A Single-Arm, Single-Site, Single-Dose Phase 1 Study Assessing the Safety of Bryostatin in the Treatment of Patients With Multiple Sclerosis
Phase: PHASE1
Conditions: Multiple Sclerosis
Sponsor: Robert Fox

 
Bryostatin 1 Study NTRP103-301  
 
Protocol v. 4.3 28Oct2024                                                                           
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STUDY PROTOCOL 
 
Title: 
A Single-Arm, Single-Site, Single-Dose Phase 1 Study Assessing 
the Safety of Bryostatin in the Treatment of Patients with Multiple 
Sclerosis 
 
Protocol Number: 
 
NTRP103-301 
Study Phase: 
1 
Date: 
 28 Oct 2024  
Study Drug: 
Bryostatin 1 
Investigational new Drug 
Application (IND) Number: 
 170476 
 Clinicaltrials.gov 
 NCT06190912 
Version: 
v. 4.3 
Sponsor-Investigator/PI: 
Robert Fox, MD 
 
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. 

 
Bryostatin 1 Study NTRP103-301  
 
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SIGNATORY PAGES 
 
SPONSOR- INVESTIGATOR’S SIGNATURE PAGE 
 
 
Title: A Single-Arm, Single-Site, Single-Dose Phase 1 Study Assessing the Safety of 
Bryostatin in the Treatment of Patients with Multiple Sclerosis 
Protocol Number:  NTRP103-301 
Protocol Version and Date:  v4.3; 28Oct2024  
Sponsor-Investigator:  
Robert J Fox, MD 
Signature:                    
Date: 

 
Bryostatin 1 Study NTRP103-301  
 
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PRINCIPAL INVESTIGATOR’S (PI) SIGNATURE PAGE 
 
Protocol Title: A Single-Arm, Single-Site, Single-Dose Phase 1 Study Assessing the Safety of Bryostatin in the 
Treatment of Patients with Multiple Sclerosis 
 
Protocol Number: NTRP103-301 
  
Protocol Version and Date: v 4.3; 28Oct2024 
 
Investigational Medicinal Product: Bryostatin 1  
 
Principal Investigator’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:   
Robert J. Fox, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature 
Date 

 
Bryostatin 1 Study NTRP103-301  
 
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STUDY CONTACT INFORMATION 
 
 
 
 
Sponsor-Investigator/PI :  
Robert Fox, MD 
JJN5 Administration Offices 
9211 Euclid Ave 
Cleveland, OH 44106 
216-445-1915 
foxr@ccf.org 
Co-PI: 
Sarah Planchon Pope, Ph.D. 
216-636-1232 
planchs@ccf.org 
Project Manager: 
Alexis Novak 
novaka5@ccf.org 

 
Bryostatin 1 Study NTRP103-301  
 
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STUDY ADMINISTRATIVE STRUCTURE 
 
 
Cleveland Clinic Neurological Institute 
Robert Fox, M.D., Sponsor-Investigator/PI 
Jeffrey Cohen, M.D. 
Daniel Ontaneda, M.D., Ph.D. 
Sarah Planchon Pope, Ph.D. 
Stephen Rao, Ph.D. 
Rachel Galioto, Ph.D. 
Mark Lowe, Ph.D. 
Ken Sakaie, Ph.D. 
Kunio Nakamura, Ph.D. 
Brittany Lapin, Ph.D., Study Statistician 
Synaptogenix, Inc. - Sponsor 
Alan Tuchman, M.D., CEO 
Daniel Alkon, M.D., President 
Funding; Protocol development 
Study Medical Monitor/Emergency Contact Information: 
Stephen Krieger, MD 
The Corinne Goldsmith Dickinson Center for MS 
Mount Sinai Hospital 
5 E 98th St 
New York, NY 10029 
Central Laboratory:   
Cleveland Clinic Laboratories 
9500 Euclid Avenue, L20 
Cleveland, OH 44195 
Central Electrocardiogram (ECG):   
Cleveland Clinic  
9500 Euclid Avenue, J20 
Cleveland, OH 44122 

 
Bryostatin 1 Study NTRP103-301  
 
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PROTOCOL SYNOPSIS 
 
Name of Sponsor-Investigator: 
Robert Fox, MD 
Name of Study Medication:   
bryostatin  
Name of Active Ingredient: 
bryostatin 1 
Title of Study: A Single-Arm, Single-Site, Single-Dose Phase 1 Study Assessing the Safety of 
Bryostatin-1 in the Treatment of Patients with Multiple Sclerosis 
Study center(s): Cleveland Clinic Neurological Institute 
Protocol Number: NTRP103-301 
Study Duration: 42 weeks 
Study Phase: 1 
Objective: To evaluate the safety of bryostatin 1 (hereafter referred to as bryostatin) for the treatment of 
multiple sclerosis (MS). 
Study Drug: bryostatin 
Route of Administration: Intravenous by continuous infusion over 45±5 minutes 
Number of Participants: 20 evaluable participants 
Study Design 
This is a single-site, single-arm, single-dose, Phase 1 study of the safety of bryostatin in participants with 
MS receiving any disease modifying therapy (DMT). The study is 42 weeks in duration, including safety 
and exploratory outcomes evaluation at 30 days after the last full assessment (Week 28) and long-term 
follow-up at 12 weeks after the last full assessment (Week 28). Participants will receive a total of 14 doses 
over 26 weeks. 
  
Treatment 
Eligible participants will be treated with bryostatin over a 26-week period. Doses 1, 2, 8, and 9 of the 
study drug will be a loading dose 20% higher (i.e., 24 µg) than the assigned fixed dose and will be 
administered one week apart. Otherwise, the assigned fixed dose is 20 µg. Drug is administered 
intravenously (IV) by continuous infusion over 45(±5) minutes. Participants are scheduled to receive 14 
doses over 26 weeks. 
 
Primary Objective: Safety and Tolerability 
 
Primary Outcome Measures 
Frequency of treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) 
Frequency of study medication discontinuation  
Potential central nervous system (CNS) inflammatory effects as captured by clinical monitoring and MRI 
 

Bryostatin 1 Study NTRP103-301 
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Name of Sponsor-Investigator: 
Robert Fox, MD 
Name of Study Medication: 
Bryostatin  
Name of Active Ingredient: 
Bryostatin 1 
Exploratory Objectives: Assess Signals of Efficacy 
 
Exploratory Outcome Measures 
Changes from baseline to Week 11, Week 28, and Week 40 in the following: 
• 
MRI biomarkers   
- lesion volume and brain parenchymal fraction 
- default mode network node connectivity 
- diffusion MRI measures of tissue integrity- anatomical connectivity of transcallosal motor pathway 
- myelin water fraction 
- measures of myelination derived from magnetization transfer ratio, quantitative T2* and quantitative 
susceptibility mapping 
- grey matter atrophy, including grey matter fraction, white matter fraction, and cortical atrophy as 
measured by CLADA 
• 
Expanded Disability Status Scale (EDSS) 
• 
Montreal Cognitive Assessment (MoCA) test 
• 
Controlled Oral Word Association Test (COWAT) 
• 
MS Performance Test Domains 
- lower extremity function 
- upper extremity function 
- cognition 
• 
Quality of Life in Neurological Disorders (Neuro-QoL) 
Change from baseline to Week 28 and Week 40 in the following: 
• 
California Verbal Learning Test- 3rd Edition (CVLT 3) 
• 
Brief Visuospatial Memory Test - Revised (BVMT-R) 
• 
Judgement of Line Orientation (JOLO) 
• 
Boston Naming Test (BNT) 
• 
Delis–Kaplan Executive Function System (D-KEFS) Sorting Test 
 
 The time-course of changes will be assessed for those outcomes with more frequent assessments (i.e., 
COWAT, MoCA, and MSPT) 
Statistical Considerations: 
 
Treatment emergent adverse events (TEAEs) and other safety data will be analyzed descriptively in all 
participants who received any dose of study drug (including partial infusions). These data will be 
summarized by time in study. 
 
All statistical tests for exploratory outcomes (efficacy signals) will be two-sided tests, with α=0.05. 
Since all of the efficacy assessments are exploratory, there will be no adjustment for multiplicity.  
 
 

Bryostatin 1 Study NTRP103-301 
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Eligibility Criteria: 
 
Inclusion 
1. Written informed consent signed by participant 
2. English-speaking 
3. Hospital Anxiety and Depression Scale <11 
4. Male and female participants, 18-65 years of age inclusive 
5. Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria (any form 
of MS).1 A diagnosis of MS must be confirmed at the time of the screening visit. 
6. Processing Speed Test (PST) z-score between -1.0 and -2.5 2  
7. EDSS between 0.0 and 7.0, inclusive.  
8. Adequate vision and motor function to participate in assessment procedures 
9. Participants must be off of a DMT or on a stable dose of a DMT for at least 1 year prior to entry into the 
study, and the dose should not change during the study unless a change is required by a clinically 
significant change in the participant’s status. 
10. 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. Contraception methods resulting in an overall failure rate of <1 % per year 
are required for women of childbearing potential. 
11. 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 
12. Participants should be in reasonably good health over the last 6 months and any chronic disease should 
be stable. 
 
