal places, and the minimum 
and maximum will be displayed to the same number of decimal places as reported in the raw 
data. Percentages will be displayed with 1 decimal place.  
P-values will be quoted to 3 decimal places. P-values < 0.001 will be presented as p<0.001. 
Where p < 0.05, p < 0.01, or p < 0.001, attention will be drawn to this fact using the conventional 
“*”, “**” or “***” annotation, respectively.   
6.4 Subject Disposition 
Subject disposition will be summarized as follows:   
 The number of subjects, who were enrolled in the study, were randomized, and are in 
each analysis set will be summarized by treatment group and overall for the ES.  
 The number of subjects from the main treatment period that were randomized into 
treatment period 2 and received study medication for the SA set. 
 The number of subjects who were rescreened, failed screening and the reasons for screen 
failure will be tabulated for ES 
 The number of treatment completers, early withdrawals and the reasons for withdrawals 
will be tabulated by treatment group and overall for SA and FAS set.  
 The number of subjects present at each scheduled visit and number of subjects whose SIB 
were not done within 21 days before the first study drug dose will be summarized by 
treatment group for the SA set.  
 Number of SA set subject by site will be summarized.   
6.5 Protocol Deviations 


 
 
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A summary of major protocol deviations will be summarized.   
Furthermore a listing of protocol deviations will be provided in Appendix 16.2.  
6.6 Baseline Comparability 
The comparability of treatment group with respect to subject demographics and baseline 
characteristics will be assessed in a descriptive manner, but no formal statistical testing will be 
performed. 
Standard continuous or categorical variable summaries will be presented by treatment group for 
the SA and FAS set. 
Demographic and Baseline Characteristics  
The following variables will be summarized:  
 Age at screening visit (years) 
 Gender (Male, Female) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White) 
 MMSE-2 (continuous, stratum [4-9 vs 10-15]) 
 Height, weight and BMI at screening 
 Rosen-Modified Hachinski Score  
 Years from diagnosis of AD to Screening (derived based on medical history) 
 Concurrent use of AD drugs by type (cholinesterase inhibitor, memantine, both) 
6.7 Medical History 
Separate tabulations of previous and ongoing conditions at screening will be presented by 
treatment group and overall for the SA Set. Conditions will be presented by Medical Dictionary 
of Regulatory Activities (MedDRA version 18.1) primary system organ class and preferred term. 
6.8 Prior and Concomitant Medications 
Separate tabulations will be produced for prior and concomitant medications presented by 
treatment group and overall for the SA and FAS Set. Medications will be summarized using 
Anatomical Therapeutic Chemical (ATC) level 2 and drug reference name using the World 
Health Organization (WHO) dictionary (Version WHODDE MAR2015).   
 


 
 
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Medications will be categorized by start and stop dates of medication in relation to start date of 
study drug and could be categorized in more than one category (e.g., a medication taken prior to 
first dose of study drug but on-going through the treatment period (s), will be considered both a 
prior and concomitant medication).  Prior medications are defined as all medications starting 
before the date of first dose of study medication.  Concomitant medications are defined as 
medications taken on or after the date of first dose of study medication up to the date of last 
study treatment in the main treatment period.   For subjects who received study medication 
during treatment period 2, medications started on the same day as first dose of the second 
treatment period, will be assigned to that second treatment period only.  
Frequency distribution of drugs used to treat AD by treatment arm will be presented. 
6.9 Exposure to Study Drug/Treatment compliance 
Number and percentage of subjects who did or did not have an infusion, had a full infusion, had 
partial infusion by treatment group and visit will be presented.  Descriptive statistics of the 
number of infusions will be presented by treatment group.   
Number and percentage of subjects who had 80% of the (cumulative) planned dose will be 
summarized by treatment group (see Section 6.2.8.1).   
6.10  Efficacy Analyses 
Efficacy analyses will be based on FAS by randomized treatment regardless of the treatment 
actually received. Descriptive statistics by treatment group and visit will be reported for all 
efficacy endpoints. Analyses will be performed on each dosing group vs. placebo and on the 
“pooled” dosing group vs. placebo. 
6.10.1 
Primary Endpoint 
The primary efficacy objective is to determine if treatment with bryostatin (20 or 40 µg) 
improves cognitive function as measured by improvement on SIB after 12 weeks of treatment 
compared to placebo. 
The primary efficacy endpoint is change from baseline in the Severe Impairment Battery (SIB) 
score at Week 13.  Each bryostatin group will be compared to the placebo group and the pooled 
bryostatin group to placebo group.  
The hypothesis test is as follows: 
Ho: µbryostatin ≤ µplacebo 


 
 
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H1: µbryostatin > µplacebo 
 
The null hypothesis will be rejected at a significance level of α (1-sided) = 0.10.  There will be no p-
value adjustment for multiplicity.   
6.10.2 
Primary Efficacy Analysis 
The primary endpoint will be analyzed using Mixed Model for Repeated Measures (MMRM) 
with fixed effects for treatment, baseline MMSE-2 stratum, scheduled visit (nominal) and 
scheduled visit by treatment interaction, random effect for subject and baseline SIB as a 
covariate. The model will include two treatment groups (i.e. placebo and one bryostatin dose 
group). All statistical tests will be 1-sided with α = 0.10. Least-square means (LSM) and 2-sided 
80% confidence intervals (CI) will be provided for treatment group differences and estimated 
endpoint values by visit. 
Sample SAS code for two-sided 80% confidence interval. 
Treat: 1=Placebo, 2=study drug 
Visit 13: Week 13  
 