Exclusion 
1. Evidence of significant CNS vascular disease on previous neuroimaging, including but not limited to 
cortical stroke, multiple infarcts, localized single infarcts in the thalamus, angular gyrus, multiple lacunar 
infarcts, or extensive white matter injury 
2. Clinically significant neurologic disease or condition other than MS, 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 
3.  Previous history of seizures or seizure disorders. 
4. Evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, 
neurologic, or metabolic disease within the 6 months prior to enrollment. If there is a history of cancer, 
the participant should be clear of cancer for at least 2 years prior to screening. More recent history of 
basal cell or squamous cell carcinoma and melanoma in situ (Stage 0) may be acceptable after review by 
the Medical Monitor. 
5. Estimated Glomerular Filtration Rate (eGFR) 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 screening3 
8. Use of valproic acid and/or lithium within 14 days prior to screening 
9. Use of carbamazepine within 7 days prior to screening  
10. Use of teriflunomide within 90 days prior to screening 
11. Use of dalfampridine within 7 days of screening 

Bryostatin 1 Study NTRP103-301 
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12. Current use of acetaminophen, ciprofloxacin, and/or trimethoprim/sulfamethoxazole 
13. Use of any potent or moderate inhibitor or inducer of CYP3A4, CYP2C8, or CYP2C9. Concomitant 
medicines will be examined on a case-by-case basis against the Flockhart Table by study investigator, 
and if needed, the Medical Monitor, to determine allowability 
14. Current use of St. John’s Wort, within 2 weeks prior to screening 
15. Consumption of grapefruit juice from screening until end of study  
16. At the discretion of the PI, any medical or psychiatric condition that is unstable or may require the 
initiation of additional medication or surgical intervention during the course of the study 
17. Any screening laboratory values outside the laboratory reference ranges that are deemed clinically 
significant by the PI 
18. Use of an investigational drug within 30 days prior to screening 
19. Suicidality defined as active suicidal thoughts during the 6 months prior to screening or at Baseline 
[SBQ-R], or history of suicide attempt in previous 2 years, or at serious suicide risk in study neurologist 
or PI’s judgment 
20. Major psychiatric illness such as currently uncontrolled major depression according to Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition4, 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 
21. Diagnosis of alcohol or drug abuse within the last 2 years 
22. History of prolonged QT or prolonged QT on screening ECG [QT correction with Bazett formula 
(QTcB) or QT correction by Fridericia (QTcF)>499 per central reader]5 
23. 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] 
24. Known to be seropositive for Hepatitis B or C, unless successful curative treatment for Hepatitis C (e.g., 
Harvoni) has been received, and there is documentation that there is no Hepatitis B/C virus detected 3 
months after completion of treatment 
25. Known to be seropositive for human immunodeficiency virus (HIV) 
26. Pregnancy or breastfeeding during the study. A β-hCG serum pregnancy test will be performed at 
Screening for female patients of child-bearing potential.  
27. Aspartate Amino Transferase (AST) or Alanine Aminotransferase (ALT) >3x upper limit of normal 
(ULN) and total bilirubin >2x ULN or International Normalized Ratio (INR) >1.5 
28. History of significant bleeding disorders. 
29. Moderate baseline thrombocytopenia (platelets <100K/uL). 
30. Elevated INR (>2.0). 
31. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug 
32. Any other concurrent medical condition, which in the opinion of the PI makes the participant unsuitable 
for the clinical study 
 
1 Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the 
McDonald criteria. Lancet Neurol. 2018 Feb;17(2):162-73. 
2 Benedict RHB, Amato MP, DeLuca J, Geurts JJG. Cognitive impairment in multiple sclerosis: clinical management, MRI, and therapeutic 
avenues. Lancet Neurol. 2020 Oct;19(10):860-871. doi: 10.1016/S1474-4422(20)30277-5. Epub 2020 Sep 16. PMID: 32949546. 
3 McCary CA, Yoon Y, Panagabko C, Cho W, Atkinson J, Cook-Mills JM. Vitamin E isoforms directly bind PKCα and differentially regulate 
activation of PKCα. Biochem J. 2012;441(1):189-198. doi:10.1042/BJ20111318 
4 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th Edition: DSM-5 – May 27, 2013. American 
Psychiatric Association. Washington, D.C. 
5O-Uchi J, Rice JJ, Ruwald MH, Parks XX, Ronzier E, Moss AJ, Zareba W, Lopes CM. Impaired IKs channel activation by Ca(2+)-dependent 
PKC shows correlation with emotion/arousal-triggered events in LQT1. J Mol Cell Cardiol. 2015 Feb;79:203-11. doi: 
10.1016/j.yjmcc.2014.11.020. Epub 2014 Dec 2. PMID: 25479336; PMCID: PMC4302024. 
 
 

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TABLE 1- SCHEDULE OF ACTIVITIES 
 
Week 
Scree
ning 
0 
1 
3 
5 
7 
9 
11 
13 
15 
16 
18 
20 
22 
24 
26 
28 
32 
40 
 
ET 
Day (+/- 3 
days)g 
-28 to 
-2 
0 
7 
21 
35 
49 
63 
77 
91 
105 
112 
126 
140 
154 
168 
182 
196 
224 
280 
 
 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirm 
Eligibility 
X 
  
  
  
  
  
  
 
NO CLINICAL VISIT 
 
 
 
 
 
 
 
 
 
 
 
  
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical & 
MS history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
X 
  
  
  
 X 
 
  
X 
  
  
  
 X 
 
  
 
X 
 
 
 
X 
Vital signsa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Weight 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Screening 
Labsb 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HADS 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Routine Labsc 
 
  
  
X 
  
  
  
X 
  
  
X 
  
  
  
X 
X 
 
 
 
X 
Urine 
Pregnancyg  
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Biobank 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
EDSS 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
 
X 
 
X 
 
X 
SBQ-R 
X 
  
  
X 
  
X 
  
X 
  
X  
 
X  
 
 X 
 
X 
 
 
 
X 
Neuro-QoLd 
X 
 
 
 
  
 
  
X 
 
 
 
  
 
 
 
 X 
 
X 
 
X 
Short 
Cognitive 
Battery and 
Performance 
Testd 
X 
  
  
X 
  
X 
  
X 
 
X  
 
X  
 
 X 
 
X 
 
X 
 
X 
Extensive 
Cognitive 
Batterye 
X 
  
  
  
  
  
  
 
  
  
  
  
  
  
 
X 
 
X 
 
X 
ECG 
X 
  
  
  
  
  
  
X 
  
  
  
  
   
  
 
X 
 
 
 
X 
MRI 
X 
  
  
  
  
  
  
X 
  
  
  
  
  
  
 
X 
 
X 
 
X 
Study Drug 
Dose 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Con meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
a Vital signs prior to infusion, and 30, 60 and 90 minutes from start of the infusion (+/-5 min) 
b Screening labs: Complete blood count (CBC)/hematology including differential, coagulation, clinical chemistry, gamma 
glutamyl transferase, lactate dehydrogenase, uric acid, bilirubin, thyroid stimulating hormone (TSH), β-hCG serum 
pregnancy test, creatine phosphokinase (CK) and B12  
c Routine labs: Complete blood count (CBC)/hematology including differential, coagulation, clinical chemistry, gamma 
glutamyl transferase, lactate dehydrogenase, uric acid, bilirubin  
d Short Cognitive Battery and Performance Test: MSPT, MoCA, COWAT  
eExtensive Cognitive Battery: BNT, BVMT-R, CVLT 3, D-KEFS Sorting, and JOLO  
f ±3 Days does not apply to the Screening period, which is a maximum of 28 days  
ET, early termination. 
g Urine pregnancy test to be performed prior to study drug infusion. 

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STUDY FLOW CHART 
 
  
 
 
 

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LIST OF ABBREVIATIONS 
9HPT 
9-hole Peg Test 
AChEI 
Acetylcholinesterase inhibitor 
AD 
Alzheimer’s disease 
ADCS-
ADL-Sev 
Alzheimer's Disease Cooperative Study Activities of Daily Living 
Inventory for Severe Alzheimer's Disease 
AE 
AESI 
Adverse Event 
Adverse Event of Special Interest  
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Amino Transferase  
AUC 
Area under the ROC Curve 
β-hCG 
Human chorionic gonadotropin-beta subunit 
BNT 
Boston Naming Test 
BSA 
Body Surface Area 
BUN 
Blood Urea Nitrogen  
BVMT-R 
Brief Visuospatial Memory Test – Revised 
CAS 
Completer Analysis Set  
CBC 
Complete Blood Count  
CFR 
Code of Federal Regulations  
CGI-I 
Clinical Global Impression-Improvement Scale 
CI 
Cognitive Impairment 
CL 
Clearance  
Cmax 
Peak Drug Concentration 
CNS 
Central Nervous System  
COWAT 
Controlled Oral Word Association Test 
CK 
Creatine phosphokinase  
C-SSRS 
Columbia Suicide Severity Rating Scale 
CVLT 3 
California Verbal Learning Test- 3rd Edition 
DMT 
Disease Modifying Therapy 
DSC 
DSMB 
Digit Symbol Coding 
Data Safety Monitoring Board  
D-KEFS 
Delis–Kaplan Executive Function System 
DTI 
Diffusion Tensor Imaging 
EAE 
Experimental Autoimmune Encephalomyelitis 
EC 
Ethics Committee 
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form  
EDC 
Electronic Data Capture  
EDSS 
Expanded Disability Status Scale 
EOS 
End of Study 
EMG 
Electromyography  
ET 
Early Termination 
FAS 
Full Analysis Set  
FDA 
Food and Drug Administration  
FLAIR 
FXS 
Fluid-Attenuated Inversion Recovery 
Fragile X Syndrome 
GCP 
Good Clinical Practice  

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GCT 
gamma glutamyl transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practice 
HADS 
Hospital Anxiety and Depression Scale 
HIV 
Human Immunodeficiency Virus 
HED 
Human Equivalent Dose 
HVLT-R 
Hopkins Verbal Learning Test-Revised 
IB 
Investigator Brochure  
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonisation  
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug  
INR 
International Normalized Ratio  
IP 
Intraperitoneal Injection 
IRB 
Institutional Review Board  
IU 
International Unit  
IV 
Intravenous  
JOLO 
Judgement of Line Orientation 
LCLA 
Low-contrast Letter Acuity 
LD50 
Dosage causing the death of 50% (one half) of a group of test animals 
LDH 
LLOQ 
Lactate Dehydrogenase 
Lower Limit of Quantitation  
MDT 
MedDRA 
Manual Dexterity Test 
Medical Dictionary for Regulatory Activities 
mGRE 
Multi-echo gradient recalled echo 
MMRM 
Mixed Model for Repeated Measures  
MMSE 
Mini Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
MOG 
Myelin Oligodendrocyte Glycoprotein 
MP2RAGE 
Magnetization Prepared 2 RApid Gradient Echo 
MSFC 
Multiple Sclerosis Functional Composite 
MSPT 
Multiple Sclerosis Performance Test 
MRI 
Magnetic Resonance Imaging  
MTD 
Maximum Tolerated Dose  
MTR 
Magnetization Transfer Ratio 
MS 
Multiple Sclerosis 
NCI 
Neuro-QoL 
National Cancer Institute 
Quality of Life in Neurological Disorders Survey 
NOAEL 
No Adverse Effect Level  
NPI 
Neuropsychiatric Inventory 
NS 
Normal Saline 
NYHA 
New York Heart Association 
PASAT 
Paced Auditory Serial Addition Test 
PBMC 
Peripheral Blood Mononuclear Cell 
PE 
Physical Examination 
PET 
polyethylene glycol, ethanol, and Tween 80 
PI 
Principal Investigator  
PK 
Pharmacokinetics  