PROC MIXED DATA = <DATASET>;  
  CLASS TREAT VISIT BASE_MMSE_STRATUM SUBJID; 
  MODEL CHANGE = TREAT VISIT TREAT*VISIT BASE_MMSE_STRATUM 
BASELINE_SIB/       
                           DFM=KENWARDROGER ;  
  REPEATED VISIT / TYPE=UN  SUB=SUBJID  GROUP=TREAT; 
  LSMEANS TREAT*VISIT/PDIFF=CONTROL('1'  '13') ALPHA=0.2;  
RUN;   
  
Sample SAS code for one-sided p-value and 80% confidence interval. 
PROC MIXED DATA = <DATASET>;  
  CLASS TREAT VISIT BASE_MMSE_STRATUM SUBJID; 
  MODEL CHANGE = TREAT VISIT TREAT*VISIT BASE_MMSE_STRATUM 
BASELINE_SIB/       
                             DDFM=KENWARDROGER ;  
  REPEATED VISIT / TYPE=UN  SUB=SUBJID  GROUP=TREAT;  


 
 
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  LSMEANS TREAT*VISIT/PDIFF=CONTROLU('1'  '13') ALPHA=0.2;  
RUN; 
 
Note: the SAS code could be modified due to data limitation and convergence issue.   
6.10.3 
Sensitivity Analysis 
No sensitivity analysis is planned for the study. 
6.10.4 
Exploratory Analysis 
Exploratory analyses will be performed to evaluate the impact of baseline covariates on the 
primary efficacy variables. Such analyses may be described in the clinical study report. 
 A re-analysis of the primary endpoint using the MMRM model and excluding all patients 
from sites that recruited 2 or fewer patients. 
 Last observation carried forward (LOCF) analysis:  Missing SIB assessment at Week 13 
will be imputed using the LOCF method for subjects with post-baseline assessments. An 
analysis of covariance (ANCOVA) for the Week 13 Visit will be conducted. The model 
will include treatment, and baseline SIB as a covariate.   
 Site will be added as an additional covariate in above ANCOVA to assess site effect.  
 Use of AChEI, Memantine at baseline will be added as an additional covariate in above 
ANCOVA to assess site effect.  
 Subjects will be divided into two subgroups: 1) baseline SIB<=median baseline SIB, 2) 
baseline SIB>median baseline SIB.  An analysis of covariance (ANCOVA) for the Week 
13 Visit will be conducted to assess treatment difference (low dose vs. placebo, high dose 
vs. placebo). The model will include treatment, and baseline SIB as a covariate.  Missing 
SIB assessment at Week 13 will be imputed using the LOCF method for subjects with 
post-baseline assessments. 
 The Following responder analyses at week 13 will be conducted to compare the 
proportions of responders between treatment groups (low dose vs. placebo, high dose vs. 
placebo, pooled dose vs. placebo) using CMH approach. Missing assessment at Week 13 
will be imputed using the LOCF method for subjects with post-baseline assessments. 
A. A responder is defined as a subject who had improvement on the SIB. 
B. A responder is defined as a subject who had improvement of at least 3.9 points on the 
SIB. 
C. A responder is defined as a subject who had improvement of at least 6.5 points on the 
SIB.  
D. A responder is defined as a subject who had improvement either on SIB or on ADCS-
ADL-SIV. 


 
 
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The same analyses will be performed for pooled dose vs. placebo. 
6.10.5 
Secondary Endpoints 
Secondary endpoints for ADCS-ADL-SIV, MMSE-2 (excludes MMSE Stratum variable), NPI at 
week 13 will be analyzed using a statistical model similar to the one used for analysis of the SIB. 
The CGI-I secondary endpoint will be analyzed in similar fashion except the model will not have 
a baseline value used as a covariate.   
The secondary efficacy endpoints will not be formally tested against the null hypothesis; 
however, p-values and CI will be used to support the results of the primary endpoint analysis.   
6.10.6 
Exploratory Endpoints 
The exploratory PK endpoints will be addressed in a separate analysis plan. 
The following exploratory endpoints will be analyzed using the same statistical model as the 
primary endpoint: 
 Change from baseline in SIB and MMSE Scores at the 30-day follow up 
 Change from Week 13 in SIB and MMSE Scores at the 30-day follow up. 
Subjects who are randomized at treatment period 2 will be excluded at the 30-day follow up.  
ANCOVA model described in section 6.10.4 will be used for SIB, ADCS-ADL, NPI, and 
MMSE-2 by visit.   
ANCOVA model will be used for ADCS-ADL, NPI, and MMSE-2 at Week 13. Missing 
assessment at Week 13 will be imputed using the LOCF method for subjects with post-baseline 
assessments.  
Subjects will be divided into two subgroups: 1) baseline ADCS-ADL <= median baseline 
ADCS-ADL, 2) baseline ADCS-ADL > median baseline ADCS-ADL.  An analysis of 
covariance (ANCOVA) for the Week 13 Visit will be conducted to assess treatment difference 
(low dose vs. placebo, high dose vs. placebo). The model will include treatment, and baseline 
ADCS-ADL as a covariate.  Missing ADCS-ADL assessment at Week 13 will be imputed using 
the LOCF method for subjects with post-baseline assessments. The same analyses for NPI, and 
MMSE-2 at Week 13 will also be conducted.  
The effects of center and treatment by center interaction will be explored using an analysis of 
covariance (ANCOVA) model as describe in section 6.10.4 if data permit. Low enrolling centers 
may be pooled if appropriate. Stepwise covariates selection approach may be applied. These will 
explored as post hoc analyses.  
6.10.7 
Multiplicity 