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PKC 
Protein Kinase C  
PPMS 
Primary Progressive Multiple Sclerosis 
PRN 
As Needed 
PST 
Processing Speed Test 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time  
PVC 
Polyvinylchloride 
QTcB 
QT correction with Bazett formula 
QTcF 
QT correction by Fridericia 
RBANS 
Repeatable Battery of Assessments for Neuropsychological Status 
RMS 
Relapsing Multiple Sclerosis 
RRMS 
Relapsing Remitting Multiple Sclerosis 
rs-fMRI 
Resting State-Functional Magnetic Resonance Imaging 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SAS 
Safety Analysis Set 
SD 
Standard Deviation  
SDMT 
Symbol Digit Modality Test 
SIB 
Severe Impairment Battery 
SOC 
System Organ Classes 
SOP 
Standard Operating Procedures 
SPMS 
Secondary Progressive Multiple Sclerosis 
SBQ-R 
Suicide Behaviors Questionnaire-Revised 
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
T25FW 
Timed 25-Foot Walk 
TEAE 
Treatment Emergent Adverse Events 
TSH 
Thyroid Stimulating Hormone 
Tmax 
Time-to-Peak Measure 
ULN 
Upper Limit of Normal  
USP 
United States Pharmacopeia  
US 
United States  
ViSTa 
Visualization of Short Transverse 
WST 
Walking Speed Test 
 
 
 
 

Bryostatin 1 Study NTRP103-301 
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Table of Contents 
SIGNATORY PAGES ........................................................................................................................................................................ 2 
SPONSOR- INVESTIGATOR’S SIGNATURE PAGE ....................................................................................................................... 2 
PRINCIPAL INVESTIGATOR’S (PI) SIGNATURE PAGE ............................................................................................................... 3 
STUDY CONTACT INFORMATION.................................................................................................................................................... 4 
STUDY ADMINISTRATIVE STRUCTURE ............................................................................................................................................ 5 
PROTOCOL SYNOPSIS .................................................................................................................................................................... 6 
TABLE 1- SCHEDULE OF ACTIVITIES ...................................................................................................................................................... 10 
STUDY FLOW CHART .................................................................................................................................................................... 11 
LIST OF ABBREVIATIONS .............................................................................................................................................................. 12 
TABLE OF CONTENTS ................................................................................................................................................................... 15 
1. INTRODUCTION ....................................................................................................................................................................... 18 
1.1. 
MULTIPLE SCLEROSIS ............................................................................................................................................................ 18 
1.2. 
RATIONALE FOR THE USE OF BRYOSTATIN IN THE TREATMENT OF MS................................................................................... 20 
2.1. 
TOXICOLOGY ............................................................................................................................................................................. 20 
2.2. 
PHARMACOKINETICS (PK) ........................................................................................................................................................... 20 
2.3. 
ADSORPTION, DISTRIBUTION, METABOLISM, EXCRETION (ADME) ...................................................................................................... 21 
2.4. 
DRUG-DRUG INTERACTIONS (DDI) ................................................................................................................................................ 21 
2.5. 
GENOTOXICITY .......................................................................................................................................................................... 22 
2.6. 
REPRODUCTIVE TOXICOLOGY ........................................................................................................................................................ 22 
2.7. 
SAFETY PHARMACOLOGY ............................................................................................................................................................. 22 
3. CLINICAL TRIAL DATA ............................................................................................................................................................... 23 
3.1 ONCOLOGY DATA .......................................................................................................................................................................... 23 
3.2 ALZHEIMER’S DISEASE DATA ........................................................................................................................................................ 24 
3.2.1 Study NTRP101-204 ............................................................................................................................................................... 24 
3.2.2 Study NTRP-101-203 .............................................................................................................................................................. 24 
3.2.3 Study NTRP101-202 ............................................................................................................................................................... 26 
3.2.4 Study NTRP101-201 ............................................................................................................................................................... 30 
4. STUDY OBJECTIVES .................................................................................................................................................................. 31 
4.1 PRIMARY OBJECTIVE...................................................................................................................................................................... 31 
4.2 EXPLORATORY OBJECTIVE ............................................................................................................................................................. 31 
5. INVESTIGATIONAL PLAN .......................................................................................................................................................... 31 
5.1 OVERVIEW OF STUDY DESIGN ........................................................................................................................................................ 31 
5.2 DOSE RATIONALE/JUSTIFICATION .................................................................................................................................................. 31 
5.3 RISK/BENEFIT ................................................................................................................................................................................ 33 
5.4 STUDY ENDPOINTS ......................................................................................................................................................................... 34 
Safety Assessments ........................................................................................................................................................................ 34 
5.5 STUDY POPULATION – ELIGIBILITY REQUIREMENTS ...................................................................................................................... 34 
6.0. PRODUCTS USED IN THIS STUDY............................................................................................................................................ 36 
6.1 BRYOSTATIN .................................................................................................................................................................................. 36 
6.2 PACKAGING AND LABELING OF STUDY DRUG ................................................................................................................................ 37 
6.3 STORAGE AND PREPARATION OF STUDY DRUG .............................................................................................................................. 37 
6.4 STUDY DRUG ACCOUNTABILITY AND DISPOSAL ............................................................................................................................ 38 
6.5 BLINDING ....................................................................................................................................................................................... 38 
6.6 STUDY DRUG ADMINISTRATION .................................................................................................................................................... 38 

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7. STUDY PROCEDURES AND ASSESSMENTS ................................................................................................................................. 38 
7.1 ASSESSMENTS ................................................................................................................................................................................ 38 
Safety .............................................................................................................................................................................................. 39 
Exploratory Efficacy Assessments ................................................................................................................................................... 40 
7.2 VISIT PROCEDURES ........................................................................................................................................................................ 42 
7.3 CONCOMITANT MEDICATIONS ....................................................................................................................................................... 48 
8. ADVERSE EVENTS AND OTHER SAFETY EVALUATIONS .............................................................................................................. 49 
8.1 DEFINITION OF ADVERSE EVENTS .................................................................................................................................................. 49 
8.2 ADVERSE EVENTS OF SPECIAL INTEREST (AESI) ........................................................................................................................... 49 
8.2.1 MYALGIA .................................................................................................................................................................................... 49 
8.2.2 SYSTEMIC INFUSION RELATED REACTIONS ................................................................................................................................. 50 
8.2.3 INFUSION SITE REACTIONS .......................................................................................................................................................... 51 
8.3 DEFINITION OF SERIOUS ADVERSE EVENT ..................................................................................................................................... 52 
8.4 ASSESSMENT OF INTENSITY ........................................................................................................................................................... 52 
8.5 RELATIONSHIP TO STUDY DRUG .................................................................................................................................................... 52 
8.7 REPORTING ADVERSE EVENTS ....................................................................................................................................................... 53 
8.8 CRITERIA FOR WITHDRAWAL OF PARTICIPANTS ............................................................................................................................ 55 
8.9 CRITERIA FOR PERMANENT DISCONTINUATION OF STUDY DRUG .................................................................................................. 55 
8.10 STUDY DISCONTINUATION ........................................................................................................................................................... 55 
9. CLINICAL DATA AND SAFETY MONITORING .............................................................................................................................. 56 
10. DATA ANALYSIS / STATISTICAL METHODS .............................................................................................................................. 57 
10.1 SAMPLE SIZE DETERMINATION .................................................................................................................................................... 57 
10.2 STATISTICAL METHODS ............................................................................................................................................................... 57 
10.3 SAFETY AND TOLERABILITY OUTCOMES ...................................................................................................................................... 58 
10.4 SAFETY ASSESSMENTS ................................................................................................................................................................. 58 
10.5 ANALYSIS OF SAFETY DATA ........................................................................................................................................................ 58 
10.6 PHYSICAL EXAMINATION ............................................................................................................................................................. 59 
10.7 VITAL SIGNS ................................................................................................................................................................................ 59 
10.8 ECG ............................................................................................................................................................................................. 59 
10.9 THE SUICIDE BEHAVIORS QUESTIONNAIRE-REVISED (SBQ-R) ................................................................................................... 59 
10.10 Patient-Reported Outcomes (PROs) ..................................................................................................................................................... 59 
10.11 Magnetic Resonance Imaging (MRI) ................................................................................................................................................... 59 
10.12 EXPLORATORY OUTCOMES ........................................................................................................................................................ 59 
10.13 ANALYSIS OF EXPLORATORY ENDPOINTS .................................................................................................................................. 60 
11. DATA MONITORING ............................................................................................................................................................... 60 
11.1 SOURCE DOCUMENTATION ........................................................................................................................................................... 60 
11.2 STUDY DOCUMENTATION AND RECORD RETENTION ................................................................................................................... 60 
11.3 SYNAPTOGENIX SITE MONITORING .............................................................................................................................................. 60 
11.4 QUALITY ASSURANCE AND QUALITY CONTROL .......................................................................................................................... 61 
11.5 AUDITS AND INSPECTION ............................................................................................................................................................. 61 
12. ETHICS ................................................................................................................................................................................... 61 
12.1 INSTITUTIONAL REVIEW BOARD .................................................................................................................................................. 61 
12.2 ETHICAL CONDUCT OF THE STUDY .............................................................................................................................................. 62 
12.3 WRITTEN INFORMED CONSENT .................................................................................................................................................... 62 
13. STUDY MANAGEMENT ........................................................................................................................................................... 62 
13.1 DATA COLLECTION AND MANAGEMENT ...................................................................................................................................... 62 
13.2 DATA QUALITY CONTROL ............................................................................................................................................................ 62 
13.3 DATA MANAGEMENT AND DATA STORAGE ................................................................................................................................. 63 
13.4 INSPECTION OF RECORDS ............................................................................................................................................................. 63 
13.5 RETENTION OF RECORDS .............................................................................................................................................................. 63 