 
 
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All secondary endpoints and the supportive analyses will be considered as descriptive evidence 
of efficacy and will be analyzed without any procedures to account for multiple comparisons.   
6.11 Pharmacodynamic Analyses 
PKCε concentration prior to the infusion, at the end of infusion (+5minute window) and 60 
minutes after completion of infusion (±5minutes) will be collected from selected sites for doses 
1, 3, and 7, respectively. Descriptive summary will covered by WCT Bioanalytical Sciences 
Group. 
6.12 Safety Analyses 
The safety analyses will be presented by the actual treatment received for the SA Set. 
6.12.1 
Adverse Events 
A TEAE in the main treatment period is defined as follows: 
 Any AE with an onset on or after the first dose of study drug and through 30 days after 
the last dose of study drug in the main treatment period.  
 Any pre-existing AE that has worsened in severity on or after the first dose of study drug 
and through 30 days after the last dose of study drug in the main treatment period.  
A TEAE in treatment period 2 is defined as follows: 
 Any AE that has an onset on or after the first dose of treatment period 2 at the Week 13 
Visit  
A treatment-related AE is defined as an AE as being possibly or probably related to the study 
drug. If an AE has a missing relationship, it is assumed to be related to the study drug for 
analysis purposes. 
Maximum severity will be assumed for an AE with missing severity.  
The following tables will be presented for AEs in the main treatment period: 
 Overall incidence and the number of AEs, SAEs, treatment emergent adverse events of 
special interest (AESIs)-myalgia, TEAEs leading to withdrawal of study drug. 
 TEAE by system organ class and preferred term, incidence and number of events 
 Treatment related  TEAE by system organ class and preferred term, incidence and 
number of events 
 Serious TEAE by system organ class and preferred term, incidence and number of events 


 
 
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 TEAESI-myalgia by system organ class and preferred term, incidence and number of 
events 
 TEAEs leading to  withdrawal of study drug by system organ class and preferred term, 
incidence and number of events 
 TEAE by system organ class, preferred term and maximum severity,  incidence 
 Listing of serious TEAEs (presented in the Table section of the appendices) 
 Listing of deaths (presented in the Table section of the appendices) 
 Listing of relationship of AE verbatim term with MedDRA 
Adverse events will be coded using MedDRA version 18.1. 
A complete subject listing of all AEs will be provided. This listing will include treatment, AE 
verbatim term, primary system organ class and preferred term, the time of onset and cessation of 
event relative to the first dose of study medication, duration of AE (for ongoing AEs, no duration 
will be calculated), whether serious, severity, relationship to study medication, action taken and 
outcome.  
 
6.12.2 
Laboratory Data 
Descriptive statistics of the observed values and change from baseline (continuous data) will be 
presented by treatment group and visit for each hematology, coagulation, CBC with differential, 
and serum chemistry parameter. Each measurement (continuous data) will be classed as below, 
within, or above normal range, based on ranges supplied by the laboratory used. Shift tables in 
relation to the normal range from baseline to each follow-up visit will be presented.   
 Liver Function Parameter Abnormalities 
The number and percentage of subjects meeting certain liver function abnormality categories will 
be summarized by visit and any post-baseline visit (e.g., post-dose) during the treatment period: 
 Alanine Aminotransferase (AST) assessment > 3 times upper limit of normal (ULN), 
 Aspartate aminotransferase (AST) > 3xULN, 
  ALT or AST: > 3xULN;  > 10xULN; > 20xULN  
 Total Bilirubin: > 1.5xULN;  > 2xULN  
 Alkaline Phosphatase: > 1.5xULN; >2xULN 
 (ALT or AST > 3xULN) and total bilirubin>2xULN 
 (ALT or AST>3xULN) and total bilirubin>2xULN and alkaline phosphatase<2xULN 
 


 
 
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Box plots for the above lab parameters will be provided for changes from baseline and maximal 
change. In addition, Scatter Plots of LFT Parameters Post-Baseline vs Baseline. 
Lab Parameter Shift Tables 
Shift tables in relation to the normal range from screening to each follow-up visit will be 
presented for Hematology and Chemistry. In addition, Shifts from baseline will be evaluated for 
following Lab parameters based on Common Terminology Criteria for Adverse Events (CTCAE 
4.03, 2010-06-14) grade. The baseline and highest post-dose results for each of these parameters 
will be categorized by CTCAE grade. The number and percentage of subjects in each baseline by 
post-baseline category will be summarized by analysis category. Separate shift tables will be 
prepared for the highest post-dose assessment and one for the last post-dose assessment during 
the treatment period.  This will include all scheduled and unscheduled laboratory assessments.   
A table displaying the CTCAE grades for lab parameters of interest is provided below: 
Parameter (unit) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
APTT (seconds) 
>ULN-1.5xULN 
>1.5xULN-2.5xULN 
> 2.5xULN 
---- 
Alkaline phosphate 
(U/L) 
>ULN-2.5xULN 
>2.5xULN-5xULN 
>5xULN-20xULN 
>20xULN 
ALT (U/L) 
>ULN-3xULN 
>3xULN-5xULN 
>5xULN-20xULN 
>20xULN 
AST (U/L) 
>ULN-3xULN 
>3xULN-5xULN 
>5xULN-20xULN 
>20xULN 
Total bilirubin (µmol/L) 
>ULN-1.5xULN 
>1.5xULN-3xULN 
>3xULN-10xULN 
>10xULN 
 
Creatinine  
> 1-1.5x baseline or 
> ULN-1.5xULN 
>1.5-3.0 x baseline or  
> 1.5xULN-3.0xULN 
> 3.0- 6.0 x baseline 
or >3xULN-6xULN 
>6x baseline 
or > 6xULN 
 
Creatinine clearance  
60<=RESULT<LLN 
ml/min   
59-30 ml/min 
29-15 ml/min 
<15 ml/min 
 
WBC decreased 
<LLN - 3000/mm3; 
<LLN - 3.0 x 10e9 
/L 
<3000 - 2000/mm3; 
<3.0 - 2.0 x 10e9 /L 
<2000 - 1000/mm3; 
<2.0 - 1.0 x 10e9 /L 
<1000/mm3; 
<1.0 x 10e9 /L 
 
PLT (PLAT/Platelet 
count) 
<LLN - 
75,000/mm3; <LLN 
- 75.0 x 10e9 /L 
<75,000 - 
50,000/mm3; <75.0 - 
50.0 x 10e9 /L 
<50,000 - 
25,000/mm3; <50.0 
- 25.0 x 10e9 /L 
<25,000/mm3; 
<25.0 x 10e9 
/L 
 
 
Hemoglobin (anemia) 
Hemoglobin (Hgb) 
<LLN - 10.0 g/dL; 
<LLN - 6.2 mmol/L; 
<LLN - 100 g/L 
Hemoglobin (Hgb) 
<LLN 10.0 - 8.0 
g/dL;  
<LLN 6.2 - 4.9 
mmol/L;  
<LLN 100 – 80 g/L 
Hgb <8.0 g/dL; <4.9 
mmol/L; <80 g/L  
 - 
 
 
 
INR 
>1 - 1.5 x ULN; >1 - 
1.5 times above 
baseline if on 
anticoagulation  
>1.5 - 2.5 x ULN; 
>1.5 - 2.5 times 
above baseline if on 
anticoagulation 
>2.5 x ULN; >2.5 
times above baseline 
if on anticoagulation 
  - 


 
 
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CPK/CK (increase) 
>ULN - 2.5 x ULN 
>2.5 x ULN - 5 x 
ULN 
>5 x ULN - 10 x 
ULN 
>10 x ULN 
 
6.12.3 
Vital Signs 
Descriptive statistics for observed values and changes from baseline in the following vital signs 
will be presented by treatment group and visit: 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
 Pulse rate (bpm)  
 Respiration rate (breaths/min) 
 Body temperature (degrees Celsius) 
 
 
Vital sign values will be categorized into clinical concern (CS) categories if applicable. 
Vital Sign 
PCS categories 
Systolic blood pressure 
120-139; 140-159; ≥160 mmHg 
Diastolic blood pressure 
80-89; 90-99; ≥ 100 mmHg 
Pulse rate 
<60 or >100 bpm   
Respiratory Rate 
> 27 breaths/min 
 
Number and percent of subjects falling into these categories will be summarized by Visit and 
Any time, post-baseline during the treatment period. For scheduled visits (excluding Week 13 
Visit) where multiple assessments are collected (pre and post infusion), worst case will be 
counted for that visit. 
Box plots for the above vital signs will be provided for changes from baseline by visit and 
maximal change. 
Shifts from baseline to worst for hyper and hypotension for CTCAE will be evaluated for based 
on Common Terminology Criteria for Adverse Events (CTCAE 4.03, 2010-06-14) grade. The 
baseline and highest post-dose results for each of these blood pressure will be categorized by 
CTCAE grade. Separate shift tables will be prepared for the highest post-dose assessment and 
one for the last post-dose assessment during the treatment period.  This will include all scheduled 
and unscheduled vital assessments.   
 


 
 
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A table displaying the CTCAE grades for hyper and hypotension is provided below: 
Parameter (unit) 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Systolic BP (mmHg)  120 - 139 mmHg   140 - 159 mmHg  
>=160 mm Hg  
- 
Diastolic BP 
(mmHg) 
80 - 89 mmHg 
90 - 99 mmHg 
 >=100 mm Hg 
- 
 
6.12.4 
Electrocardiogram Data 
Descriptive statistics for observed values and changes from baseline in the following ECG 
variables will be tabulated at each post-baseline visit:   
 Heart rate (bpm) 
 PR interval (ms) 
 RR interval (ms)  
 QT interval (ms)  
 QRS Duration, (ms)  
 QTcF interval (ms) [Fridericia’s formula - QTcF]  
ECG Result Interpretation (Normal, Abnormal Not Clinically Significant [NCS], and 
Abnormal Clinically Significant [CS]) will be summarized by treatment group and visit. 
The incidence of ECG abnormalities for subjects with any abnormal CS ECG result will be 
presented by treatment group and visit.   
QTcF values will be categorized into the following categories: 
 < 450 ms 
 450-480 ms 
 481-500 ms 
 > 500 ms 
Number and percent of subjects that fall into these categories will be presented by treatment 
group and visit. Box plots for ECG data will be provided for changes from baseline by visit and 
maximal change. 
6.12.5 
Physical Examination 


 
 