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13.6 CONFIDENTIALITY ........................................................................................................................................................................ 63 
13.7 PROTOCOL AMENDMENTS ............................................................................................................................................................ 63 
13.8 PROTOCOL DEVIATIONS ............................................................................................................................................................... 64 
13.9 DATA CORRECTIONS .................................................................................................................................................................... 64 
13.10 INSURANCE ................................................................................................................................................................................ 64 
14. PUBLICATION AND DISCLOSURE POLICY ................................................................................................................................. 64 
15. APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS ...................................................................................................... 65 
16. APPENDIX 2 - LIST OF REFERENCES ......................................................................................................................................... 66 
 
 
 
 
 

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1. INTRODUCTION  
1.1. Multiple Sclerosis 
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system 
(CNS) that often leads to severe neurologic disability and, most typically, begins in early adulthood. 
Approximately 2.8 million people worldwide are living with MS,1 with the disease affecting young adults 
primarily (mean age at diagnosis of ~30 years) and women affected at least twice as often as men in most 
types of MS.2, 3 
Clinical signs of MS can occur alone or in combination and include weakness, spasticity, gait and 
coordination disturbances, sensory dysfunction, visual loss, sexual dysfunction, fatigue, depression, chronic 
pain, sleep disorders, and cognitive impairment.4 MS is degenerative, and assistance in walking is required 
usually within 15 years of disease onset [Expanded Disability Status Scale (EDSS) score, 6.0].5 Thus, 
irreversible disease progression is an important factor in selecting appropriate treatment by patients and their 
physicians. While the disease is devastating physically, MS also creates substantial economic burden on 
patients, their families, and society as a whole, with total annual costs of approximately $85 Billion in the 
US alone (2019).6 
MS is classified into three clinical phenotypes: relapsing remitting (RRMS), secondary progressive 
(SPMS), and primary progressive (PPMS) based on current course. Each of these phenotypes can be 
classified as active or non-active, based on the presence or absence of clinical relapses and the presence and 
character of lesions on MRI. The term “Relapsing MS” (RMS) includes RRMS and early stages of SPMS, 
where patients experience progression with superimposed relapses.7 
 
Demyelination and potential remyelination 
Immunologic changes that occur in MS can lead to the infiltration of immune cells into the CNS and 
activation of specific cell types in the brain that surround neurons, including microglia, and the destruction 
of myelin-producing oligodendrocytes. The inflammatory response in the CNS leads to damage to the 
myelin sheath surrounding neurons, with eventual demyelination and, in some cases, axon loss.8, 9 The 
demyelinated lesions appear as plaques or lesions on magnetic resonance imaging (MRI), often surrounding 
blood vessels. While the demyelination process continues, other mechanisms attempt to repair the damage. 
Oligodendrocyte precursor cells migrate to the lesions and differentiate into myelin-producing 
oligodendrocytes, which can re-wrap the damaged axons with myelin, although the new sheath is usually 
not as thick as the original.10 Remyelination appears to occur more consistently in early stages of the 
disease, with over 20% of demyelinated lesions observed to have completely remyelinated.11 This 
demonstrates that repair is possible and provides hope that if the inflammatory processes could be halted 
and/or the repair mechanisms could be potentiated, the tissue damage due to neuroinflammation may be 
reduced and reversed. In vitro studies indicate that protein kinase C (PKC) modulation by bryostatin can 
decrease the expression of pro-inflammatory cytokines and promote the expression of anti-inflammatory 
ones, implicating PKC as a key target in regulation of the innate immune system.12 Murine experimental 
autoimmune encephalomyelitis (EAE) studies demonstrated that bryostatin was “highly effective at 
attenuating the neurologic deficits associated with” myelin oligodendrocyte glycoprotein (MOG)-induced 
EAE 12. The effect on neuroinflammation and innate immunity is through the activity of bryostatin as a PKC 
modulator, as in vitro experiments demonstrated that the activation of microglia and macrophages occurs in 
a PKC-dependent manner.13   
 
Structural impairment in MS  
Functional degeneration in MS is reflected in the substantial inflammation, demyelination, and 
neurodegeneration that occurs during the course of the disease and results in the progressive loss of brain 
gray and white matter. These structural changes can be detected using MRI data, an important tool in the 
diagnosis of MS, in monitoring disease progression, and in determining the efficacy of disease modifying 

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therapies.14 Inflammation, axon demyelination (remyelination), changes in the appearance of plaques or 
lesions, brain atrophy, and, possibly, changes in brain functional status, all of which are consistent with a 
diagnosis of MS, can be assessed through the use of different types of MRI. Conventional T2- and T1-
weighted MRI can detect focal inflammation, but quantitative analysis methods are required to detect global 
and regional brain volume loss, changes in lesions and plaques, and changes in myelination. MRI 
measurements of gray matter atrophy (linked to neurodegeneration in progressive MS) and magnetization 
transfer ratio (MTR) (a marker of myelin density) have been associated with long-term disability 
accumulation and cognitive decline.15-17 A relatively new MRI sequence, Magnetization Prepared 2 RApid 
Gradient Echo (MP2RAGE), has been shown to be superior to other types of MRI (2D fluid-attenuated 
inversion recovery and conventional MP-RAGE) in localizing MS lesions due to its superior gray matter to 
white matter contrast.18-20 Together, these MRI methods can detect sensitive and reliable biomarkers of MS 
(inflammation, brain volume changes, myelination changes, and lesion changes) that enable monitoring of 
MS disease progression and assessing the efficacy of new therapies. As described previously, studies 
indicate that bryostatin can modulate PKC and affect neuroinflammation and innate immunity to create a 
less inflammatory tissue environment.12, 13, 21 Thus, bryostatin treatment may result in reduced inflammation, 
a slowing of demyelination or increased remyelination, fewer or resolved lesions, and reduced brain volume 
changes, all of which can be quantitated by MRI. 
 
Cognitive impairment in MS 
Cognitive impairment (CI) is a common feature of MS, occurring in approximately 50% of patients.22 
Cognitive domains shown to be affected predominantly in MS include recent/episodic working memory and 
information processing speed, with lesser effects in executive functioning and spatial perception 22. 
Cognitive impairment negatively impacts quality of life, the ability to engage in daily activities, and 
continued employment for people with MS.23 Information processing speed is measured routinely in MS 
clinics and clinical trials through the use of a variety of tests such as the Paced Auditory Serial Addition 
Test (PASAT),24 the Symbol Digit Modality Test (SDMT),25 and the newer iPad-based Processing Speed 
Test (PST).26 Currently, no effective pharmaceutical interventions have been demonstrated to improve 
cognitive impairment in MS,27 and cognitive rehabilitation is the only available intervention to improve CI; 
however, its effectiveness is controversial.23 Trials of bryostatin in memantine-free Alzheimer’s disease 
(AD) patients suggest that the agent may improve cognitive ability as some participants demonstrated 
improvement in the Severe Impairment Battery (SIB) compared to those who received placebo.28 
Additionally, in another randomized, placebo-controlled, AD trial, an increase in PKC activity was 
measured following bryostatin administration, and participants who received the study drug demonstrated a 
temporary improvement on the Mini Mental Status Examination (MMSE) compared to those receiving 
placebo.29   
 
Neurogenesis stimulation 
 
The potential mechanism underlying the observed cognitive improvement in the bryostatin AD trials 
may be a result of neuroprotection and synaptogenesis, primarily in the hippocampus.30, 31 In an animal 
model, bryostatin prevented neuronal damage and the restoration of dendritic spines and their synapses.32 It 
also decreased the level of apoptosis and necrosis of neurons in an ischemic brain injury model.33 In cortical 
cultures, bryostatin increases synaptogenesis and decreases immature dendritic spine density in a PKC-
dependent manner.30 The PKC effect may be a result of a PKC-dependent increase in protein level and 
cellular distribution of HuD, a mRNA-binding protein which is important in post-transcriptional 
regulation.34 The up-regulation of HuD leads to an increase in mRNA stability, and subsequently increased 
expression, of several neurotrophic factors in cultured hippocampal neurons. These effects make bryostatin 
an attractive candidate for cognitive restoration in people with MS.  
 

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1.2. Rationale for the use of bryostatin in the treatment of MS 
Bryostatin has demonstrated pre-clinical efficacy for anti-inflammation, synaptogenesis associated with 
induction of synaptic growth factors (BDNF, NGF, IGF) and anti-apoptosis (prevention of neuronal death). 
Bryostatin has also been shown to be safe and well-tolerated in the clinic with demonstrated improvements 
in various measures of cognition in moderate to severely impaired AD patients.  
Bryostatin was shown to act on antigen-presenting cells to promote differentiation of lymphocytes into 
Th2 cells, an action that might benefit Th1-driven inflammation in MS and to provide benefit in mice with 
experimental autoimmune encephalomyelitis (EAE), a well-established experimental MS animal model. In 
that study, preventative treatment with bryostatin abolished the onset of neurologic deficits. Most 
remarkably, bryostatin reversed neurologic deficits 28 days after EAE.21 
 
These results, and others, suggest that bryostatin may improve inflammation in MS, demyelination via 
oligodendrocyte-mediated, growth factor-dependent remyelination, and cognition by way of the prevention 
and amelioration of synaptic loss in brain tissues.35 
 
2. NONCLINICAL STUDIES 
2.1. Toxicology  
       Single dose toxicity of bryostatin has been determined in four studies conducted under the National 
Cancer Institute’s (NCI) former investigational new drug (IND), including three IV toxicity studies in mice 
and one IV toxicity study in rats. These studies were conducted using two different dosing formulations: 
bryostatin in ethanol/saline or bryostatin in polyethylene glycol, ethanol, and Tween 80 (PET) diluent. 
LD50 ranged from a low of 38 µg/kg to 75 µg/kg.  
      A 21-day repeat-dose toxicity study was performed in rats at doses of 0, 10, 15, and 25 µg/m2 with the 
PET formulation resulting in no relevant toxicology findings. The maximum tolerated dose (MTD) and no 
adverse effect level (NOAEL) were noted to be 25 µg/m2, the highest dose studied. However, since there 
were no toxicologically relevant findings, the report suggested that the MTD and NOAEL are greater than 
25 µg/m2. 
      Two non-GLP dose range-finding IV toxicology studies were performed in the rat and dog to 
characterize the toxicity of bryostatin and to estimate the MTD when administered by bolus injection and 
continuous 1-hour IV infusion. In the Sprague-Dawley rat, bryostatin was tolerated at up to 10 µg/kg 
(infusion) and 15 µg/kg (bolus) with no significant differences in toxicity noted between the two routes of 
administration. In the beagle dog, bryostatin was tolerated at doses up to 15 µg/kg (infusion and bolus). 
There were no significant differences in toxicity between the two routes of administration.  
 