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The body systems within the physical examination (PE) data will be summarized by treatment 
group and visit (Normal; Abnormal NCS, Abnormal CS). Changes from baseline will also be 
tabulated. Details of CS findings will be listed.  
Descriptive statistics for observed values and changes from baseline in weight will be presented 
by treatment group and visit.  Number and percentage of subjects with > 10% change from 
baseline (increase or decrease) will also be summarized.  
6.12.6 
Second Treatment Period Analyses 
AEs (i.e. an AE has an onset on or after the first dose of the second treatment period or a pre-
existing AE that has worsened in severity on or after the first dose of the second treatment 
period.) will be summarized by treatment. 
The following tables will be presented for AEs in the second treatment period:  
 Overall incidence and the number of AEs, SAEs, treatment emergent adverse events of 
special interest (AESIs)-myalgia, TEAEs leading to withdrawal of study drug, Period 2  
 AE by system organ class and preferred term, incidence and number of events, Period 2 
7 INTERIM ANALYSIS 
No formal interim analyses are planned.   
8 DATA SAFETY MONITORING BOARD ANALYSIS 
Data safety monitoring board (DSMB) analyses/summaries are described separate from this 
document.  
9 CHANGES TO PLANNED PROTOCOL ANALYSIS 
  
 
 


 
 
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10 REFERENCES 
1. SAS Institute Inc.  The SAS System, Version 9.3.  Cary, NC, SAS Institute Inc. 2012. 
 
 


 
 
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11 LIST OF TABLES, FIGURES AND LISTINGS 
The following table includes details of the tables, figures and listings to be included within each 
section of the eCTD. The eCTD section is shown in bold. The following validation methods 
maybe used  
 Independent programming of numbers and manual review of format (IP) 
 Independent programming by statistician of numbers and manual review of format (Stat 
IP) 
 Manual review (MR) 
 Code review (CR) 
 
Table 
Number 
Table Title 
Validation 
Method 
Shell 
Number 
(If Repeat) 
14.1 
Demographics Data 
 
 
14.1.1 
Disposition 
 
 
14.1.1.1 
Subject Disposition, Analysis Sets 
Enrolled Set 
 
 
14.1.1.2 
Subject Disposition, Second 12-Week 
Treatment Phase 
 
 
14.1.1.3 
Subject Disposition, Screen Failures 
Enrolled Set 
 
 
14.1.1.4 
Inclusion/Exclusion Criteria not met 
Enrolled Set 
 
 
14.1.1.5 
Subject Disposition, Early Withdrawals 
Safety Analysis Set 
 
 
14.1.1.6 
Subject Disposition, Early Withdrawals 
Full Analysis Set 
 
 
14.1.1.7 
Subject Disposition, Safety Analysis Set by 
Site 
Safety Analysis Set 
 
 
14.1.1.8 
Subject Disposition, Safety Analysis Set by 
Site 
Full Analysis Set 
 
 
14.1.1.9 
Subject Disposition, Visits 
Safety Analysis Set 
 
 
14.1.1.10 
Subject Disposition, Visits 
 
 


 
 
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Full Analysis Set 
14.1.2 
Demographics 
 
 
14.1.2.1 
Demographics 
Safety Analysis Set 
 
 
14.1.2.2 
Demographics 
Full Analysis Set 
 
 
14.1.2.3 
Baseline Characteristics 
Safety Analysis Set 
 
 
14.1.2.4 
Baseline Characteristics 
Full Analysis Set 
 
 
14.1.3 
Baseline Characteristics 
 
 
14.1.3.1 
Prior Medical History 
Safety Analysis Set 
 
 
14.1.3.2 
Prior Medical History 
Full Analysis Set 
 
 
14.1.3.3 
Ongoing Medical Conditions at Screening 
Safety Analysis Set 
 
 
14.1.3.4 
Ongoing Medical Conditions at Screening 
Full Analysis Set 
 
 
14.1.3.5 
Prior Medications 
Safety Analysis Set 
 
 
14.1.3.6 
Prior Medications 
Full Analysis Set 
 
 
14.1.3.7 
Major Deviations 
Full Analysis Set 
 
 
14.2  
Efficacy Data 
 
 
14.2.1 
Primary Efficacy Endpoint 
 
 
14.2.1.1 
Severe Impairment Battery (SIB) Scale 
Full Analysis Set 
 
 
14.2.1.2 
Mixed Models for Repeated Measures 
Analysis of Change from Baseline in SIB 
Total Score 
Full Analysis Set 
 
 
14.2.1.3 
Mixed Models for Repeated Measures 
Analysis of Change from Baseline in SIB 
Total Score 
 
 


 
 
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Per Protocol Analysis Set 
14.2.1.4 
Analysis of Covariance of Change from 
Baseline in SIB Total Score at Week 13 
(LOCF) 
Full Analysis Set 
 
 
14.2.2.1 
Alzheimer Disease Cooperative Study 
Activities of Daily Living Inventory Severe 
Impairment Version (ADCS-ADL-SIV) 
Full Analysis Set 
 
 
14.2.2.2 
Mixed Models for Repeated Measures 
Analysis of Change from Baseline in 
ADCS-ADL-SIV Total Score 
Full Analysis Set 
 
 
14.2.2.3 
Mini Mental State Examination Version 2 
(MMSE-2) 
Full Analysis Set 
 
 
14.2.2.4 
Mixed Models for Repeated Measures 
Analysis of Change from Baseline in 
MMSE-2 Total Score 
Full Analysis Set 
 
 
14.2.2.5 
Neuropsychiatric Inventory (NPI) Scale 
Full Analysis Set 
 
 
14.2.2.6 
Mixed Models for Repeated Measures 
Analysis of Change from Baseline in NPI 
total Score 
Full Analysis Set 
 
 
14.2.2.7 
Clinical Global Impression of Improvement 
(CGI-I) 
Full Analysis Set 
 
 
14.2.2.8 
Mixed Models for Repeated Measures 
Analysis of CGI-I Score 
Full Analysis Set 
 
 
14.2.3 
Exploratory Endpoints 
 
 
14.2.3.1.1 
Analysis of Covariance of Change from 
Baseline in SIB Total Score  
Full Analysis Set 
 
 


 
 
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14.2.3.1.2  
Analysis of Covariance of Change from 
Baseline in SIB Total Score to Assess Site 
Effect  
Full Analysis Set 
 
 
14.2.3.1.3 
Analysis of Covariance of Change from 
Baseline in SIB Total Score of Use of 
AChEI or Memantine at Baseline as an 
Additional Covariate  
Full Analysis Set 
 
 
14.2.3.1.4a 
Analysis of Covariance of Change from 
Baseline in SIB Total Score, <= Median 
Baseline SIB Total Score  
Full Analysis Set  
 
 
14.2.3.1.4b 
Analysis of Covariance of Change from 
Baseline in SIB Total Score, > Median 
Baseline SIB Total Score  
Full Analysis Set  
 
 
14.2.3.1.5a 
A Responder Analysis (CMH) of Subject 
Who Had Improvement on SIB Total Score 
at Week 13    
Full Analysis Set  
 
 
14.2.3.1.5b 
A Responder Analysis (CMH) of Subject 
Who Had Improvement of at Least 3.9 
Points on SIB Total Score at Week 13    
Full Analysis Set  
 
 
14.2.3.1.5c 
A Responder Analysis (CMH) of Subject 
Who Had Improvement of at Least 6.5 
Points on SIB Total Score at Week 13    
Full Analysis Set  
 
 
14.2.3.1.6 
Mixed Models for Repeated Measures 
Analysis of Change from Baseline in SIB 
Total Score Excluding All Patients from 
Sites that Recruited 2 or Fewer Patients  
Full Analysis Set 
 
 
14.2.3.1.7 
Mixed Models for Repeated Measures 
Analysis of Changes from Baseline and 
Week 13 in SIB Total Score at 30-day 
Follow up 
 
 


 
 
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Full Analysis Set 
14.2.3.2.1 
A Responder Analysis (CMH) of Subjects 
Who Had Improvement either on SIB or on 
ADCS-ADL-SIV  
Full Analysis Set  
  
 
14.2.3.2.2 
Analysis of Covariance of Change from 
Baseline in ADCS-ADL-SIV Total Score   
Full Analysis Set 
 
 
14.2.3.2.3 
Analysis of Covariance of Change from 
Baseline in ADCS-ADL-SIV Total Score to 
Assess Site Effect  
Full Analysis Set 
 
 
14.2.3.2.4a 
Analysis of Covariance of Change from 
Baseline in ADCS-ADL-SIV Total Score, 
<= Median Baseline ADCS-ADL-SIV Total 
Score  
Full Analysis Set  
 
 
14.2.3.2.4b 
Analysis of Covariance of Change from 
Baseline in ADCS-ADL-SIV Total Score, > 
Median Baseline ADCS-ADL-SIV Total 
Score  
Full Analysis Set  
 
 
14.2.3.2.5 
Analysis of Covariance of Change from 
Baseline in MMSE-2 Total Score   
Full Analysis Set 
 
 
14.2.3.2.6 
Analysis of Covariance of Change from 
Baseline in MMSE-2 Total Score to Assess 
Site Effect  
Full Analysis Set 
 
 
14.2.3.2.7a 
Analysis of Covariance of Change from 
Baseline in MMSE-2  Total Score, <= 
Median Baseline MMSE-2  Total Score  
Full Analysis Set  
 
 
14.2.3.2.7b 
Analysis of Covariance of Change from 
Baseline in MMSE-2 Total Score, > Median 
Baseline MMSE-2 Total Score  
Full Analysis Set  
 
 


 
 
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14.2.3.2.8 
Analysis of Covariance of Change from 
Baseline in NPI Total Score   
Full Analysis Set 
 
 
14.2.3.2.9 
Analysis of Covariance of Change from 
Baseline in NPI Total Score to Assess Site 
Effect  
Full Analysis Set 
 
 
14.2.3.2.10a 
Analysis of Covariance of Change from 
Baseline in NPI Total Score, > Median 
Baseline NPI Total Score  
Full Analysis Set  
 
 
14.2.3.2.10b 
Analysis of Covariance of Change from 
Baseline in NPI Total Score, <= Median 
Baseline NPI Total Score  
Full Analysis Set  
 
 
14.3 
Safety Data 
 
 
14.3.1 
Displays of Adverse Events 
 
 
14.3.1.1 
Adverse Events, Overview of Treatment-
Emergent Adverse Events (TEAE) 
Safety Analysis Set 
 
 
14.3.1.2 
Adverse Events, TEAEs by Primary System 
Organ Class and Preferred Term 
Safety Analysis Set 
 
 
14.3.1.3 
Adverse Events, Treatment-Related TEAEs 
by Primary System Organ Class and 
Preferred Term 
Safety Analysis Set 
 
 
14.3.1.4 
Adverse Events, TEAEs leading to Study 
Drug Discontinuation by Primary System 
Organ Class and Preferred Term 
Safety Analysis Set 
 
 
14.3.1.5 
Adverse Events, Serious TEAEs by Primary 
System Organ Class and Preferred Term 
Safety Analysis Set 
 
 
14.3.1.6 
Adverse Events, Treatment-Related Serious 
TEAEs by Primary System Organ Class and 
Preferred Term 
 
 


 
 