Detailed results can be found in the Investigator’s Brochure, v 8.0. 
2.2. Pharmacokinetics (PK) 
 Limited PK data are available in animals. The pharmacokinetics of bryostatin was analyzed in female 
CD1/F2 mice using [C26-3H]-labeled bryostatin by IV and IP administration.36 Following IV administration 
of 40 µg/kg (120 mg/m2), the plasma disappearance curve for bryostatin could be described by a 2-
compartment model, with a distribution t½ of 1.05 hours and an elimination t½ of 22.96 hours. In contrast, 
following IP administration, the plasma disappearance curve was better described by a first-order absorption 
one-compartment model, with an absorption t½ of 0.81 hours and an elimination t½ of 28.76 hours. Urinary 
excretion represented the major pathway of elimination in the first 12 hours after IV administration, with 
23.0 ± 1.9% (mean ± standard deviation) of the administered dose excreted. Approximately equal amounts 
of radioactivity (40%) were excreted in feces compared with urine within 72 hours after IV administration. 
A greater area under the curve, longer mean resident time, and lower clearance were observed with IP 
administration compared with IV administration. Bryostatin was widely distributed to various tissues 

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following both IV and IP administration. However, accumulation was observed in the lungs, liver, 
gastrointestinal (GI) tract, and fatty tissue.36  
2.3. Adsorption, Distribution, Metabolism, Excretion (ADME) 
A pharmacokinetic, excretion, mass balance, metabolism and distribution study was assessed in male, 
Sprague-Dawley rats by administering a single dose of [C26-3H]-labeled bryostatin by IV infusion over 45 
minutes. Tritiated bryostatin was shown to have a short distribution half-life, a long terminal half-life, low 
clearance, and a high-volume of distribution. In rat plasma tritiated bryostatin was predominant while only a 
single minor metabolite (M16) was detected. In rat feces tritiated bryostatin and 17 metabolites were 
observed. The structures of metabolites were not characterized by liquid chromatography-high resolution 
MS due to low concentrations.  A more detailed summary is found in the Investigator’s Brochure, v 8.0.  
2.4. Drug-drug Interactions (DDI) 
In consideration of potential drug-drug interactions (DDI), the metabolism of bryostatin by seven CYP 
isoforms (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) was investigated.37, 38, 39 
 
Cytochrome P450 
Enzyme 
Is Bryostatin a 
Substrate? 
Is Bryostatin an 
Inhibitor?1 
Is Bryostatin an Inducer?2 
3A4 
Yes 
No 
Yes, but not at 
physiologic doses3 
2C8 
Yes 
No 
 
2C9 
Yes 
No 
 
2B6 
No 
No 
Yes, but not at 
physiologic doses3 
1A2 
No 
No 
No 
2C19 
No 
No 
 
2D6 
No 
No 
 
1Decreases activity of CYP450 enzymes resulting in slower metabolism and longer systemic exposure 
2Increases activity of CYP450 enzymes resulting in faster drug metabolism and reduced systemic exposure 
3Only at a concentration of 150nM. Bryostatin 40μg fixed dose or 20μg/m2.is anticipated to produce a concentration of approximately 1nM. 
 
It was determined that bryostatin at its expected concentration for this study does not induce or inhibit 
any of the tested CYP isoforms. Further study found that bryostatin is a substrate for 3 of the enzymes – 
CYP2C8, CYP3A4, and CYP2C9.39 The relationship between these 3 CYP enzymes and medications 
commonly used by patients with MS, including the FDA approved disease modifying therapies (DMTs) for 
MS and medications commonly used in symptomatic management, were evaluated to determine potential 
DDIs with bryostatin. Medications considered included the following: disease modifying therapies 
teriflunomide, monomethyl fumarate, dimethyl fumarate, diroximel fumarate, cladribine, fingolimod, 
siponimod, ponesimod, ozanimod, interferon-β1a/b, glatiramer acetate, natalizumab, ublituximab, 
alemtuzumab, rituximab, ocrelizumab, ofatumumab; fampridine, baclofen, tizanidine, valacyclovir, 
acyclovir, methylprednisolone, prednisone, clonazepam, diazepam, amantadine, armodafinil, modafinil, 
methylphenidate, dextroamphetamine, sertraline, citalopram, escitalopram, fluoxetine, paroxetine, 
venlafaxine, duloxetine, mirtazapine, buproprion, amitriptyline, nortriptyline, imipramine, oxybutynin, 
tolterodine, solifenacin, darifenacin, sulfamethoxazole/trimethorprim, ciprofloxacin, sildenafil, tadalafil, 
vardenafil, dextromethorphan hydrobromide/quinidine sulfate, gabapentin, pregabalin, carbamazepine, and 
levetiracetam.  
Of these medications, only teriflunomide, carbamazepine, ciprofloxacin, and sulfamethoxazole were 
moderate or greater inducers or inhibitors of relevant CYP enzymes. Teriflunomide (an MS disease 
modifying therapy), is a moderate inhibitor of CYP2C9 and has a half-life of 18-19 days; therefore, 
teriflunomide is excluded from use during the trial starting 90 days before screening. Carbemazepine (an 
antiepileptic sometimes used for dysesthesias and/or mood) is a strong inducer of CYP3A4 and a moderate 

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inducer of CYP2C9, with a half-life of approximately 35 hours; therefore, carbemazepine is excluded from 
use during the trial starting 7 days before screening. Ciprofloxacin (an antibiotic often used for treatment of 
infections, particularly bladder infections) is a moderate inhibitor of CYP3A4 and has a half-life of 4 hours. 
Because ciprofloxacin is generally used only for short periods and bryostatin has a very short half-life, 
ciprofloxacin is excluded from use the day before bryostatin infusion and on the day of bryostatin infusion. 
Sulfamethoxazole, which is a component of the antibiotic Bactrim (often used to treat infections, 
particularly bladder infections), is a moderate inhibitor of CYP2C9 and has a half-life of 6-12 hours.  
Similar to ciprofloxacin, Bactrim (trimethoprim/sulfamethoxazole) is generally used only for short periods 
and bryostatin has a very short half-life, Bactrim is excluded from use the day before bryostatin infusion and 
on the day of bryostatin infusion. 
 
In consideration of transporters, bryostatin was tested for an effect on the common human transporters 
(P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, MATE2-K, OCT1 and BSEP).40, 41 
Bryostatin was found to not be a substrate for OATP1B1, OATP1B3, OAT1, OAT3, OCT2, MATE1, 
MATE2-K, OCT1 and BSEP. One cannot come to a firm conclusion if bryostatin is or is not a substrate for 
P-gp or BCRP.  Bryostatin was found to inhibit the activity of some transporters including P-gp but not 
BCRP, OATP1B1, OAT3, MATE2-K, and BSEP. The physiologic concentrations of bryostatin expected at 
the dose used during the trial (20g) is expected to result in a Cmax cellular concentration ranging between 
0.622 and 0.722 nM [Investigator’s Brochure, v8.0, 14 Sep 2023]. The percent inhibition of each transporter 
ranges from 22% to 48% at 1M. Therefore, at the cellular concentrations anticipated, significant inhibition 
of these transport proteins are not expected.  
2.5. Genotoxicity 
Bryostatin was evaluated using the bacterial reverse mutation assay (i.e., the Ames test) with no positive 
responses observed. Bryostatin was evaluated as negative (non-clastogenic) in the micronucleus assay; it 
was also evaluated as negative (non-deoxyribonucleic acid 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. 
2.6. Reproductive Toxicology 
A developmental toxicity study of bryostatin was evaluated in SD rats by a group at the Department of 
Toxicology, College of Basic Medical Science, Secondary Military Medical University, Shanghai, China. The 
control article and bryostatin (test article) were administered intravenously on gestation days 6-15 at 0, 4, 8 
and 16 µg/kg. Results of the study showed no teratogenic effects at the doses studied.  Maternal, embryo and 
fetal toxicities were observed at 8, 16 and 4 µg/kg, respectively.42 The source, purity and quality of the 
bryostatin used in this study were not reported, nor is it known if the study was performed pursuant to FDA’s 
Good Laboratory Practice for Nonclinical Laboratory Studies (GLP) regulations (21 CFR Part 58). 
2.7. Safety Pharmacology 
Effect of bryostatin 1 on Cloned hERG Potassium Channels Expressed in Human Kidney Cells 
The objective of this study was to examine the in vitro effects of bryostatin on the hERG (human ether-
à-go-go-related gene) channel current (a surrogate for IKr, the rapidly activating delayed rectifier cardiac 
potassium current) at near-physiological temperature. Two concentrations of bryostatin (0.3 and 1 μM) were 
tested. Results show that bryostatin inhibited hERG current by (Mean ± SEM; n = 3) -0.6 ± 0.9% at 0.3 μM 
and -0.7 ± 1.2% at 1 μM versus 0.8 ± 0.4% (n = 3) in control. hERG inhibition at 0.3 and 1 μM was not 
statistically significant (P < 0.05) when compared to vehicle control values. The IC50 for the inhibitory 
effect of bryostatin on hERG potassium current was not calculated since no net current inhibition was 
observed. 
 

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Cardiovascular and Respiratory Evaluation of Intravenously Administered bryostatin in the Beagle Dog 
This study was conducted to evaluate the potential cardiovascular and respiratory effects of the test article, 
bryostatin, in conscious freely moving beagle dogs. Animals (groups of 4) were administered the control and 
test article treatments via intravenous injection at doses of 1.5, 5 and 10 μg/kg. Assessments of cardiovascular 
and respiratory effects and general toxicity were based on mortality, clinical observations, body temperature, 
blood pressure (systolic, diastolic, and mean arterial), heart rate, the electrocardiogram (QRS duration and the 
RR, PR, QT and QTc intervals), and respiratory function (respiratory rate, tidal volume, and minute volume). 
As evaluated in this study, bryostatin, at doses up to 10 µg/kg, did not produce mortality, clinical signs, or 
effects on the cardiovascular or respiratory parameters in beagle dogs.  
 