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Safety Analysis Set 
14.3.1.7 
Adverse Events, TEAEs of Special Interest - 
Myalgia 
Safety Analysis Set 
 
 
14.3.1.8 
Adverse Events, TEAEs by Primary System 
Organ Class, Preferred Term and Maximum 
Severity 
Safety Analysis Set 
 
 
14.3.1.9 
Adverse Events, Overview of Treatment-
Emergent Adverse Events (TEAE), Period 2 
Safety Analysis Set 
 
 
14.3.1.10 
Adverse Events, TEAEs by Primary System 
Organ Class and Preferred Term, Period 2 
Safety Analysis Set 
 
 
14.3.2  
Listings Of Deaths, Other Serious And 
Significant Adverse Events 
 
 
14.3.2.1 
Deaths, Listing 
Enrolled Set 
 
 
14.3.2.2 
SAE, Listing 
Safety Analysis Set 
 
 
 
14.3.2.3 
Treatment-Related TEAEs, Listing  
Safety Analysis Set 
 
 
 
14.3.2.4 
TEAEs leading to Study Drug 
Discontinuation, Listing 
Safety Analysis Set 
 
 
 
14.3.2.5 
TEAEs of Special Interest – Myalgia, 
Listing 
Safety Analysis Set    
 
 
14.3.3  
Narratives of Deaths, Other Serious and 
Certain Other Significant Adverse Events 
( This is usually not created by stats but this 
placeholder ) 
 
 
14.3.4  
Abnormal Laboratory Values 
 
 
14.3.4.1 
Hematology 
Safety Analysis Set 
 
 
14.3.4.2 
Shift Table-Hematology 
Safety Analysis Set 
 
 


 
 
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14.3.4.3 
Chemistry 
Safety Analysis Set 
 
 
14.3.4.4 
Shift Table-Chemistry 
Safety Analysis Set 
 
 
14.3.4.5 
Liver Function Abnormalities 
Safety Analysis Set 
 
 
14.3.4.6 
Shift for Selected Lab Parameters from 
Baseline to Last Assessment Based on 
CTCAE Grade 
Safety Analysis Set 
 
 
14.3.4.7 
Shift for Selected Lab Parameters from 
Baseline to Highest Post-Baseline Value  
based on CTCAE Grade 
Safety Analysis Set 
 
 
14.3.5  
Extent Of Exposure, Dosage Information, 
And Compliance 
 
 
14.3.5.1 
Infusions 
Safety Analysis Set 
 
 
14.3.6  
Vital Signs And Physical Examination 
 
 
14.3.6.1 
Vital Signs 
Safety Analysis Set 
 
 
14.3.6.2.1 
Vital Sign Data outside Clinical Concern 
Range 
Safety Analysis Set 
 
 
14.3.6.2.2 
Shift for Systolic BP and Diastolic BP from 
Baseline to Worst CTCAE Grade 
Safety Analysis Set 
 
 
14.3.6.3 
Physical Examinations 
Safety Analysis Set 
 
 
14.3.6.4 
Physical Examinations, Changes from 
Baseline  
Safety Analysis Set 
 
 
14.3.6.5 
Physical Examination-Weight 
Safety Analysis Set 
 
 
14.3.6.6 
Physical Examination-Weight Data outside 
Clinical Concern Range 
Safety Analysis Set 
 
 


 
 
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14.3.7  
Other Safety 
 
 
14.3.7.1 
ECGs 
Safety Analysis Set 
 
 
14.3.7.2 
ECG Result Interpretations 
 
 
14.3.7.3 
ECG Abnormalities for Subjects with Any 
Abnormal Clinically Significant ECG 
Interpretation 
 
 
14.3.7.4 
QTcF Categories 
Safety Analysis Set 
 
 
14.3.7.5 
Columbia-Suicide Severity Rating Scale (C-
SSRS) at Screening 
Safety Analysis Set 
 
 
14.3.7.6 
Columbia-Suicide Severity Rating Scale (C-
SSRS) at Post-baseline Visits 
Safety Analysis Set 
 
 
14.3.8  
Concomitant Medication 
 
 
14.3.8.1 
Concomitant Medications 
Safety Analysis Set 
 
 
 
Figure 
Number 
Figure Title 
Validation 
Method 
Shell Number 
(if repeat) 
 
14.2.1 
Mean (+/- SE) Change from baseline in 
Severe Impairment Battery (SIB) Over 
Time 
Full Analysis Set 
 
 
 
14.3.1.1 
Box Plot of Change from Baseline in Heart 
Rate (beats/min)             
Safety Analysis Set 
 
 
 
14.3.1.2 
Box Plot of Change from Baseline in PR 
(msec)  
Safety Analysis Set 
 
 
 
14.3.1.3 
Box Plot of Change from Baseline in RR 
(msec) 
Safety Analysis Set 
 
 
 
14.3.1.4 
Box Plot of Change from Baseline in QT 
(msec) 
 
 


 
 
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Figure 
Number 
Figure Title 
Validation 
Method 
Shell Number 
(if repeat) 
Safety Analysis Set 
 
14.3.1.5 
Box Plot of Change from Baseline in QRS 
(msec) 
Safety Analysis Set 
 
 
 
14.3.1.6 
Box Plot of Change from Baseline in QTcF 
(msec) 
Safety Analysis Set 
 
 
 
14.3.2.1 
Box Plot of Change from Baseline in 
Systolic Blood Pressure (mmHg) 
Safety Analysis Set 
 
 
 
14.3.2.2 
Box Plot of Change from Baseline in 
Diastolic Blood Pressure (mmHg) 
Safety Analysis Set 
 
 
 