3. CLINICAL TRIAL DATA 
3.1 Oncology Data 
Safety data are available from published clinical studies of bryostatin for the treatment of cancer. 
Altogether, over 1400 oncology participants received bryostatin, mainly under NCI’s IND # 42,780, with 
exposures to bryostatin in both single and combination agent studies. About 584 participants received 
bryostatin as monotherapy, with dose levels ranging from 5 μg/m2 to >180 μg/m2. Most participants in both 
the monotherapy and combination therapy studies received bryostatin at doses >25 μg/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 participants received treatment for several weeks (See 
Investigators Brochure, v 8.0). 
Adverse events, occurring in the single agent studies that resulted in discontinuation from the studies, 
were myalgia (28 participants), acute transient reaction (dyspnea, flushing, hypotension, and bradycardia; 4 
participants each), phlebitis (attributed to 60% ethanol concentration in earlier formulations, 6 participants), 
fatigue (3 participants), and 1 participant 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 were reported in the single agent clinical studies in cancer participants 
including alkaline phosphatase (ALP) (elevated; participant had pre-existing liver metastases), allergic 
reaction, anemia, anorexia, arthralgia, ataxia, cardiac arrhythmias, cardiovascular, coagulation, community-
acquired pneumonia, congestive heart failure, constipation, dermatitis, dermatologic, diarrhea, dyspnea, 
edema/weight gain, fever, gastrointestinal, genitourinary, granulocytopenia, headache, hepatic, 
hyperbilirubinemia, hyperglycemia, hypokalemia, hyponatremia, infection, leg weakness, lymphedema, 
lymphocytopenia, myocardial infarction, neurotoxicity, neutropenia, pain (abdominal, back, eye, site not 
specified), pulmonary, pulmonary embolus from inferior vena cava tumor thrombus, sepsis and pneumonia 
without neutropenia, syncope, and urinary frequency. The absence of a Placebo-control group in bryostatin 
oncology studies makes it difficult to determine the extent to which underlying disease or concomitant 
medications may have contributed to this safety profile. 
       
As a single agent and in combination with chemotherapeutic agents, bryostatin’s outcomes were not 
very compelling; consequently, on August 19, 2011, in its Annual Report to FDA, the NCI indicated that it 
chose not to pursue further studies and requested that its IND be withdrawn.  
 
 
 

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3.2 Alzheimer’s Disease Data 
 
3.2.1 Study NTRP101-204 
This multicenter, double-blind, parallel-group, placebo-controlled, randomized clinical study was 
designed to evaluate bryostatin versus placebo for subjects with moderate and moderately severe (MMSE-2 
score of 10 to 18, inclusive) AD in subjects who were not receiving memantine treatment. The study 
included a Screening period (approximately 4 weeks), 2 treatment periods, and a safety follow-up visit 
30 days after the final dose of study drug. The first treatment period of the study was 15 weeks in duration 
(11 weeks of dosing with study drug plus follow-up with safety and efficacy evaluation 30 days after the last 
treatment). One hundred twenty-two eligible subjects were stratified based on Severe Impairment Battery 
(SIB) total scores at Baseline and were randomized 1:1 to treatment with bryostatin 20 μg or placebo for 
2 identical courses of treatment. Study drug was administered by intravenous infusion over 45 minutes (±5 
minutes). The first 2 doses of study drug were a loading dose 20% higher (i.e., 24 μg) than the assigned dose 
and were administered 1 week apart. Thereafter, the assigned dose of 20 μg was commenced with the third 
dose and administered every other week for 5 doses. The second treatment period, beginning at Week 15, 
was identical to the first, including the loading doses. Assessments performed during visits included the 
SIB, the Mini Mental State Examination (Second Edition; MMSE-2), Alzheimer’s Disease Cooperative 
Study - Activities of Daily Living - Severe Impairment Version (ADCS-ADL-Sev), Neuropsychiatric 
Inventory (NPI), Columbia Suicide Severity Rating Scale (C-SSRS), laboratory testing, electrocardiograms 
(ECGs), physical examinations, and vital signs. Findings are as follows: 
 
• Bryostatin was generally well tolerated, and there were no new safety findings. The overall treatment-
emergent adverse event (TEAE) profile was similar between the placebo and bryostatin groups. A similar 
number of subjects had treatment-related TEAEs in the placebo and bryostatin groups (13 events in 
8 [13.8%] subjects and 15 events in 10 [16.9%] subjects, respectively). Most TEAEs were not considered 
treatment related. There were no treatment-emergent adverse events of special interest (e.g., myalgia) and no 
fatal TEAEs. 
• The primary efficacy endpoint of the study was not met; the LS mean difference in change from Baseline in 
SIB total score for bryostatin versus placebo was not statistically significant at Week 28 (0.8 [95% CI: -1.9, 
3.6]; P = 0.563). Sensitivity and supportive analyses were broadly consistent with the primary efficacy 
endpoint analysis. 
• A subgroup of subjects with moderately severe AD may derive some benefit from treatment with bryostatin. 
Statistically significant differences in change from Baseline in SIB total score were noted for bryostatin versus 
placebo in the subgroup of subjects with Baseline MMSE-2 score of 10 to 14 at Week 20 (LS mean difference: 
5.7 [95% CI: 0.5, 11.0]; P = 0.033), Week 24 (LS mean difference: 6.6 [95% CI: 0.5, 12.7]; P = 0.036), and 
Week 30 (LS mean difference: 7.9 [95% CI: 0.3, 15.5]; P = 0.042).  
 
Exploratory analyses that referenced additional SIB endpoints specified in the clinical study protocol 
provided additional support for the potential benefit of bryostatin in the cohort of subjects with Baseline 
MMSE-2 score of 10 to 14; there is consistent and significant divergence of the bryostatin group from 
placebo when the mean change from Baseline in SIB total scores at time points from Week 13 through 
Week 42 is considered. These differences are further reinforced by the exploratory trend analysis showing a 
significant downward trend for the placebo group (P <0.001) and the absence of such a trend for the 
bryostatin group (P >0.05). 
 
3.2.2 Study NTRP-101-203  
NTRP-101-203 was a randomized, double-blind, placebo-controlled, Phase 2 trial that compared 
bryostatin to placebo for the treatment of moderately severe to severe AD in participants not receiving 
memantine treatment. The study was 15 weeks in duration, including a safety and efficacy evaluation at 30 

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days after the last dose of study drug. Seven fixed doses of the study drug (20 μg) and placebo control were 
administered by a 45-minute continuous IV infusion over 12 weeks. The primary efficacy endpoint was 
defined as the change from baseline to Week 13 in the SIB total score. 
 
Methodology 
Eligible participants were stratified based on MMSE-2 scores 4-9 and 10-15. Stratified participants were 
randomized 1:1 to one of two treatment arms, 20 µg bryostatin or placebo, for 12 weeks (7 doses). Trial 
drug was administered IV by continuous infusion. The first two doses (24 μg) for the active treatment arm 
were loading doses (20% higher than the assigned dose of 20 μg) and were administered one week apart. 
Thereafter, the assigned dose (20 µg) commenced with the third dose and was administered every other 
week. Participants were scheduled to receive 7 doses over 12 weeks, with the primary efficacy measure 
being at Week 13, and a follow-up visit scheduled 30 days from the last dose of trial drug administration. 
 
Demographics 
A total of 111 participants were screened and randomized on a 1:1:1 basis to a treatment group. Of 
those, 3 participants withdrew prior to receiving treatment. 
 
Safety 
A total of 108 participants were analyzed (53 receiving 20 µg bryostatin, 55 receiving placebo). In the 
study there was 1 death, in the placebo arm. SAEs were fairly equivalent across arms with 3 occurring in the 
bryostatin arm (9.43%) and 6 in the placebo arm (10.91%). SAEs included gastrointestinal (GI) disorders (1 
bryostatin), death (1 placebo, cause unknown), infections and infestations (1 bryostatin, 2 placebo), injury, 
poisoning and procedural complications (2 bryostatin, 1 placebo), neoplasms benign/malignant/unspecified 
(1 placebo), nervous system disorders (1 bryostatin), psychiatric disorders (3 placebo), and renal and urinary 
disorders (1 bryostatin). Non-serious AEs were more common in the bryostatin arm (16; 30.19%) than in the 
placebo arm (4; 7.27%). Common AEs included urinary tract infections (3 bryostatin, 2 placebo), falls/skin 
abrasions (7 bryostatin, 1 placebo), and agitation (6 bryostatin, 1 placebo). 
 
Efficacy 
The efficacy of treatment, as specified in the trial, was evaluated primarily using SIB score at baseline 
compared to the final readout at Week 13. Lower scores indicate greater cognitive impairment. There was 
no difference in the modulation of SIB score in subjects treated with bryostatin or placebo. The primary 
efficacy endpoint for the change in SIB over the 13-week treatment period was not significantly different 
from placebo at Week 13. The observation of lack of benefit in SIB score was observed in both the full 
analysis set, the completer analysis set and multiple imputations set. SIB improvement was significant for 
the Week 9 measurement.  
 
There were two secondary efficacy outcomes specified in the trial. One was change in performance in 
the SIB over time, in which lower scores indicate greater cognitive impairment. For this outcome, 
differences were noted between the bryostatin and placebo groups. The placebo group out-performed the 
bryostatin group at Weeks 5 (0.7 placebo vs -0.1 bryostatin) and 15 (2.1 placebo vs 1.6 bryostatin) and the 
bryostatin group out-performed the placebo group at Week 9 (2.7 bryostatin vs 1.4 placebo). The second 
efficacy outcome was performance on the MMSE at specific timepoints, lower scores indicate greater 
cognitive impairment. Only 18 participants from each group were administered the MMSE exams. At each 
timepoint, the bryostatin group was outperformed by the placebo group, except at Week 9, where the group 
scores were equivalent.  
 
Overall, the combined data did not support the efficacy of bryostatin on cognitive improvement. 
 

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Post Hoc Analysis 
SIB score, often considered a useful outcome measure in advanced stages of AD, showed that at 
baseline, subjects in the placebo group had a higher SIB score average, indicative of moderately severe 
disease. In comparison subjects in the bryostatin group had a lower average baseline SIB score, indicative of 
more severe disease. This imbalance had almost a five-point difference observed between baseline SIB 
score in the two treated populations. This suggests the SIB grouping of more severe cases in the bryostatin 
treatment group compared to the placebo control group with less severe impairment may have obscured the 
real treatment effect and efficacy benefits. In the moderate stratum, baseline SIB imbalance was less marked 
which may have contributed to the observation of SIB improvement of 4.8 SIB points by week 13 in the 
bryostatin-treated patients. For the severe stratum, the baseline imbalance was even more marked (6.1 points 
in favor of the placebo patients and no SIB improvement observed in the bryostatin treated group. Given 
this inadvertent imbalance, another statistical analysis was conducted using each patient as his (her) own 
control. In this post-hoc analysis, patients treated with bryostatin in the Moderately Severe Cohort (10 - 15) 
showed a statistically significant benefit when compared to their individual baseline Severe Impairment 
Battery (SIB) values (p<0.0076), 2-tailed t-tests.  While Placebo patients improved to a lesser degree 
(p<0.014), Trend Analyses (measurements of slopes) were significant for the bryostatin-treatment group 
patients, but not for the Placebo patients. 
 
3.2.3 Study NTRP101-202 
NTRP 101-202 was a randomized, double-blind, placebo-controlled, Phase 2 trial assessing the safety 
and tolerability (primary objective) and efficacy (secondary objective) of bryostatin in the treatment of 
moderately severe to severe AD participants. Exploratory objectives characterize the PK and 
pharmacodynamics of bryostatin in this subject population. Seven doses of study drug were administered by 
a 45-minute continuous IV infusion over 12 weeks. 
 
Methodology 
Eligible participants with moderately severe to severe AD were stratified based on MMSE-2 scores 4-9 
vs. 10-15 and randomized 1:1:1 to one of three treatment arms: 20 μg, 40 μg, or placebo for 12 weeks. Trial 
drug was administered IV by continuous infusion. The first two doses (24 µg, 48 µg) of each of the two 
active treatment arms were a loading dose, 20% higher than the assigned dose (20 µg, 40 µg), and were 
administered one week apart. Thereafter, the assigned dose commenced with the third dose and was 
administered every other week. Participants were scheduled to receive 7 doses over 12 weeks, with the 
primary efficacy measure being at Week 13, and a follow-up visit scheduled 30 days from the last dose of 
trial drug administration. 
 
Demographics 
A total of 264 participants were screened in the trial. Of these, 147 participants were randomized on a 
1:1:1 basis to a treatment group. There were 50 participants randomized to the placebo treatment group, 49 
randomized to the 20 µg bryostatin treatment group, and 48 randomized to the 40 µg bryostatin treatment 
group. A total of 141 of the randomized participants were treated with investigational product and were 
included in the Safety Analysis Set (SAS). A total of 135 participants provided a post-baseline efficacy 
assessment and were analyzed as the Full Analysis Set (FAS). A total of 113 participants out of 147 
randomized (76.9%) performed a Week 13 evaluation of the SIB and were analyzed as the Completer 
Analysis Set (CAS). A total of 106 participants in the SAS completed the trial (75.2%). A total of 35 
participants in the SAS and 29 participants in the FAS withdrew early from the trial. The most common 
reason for early withdrawal was withdrawal of consent (18 participants), followed by AE (11 participants). 
 
Safety 
Overall, the 20 µg bryostatin treatment group showed minimal differences from the placebo treatment 

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group in safety assessments. The 40 µg bryostatin treatment group had significantly greater AEs than the 
other treatment groups. There was also no clear difference in SAEs between the 20 µg bryostatin group and 
placebo treatment groups, and again the 40 µg bryostatin treatment group had significantly greater SAEs 
than the other treatment group. 
Similarly, the placebo and 20 µg group had similar numbers of TEAEs (28 events vs 30 events, 
respectively). The TEAEs observed more often in the 20 µg treatment group vs placebo were infusion site 
reaction (8 events vs 3 events in placebo) and diarrhea (5 events vs 1 event in placebo). The 40 µg treatment 
group was associated with more TEAEs than either the 20 µg or placebo treatment groups across multiple 
system organ classes (SOC). 
The most common treatment related TEAEs were grouped infusion reactions, diarrhea, headache, 
fatigue, and myalgia. Myalgia was seen in 5 participants; 4 of those participants were given the higher dose 
of bryostatin. Myalgia observed was mostly mild and managed with analgesics. There were also more 
treatment related TEAEs of diarrhea, headache, and fatigue in the higher dose bryostatin group. Both 
bryostatin treatment groups reported higher rates of infusion site TEAEs, and in particular the 40 µg 
bryostatin treatment group reported 4 events of infusion site cellulitis. 
Although IV infusion-related reactions were also reported more often in the higher dose bryostatin 
group, none were reported following WebEx-based training on IV infusion and universal precautions, 
suggesting that this AE can be prevented. The higher dose bryostatin group also reported more TEAEs of 
seizure and fall compared to the lower dose bryostatin and placebo groups. 
A total of 97 (68.8%) participants in all treatment groups reported 287 separate TEAEs. Of these, 49 
(34.8%) participants reported 107 separate treatment-related TEAEs. There were 8 (16.7%) participants 
with 20 treatment-related TEAEs in the placebo treatment group, 17 (37.0%) participants with 30 events in 
the 20 µg bryostatin treatment group, and 24 (51.1%) participants with 57 events in the 40 µg bryostatin 
treatment group. Six participants had a TEAE that lead to trial drug discontinuation, 2 in the placebo 
treatment group, 1 in the 20 µg bryostatin treatment group, and 3 in the 40 µg bryostatin treatment group. 
Overall, 43 (30.5%) participants had a TEAE that was mild in intensity, 46 (32.6%) participants had a 
TEAE that was moderate in intensity, and 8 (5.7%) participants had a TEAE that was severe in intensity. 
There was 1 death in the trial, a subject in the 40 µg bryostatin treatment group who suffered a severe TEAE 
of worsening of AD that was unrelated to the IP. 
There were 12 (8.5%) participants who had 14 treatment emergent non-fatal SAEs during the trial; 4 
participants with 4 events in the placebo treatment group, 2 participants with 2 events in the 20 µg 
bryostatin treatment group, and 6 participants with 8 SAEs in the 40 µg bryostatin treatment group. A total 
of 4 participants in the 40 µg bryostatin treatment group had 4 events that were judged as possibly or 
probably related to the IP: 3 events of cellulitis, and 1 event of seizure. 
There were no apparent differences between treatment groups in laboratory assessments over time. No 
differences were apparent between treatment groups when examining most vital signs, physical 
examinations (PEs), and ECG. However, there was a decline in weight in the bryostatin groups, which was 
more prominent in the higher dose group: 20 µg bryostatin treatment group (mean loss of -1.65±2.77 kg) 
and the 40 µg bryostatin treatment group (-2.98±2.10 kg), while there was a slight weight gain in the 
placebo treatment group (0.442±2.52 kg). Further, 5 participants in the 40 µg bryostatin treatment group had 
5 TEAEs of weight decreased, 3 of which were judged to be related to the investigational product. No 
weight related TEAEs were observed in the 20 µg bryostatin dose group. 
There were no differences between treatment groups on the Columbia Suicide Severity Rating Scale (C-
SSRS) as most participants did not have suicidal thoughts during the trial, and there were no attempts at 
suicide by any participant during the trial. 
 
Efficacy 
Baseline scores on the SIB for the FAS were similar across all treatment groups. In the FAS, the 
treatment difference between the placebo treatment group and the 20 µg bryostatin treatment group was 

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statistically significant only at Week 5 (treatment difference 3.0[0.6, 5.3], 80%CI, P=0.056). There were no 
statistically significant differences between the placebo treatment group with either the 20 µg bryostatin 
treatment group or 40 µg bryostatin treatment group at Week 9 or Week 13. Combining the bryostatin 
treatment groups and comparing with the placebo treatment group also did not produce a statistically 
significant difference at any time point. 
For the CAS, pre-specified along with FAS to assess primary and secondary endpoints, mean scores on 
the SIB followed the same pattern seen in the FAS were similar across all treatment groups. There was a 
statistically significant difference, however, between the placebo treatment group and the 20 µg bryostatin 
treatment group at Week 5 (P=0.016). However, the treatment difference at Week 13 (primary outcome 
measure) was not met with statistical significance (P=0.070). When both bryostatin treatment groups were 
pooled, there was a statistically significant difference between the placebo treatment group and pooled 
group at Week 5 (P=0.039); however, statistically significant treatment difference at Week 13 was not met 
(P=0.094). There were no statistically significant differences between the placebo treatment group and the 
40 µg bryostatin treatment group at any time point. 
In the CAS there were significant differences in the ADCS-ADL-Sev at Week 13 between the placebo 
treatment group and the 20 µg bryostatin treatment group (P=0.082), and between the placebo treatment 
group and pooled bryostatin treatment group (P=0.087). There were no statistically significant differences 
between treatment groups for the ADCS-ADL-Sev, MMSE-2, Neuropsychiatric Inventory (NPI), or Clinical 
Global Impression- Improvement Scale (CGI-I) assays for any time point in the FAS. 
In multiple exploratory analyses adjusting for covariates for the primary endpoint, there were additional 
significant differences between the placebo treatment group and bryostatin treatment groups. In a Mixed 
Model for Repeated Measures (MMRM) analysis of change from baseline in SIB total score, excluding all 
participants from sites that recruited 2 or fewer participants during the trial, there was a significant 
difference between the placebo treatment group and the 20 µg bryostatin treatment group at Week 5 
(P=0.068). There was a significant difference between the placebo treatment group and the 20 µg bryostatin 
treatment group (P=0.031), and between the placebo treatment group and the pooled bryostatin treatment 
group in an MMRM analysis of change from baseline in SIB total score at the 30-day follow up visit 
(P=0.041). When an Analysis of Covariance (ANCOVA) was performed to assess site effect on SIB, there 
was a significant difference between the placebo treatment group and 20 µg bryostatin treatment group 
(P=0.032), and between the placebo treatment group and pooled bryostatin treatment groups (P=0.049) at 
Week 5. In an ANCOVA of change from baseline in SIB total score, with use of acetylcholinesterase 
inhibitor (AChEI) or memantine at baseline as an additional covariate, at Week 5 the 20 µg bryostatin 
treatment group and pooled bryostatin treatment groups had statistically significant treatment differences 
from the placebo treatment group (P=0.024 and P=0.027, respectively). 
In multiple exploratory analyses adjusting for covariates for secondary endpoints, there were statistically 
significant differences between the placebo treatment group and the 20 µg bryostatin treatment group at 
Week 5 (P=0.062), and the placebo treatment group and pooled bryostatin treatment group at Week 5 
(P=0.041) when performing an ANCOVA of change from baseline in ADCS-ADL-Sev total score for 
participants with > median baseline ADCS-ADL-Sev total score. 
Statistically significant difference between the placebo and 40 µg bryostatin treatment groups at Week 5 
(P=0.099) in an ANCOVA of change from baseline in NPI Total score to assess site affects was not met. 
When performing an ANCOVA of change from baseline in NPI total score for participants with > median 
baseline NPI total score, there was a near statistically significant difference between the placebo treatment 
group and the 40 µg bryostatin treatment group at Week 9 (P=0.054) but not at Week 13 (P-0.096). 
No clear differences were apparent between treatment groups for participant distress on the NPI, each 
NPI subscore at baseline, or on the NPI 10-item score. 
The results for SIB score from the MSSE-2 Stratum 1 analysis show the 20 µg bryostatin treatment 
group had a more positive response than any treatment group at Week 5 and Week 9 and the 40 µg 
bryostatin treatment group had a slightly better response at Week 13. Results for SIB score in the MSSE-2 