14.3.2.3 
Box Plot of Change from Baseline in Pulse 
Rate (beats/min) 
Safety Analysis Set 
 
 
 
14.3.2.4 
Box Plot of Change from Baseline in 
Respiration (breaths/min) 
Safety Analysis Set 
 
 
 
14.3.2.5 
Box Plot of Change from Baseline in 
Weight (kg) 
Safety Analysis Set 
 
 
 
14.3.3.1.1 
Box Plot of Alanine Aminotransferase 
(ALT) with an ULN Range 
Safety Analysis Set 
 
 
 
14.3.3.1.2 
Box Plot of Alanine Aminotransferase 
(ALT) with an LLN Range 
Safety Analysis Set 
 
 
 
14.3.3.2.1 
Box Plot of Aspartate aminotransferase 
(AST) with an ULN Range 
Safety Analysis Set 
 
 
 
14.3.3.2.2 
Box Plot of Aspartate aminotransferase 
(AST) with an LLN Range 
Safety Analysis Set 
 
 


 
 
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Figure 
Number 
Figure Title 
Validation 
Method 
Shell Number 
(if repeat) 
 
14.3.3.3.1 
Box Plot of Total Bilirubin with an ULN 
Range Safety Analysis Set 
 
 
 
14.3.3.3.2 
Box Plot of Total Bilirubin with an LLN 
Range Safety Analysis Set 
 
 
 
14.3.3.4.1 
Box Plot of Alkaline Phosphatase with an 
ULN Range 
Safety Analysis Set  
 
 
 
14.3.3.4.2 
Box Plot of Alkaline Phosphatase with an 
LLN Range 
Safety Analysis Set  
 
 
 
14.3.3.5 
Box Plot of Creatinine Clearance with an 
LLN Range 
Safety Analysis Set 
 
 
 
14.3.4.1 
Scatter Plots of LFT Parameters Post-
Baseline versus Baseline with ULN Range 
Safety Analysis Set 
 
 
 
14.3.4.2 
Scatter Plot of Maximum ALT versus 
Maximum Total Bilirubin   
Safety Analysis Set 
 
 
 
14.3.4.3 
Scatter Plot of Maximum AST versus 
Maximum Total Bilirubin   
Safety Analysis Set 
 
 
 
14.3.5 
Box plot of Baseline CPK of All Safety 
Subjects versus Those with at Least 1 
Myalgia Event 
Safety Analysis Set 
 
 
 
Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2  
Subject Data Listings 
 
 
16.2.1  
Discontinued Subjects 
 
 
16.2.1.1  
Subject Disposition 
 
 
16.2.1.2 
Screen Failures 
 
 
16.2.1.3 
Early Withdrawals  
 
 


 
 
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Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.2 
Protocol Deviations 
 
 
16.2.2.1 
Protocol Deviations  
 
 
16.2.3 
Subjects Excluded From The Efficacy Analyses 
 
 
16.2.3.1  
Major Protocol Deviations 
 
 
16.2.4  
Demographic Data 
 
 
16.2.4.1.1 
Subject Randomization 
 
 
16.2.4.1.2  
Demographic Data  
 
 
16.2.4.2.1 
Medical History-Probable Alzheimer’s Diagnosis 
 
 
 
16.2.4.2.2 
Rosen-Modified Hachinski Ischemic Scale and Total 
Score 
 
 
16.2.4.3.1 
Previous Medical History  
 
 
16.2.4.3.2 
Ongoing Medical History  
 
 
16.2.4.4 
Inclusion Criteria Not Met 
 
 
16.2.4.5 
Exclusion Criteria Not Met 
 
 
16.2.4.6 
Prior and Concomitant Medications 
 
 
16.2.5  
Compliance And/Or Drug Concentration Data 
 
 
16.2.5.1  
Infusions and Compliance 
 
 
16.2.6  
Individual Efficacy Response Data   
 
 
16.2.6.1.1 
Severe Impairment Battery (SIB) Scale, Items 1 – 20 
 
 
16.2.6.1.2 
SIB Scale, Items 21 – 40 and Total Score 
 
 
 
 
16.2.6.2 
Alzheimer Disease Cooperative Study Activities of 
Daily Living Inventory Severe Impairment Version 
(ADCS-ADL-SIV) and Total Score 
 
 
 
16.2.6.3 
Mini Mental State Examination Version 2 (MMSE-2) 
and Total Score 
 
 
16.2.6.4 
Clinical Global Impression of Improvement (CGI-I) 
 
 
16.2.6.5 
Neuropsychiatric Inventory (NPI) Scale 
 
 
16.2.7  
Adverse Event Listings 
 
 
16.2.7.1 
All Adverse Events 
 
 
16.2.7.2 
All Serious Adverse Events 
 
 
16.2.8  
Individual Laboratory Measurements And Other 
Safety 
 
 
16.2.8.1.1 
Hematology Results 
 
 


 
 
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Listing 
Number 
Listing Title 
Validation 
Method 
Shell 
Number 
(if repeat) 
16.2.8.1.2 
Chemistry Results 
 
 
16.2.8.1.3 
Laboratory Liver Function Parameter Abnormalities 
 
 
16.2.8.1.4 
Other Laboratory Tests 
 
 
16.2.8.2 
Vital Signs 
 
 
16.2.8.3 
ECG Parameters 
 
 
16.2.8.4 
Physical Examination, Abnormal Results 
 
 
16.2.8.5 
Columbia-Suicide Severity Rating Scale (C-SSRS)