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Stratum 2 analysis show the positive response varied across time point and treatment group. The placebo 
treatment group showed greater improvement in ADCS-ADL-Sev total score at Weeks 5 and 9 than either 
bryostatin treatment group in Stratum 1 or 2, and also at Week 13 in Stratum 2. At Week 13 in Stratum 1, 
the 20 µg bryostatin treatment group showed the best response compared to placebo or the 40 µg bryostatin 
treatment group. 
There was a significant difference in the FAS between the placebo treatment group and the 20 µg 
bryostatin treatment group (P=0.031), and between the placebo treatment group and the pooled bryostatin 
treatment group (P=0.041) in an MMRM analysis of change from baseline in SIB total score at the 30-day 
follow up visit. 
Additional post-hoc analyses were performed on the TEAE by MMSE-2 baseline strata, SIB by BSA-
adjusted Dose, ADCS-ADL-Sev by BSA-adjusted Dose, TEAE by BSA-adjusted Dose, SIB by memantine 
use, ADCS-ADL-Sev by memantine use, the NPI 10-item total score by memantine use, and administration 
site-specific TEAE. The SIB and ADCS-ADL-Sev scores also appeared to be affected by BSA-adjusted 
dose, as the lowest tertile of bryostatin dose in general had a better response to treatment than higher tertiles 
or placebo (these data were also not analyzed statistically). Participants treated with bryostatin who did not 
take memantine at baseline had significantly better improvement in SIB score compared to the placebo 
group in an MMRM analyses of SIB total score in both the CAS and FAS. Both the pooled bryostatin and 
20 µg bryostatin treatment groups had significantly better scores than the placebo treatment group at Weeks 
5, 13, and at 30-day Follow-up. Similar results (which were not statistically analyzed) were seen in the 
ADCS-ADL-Sev test and in the NPI 10-item score. 
 
Pharmacokinetics 
Mean plasma bryostatin concentrations increased approximately proportional to dose for an increase in 
dose between 20 µg and 40 µg, infused IV over 45 minutes. The median time-to-peak measure (Tmax) 
occurred at the end of the 45-min infusion. Mean peak drug concentration (Cmax) ranged from 0.563 ng/mL 
to 0.653 ng/mL after 20 µg and from 0.792 ng/mL to 1.34 ng/mL after 40 µg. Mean T1/2 ranged from 1.33 
h to 5.37 h. Mean CL was similar for both dose levels and ranged from 24.97 L/h to 28.42 L/h for Weeks 0 
and 3. The mean CL on Weeks 7 and 11 was slightly lower, ranging from 13.38 L/h to 23.91 L/h. 
Within a given dose level, the ranges of values for Cmax, AUClast, and AUCinf were consistent across 
weeks, and there was no indication of systemic accumulation of bryostatin during administration of 
bryostatin once every 2 weeks. 
 
Summary 
Bryostatin treatment was, in general, safe to use and well tolerated. 
 
The 20 µg bryostatin treatment group had similar numbers of TEAEs to the placebo treatment group 
except in injection site reactions and diarrhea. The 40 µg treatment group had more TEAEs and SAEs than 
the 20 µg or placebo treatment groups across many SOCs. 
The 40 µg dose of bryostatin was associated with more TEAEs. With a decrease in systemic CL 
especially noted with 40 µg bryostatin dosing, the higher drug exposure may further explain the increased 
number of TEAEs. The most common treatment related TEAEs were diarrhea, headache, fatigue, and 
myalgia, and all were reported in greater frequency with the 40 µg dose of bryostatin. Participants given the 
40 µg dose of bryostatin also reported more TEAEs of seizure and fall. 
The primary efficacy endpoint at Week 13 for the SIB and secondary efficacy endpoint for the ADCS-
ADL- Sev was not met in the FAS; however post hoc analyses showed statistically significantly differences 
from placebo at Weeks 5 and 13 in the CAS for the ADCS-ADL-Sev with the 20 µg dose. The 40 µg dose 
was not statistically significant from the placebo 
SIB improvement was nearly significant for the Week 5 FAS measurement (p< .056). No other primary 
or secondary endpoints were met in the FAS. 

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Multiple exploratory analyses in the FAS for covariates in the primary and secondary endpoints revealed 
additional significant differences, but these occurred predominantly at the Week 5 time point. 
 
3.2.4 Study NTRP101-201 
This was a randomized, double-blind, Placebo-controlled safety study of a single dose of bryostatin in 
participants with mild to moderate AD (MMSE: 14-26). Participants were randomized 2:1 to receive 
bryostatin 25 µg/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 PE, 
hematology including 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. 
 
Demographics 
The study enrolled nine participants, 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 participants (range, 19-24) and 22 
(range, 16-26) for the six bryostatin-treated participants. 
 
Safety 
Bryostatin treatment was safe and well tolerated. There were no deaths or SAEs reported. No 
participants had an AE leading to withdrawal during the study. There were five treatment emergent adverse 
events occurring in three participants: 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 sign. 
 
Efficacy 
The study was not powered to detect an effect. As such, there was no difference in HVLT-R delayed 
recall or the RBANS delayed figure recall at 48 hours. Additional time points of assessment for these 
measures (day 2, day 4, and day 15) did not indicate any difference between groups. Additional endpoints 
included the change from baseline in Digit Symbol Coding (DSC), and MMSE-2 at various time points. 
There was no difference in mean values between groups for these endpoints at any time point. Both the 
treatment and the placebo group showed an improvement in the MMSE-2 score most likely due to practice 
effects since the MMSE-2 was administered five times in 2 weeks. 
 
In summary, there was no clinically significant difference between the mean or mean change from 
baseline between bryostatin and placebo in the HVLT-R or MMSE-2 assessments or any other efficacy 
assessments to suggest a treatment effect after a single dose of 25 µg/m2 bryostatin. 
 
Pharmacokinetics 
The pharmacokinetics of bryostatin were assessed in 6 participants following 25 µg/m2 bryostatin 
administered as a single 1-hour IV infusion. Individual bryostatin plasma concentrations were observed to 
increase and approach steady-state within the 1-hour infusion periods, and then rapidly decrease following 
the end of the infusion. The bryostatin maximum plasma concentrations occurred at the end of the IV 

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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 participants 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. 
 
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. Time course of 
total PKCε measured in PBMC samples from six Phase IIa subjects treated with bryostatin 1. A) Expanded 
scale (0–7 h). B) Full scale (0–340 h). There was an increase in total PKCε in the bryostatin group but not in 
the placebo at 1 h after the start of infusion (bryostatin F(7.013, 21.039) = 3.026, p = 0.023; placebo 
F(10,20) = 0.75, p = 0.67, repeated measures ANOVA; p = 0.0185 at 1 h, two-tailed matched pair t-test). 
This statistically significant increase in PKCε in patients who had received a single i.v. infusion of a single-
dose (25 mcg/m2) closely tracked a statistically significant increase of bryostatin measured in the patients’ 
blood samples.29 
 
Summary 
This was the first controlled, double-blind assessment of the safety of bryostatin treatment in 
participants with AD. The study met it primary endpoint of safety and tolerability. Bryostatin appears safe 
and well tolerated in this cohort of participants with mild to moderate AD. 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. 
 
4. STUDY OBJECTIVES 
4.1 Primary Objective 
To evaluate the safety and tolerability of bryostatin for the treatment of MS. 
4.2 Exploratory Objective 
To evaluate the changes in clinical, imaging, and cognitive measures during and following treatment as 
signals of efficacy. 
 
5. INVESTIGATIONAL PLAN 
5.1 Overview of Study Design 
NTRP103-301 is a single-site, single-arm, open-label, Phase 1 study assessing the safety and tolerability 
of bryostatin in participants with MS. Exploratory outcome measures will be assessed to capture signals of 
efficacy. The study is 42 weeks in duration. Eligible participants will be treated with bryostatin for 26 
weeks. Study drug is administered IV by continuous infusion. At weeks 0, 1, 15, and 16, the dose of study 
drug will be a loading dose 20% higher (i.e., 24 µg) than the assigned fixed dose and will be administered 
one week apart. For all other weeks of treatment, the assigned fixed dose will be 20 µg and will be 
administered every other week. Participants are scheduled to receive a total of 14 doses over 26 weeks. 
Safety and exploratory assessments will be done as indicated on the Schedule of Activities (Table 1).  
5.2 Dose Rationale/Justification 
Understood to be the mechanism of action is bryostatin’s ability to modulate Protein Kinase C (PKC). 

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Factors that drastically alter the overall effects of bryostatin on PKC modulation include the length of 
exposure to bryostatin and the concentration of bryostatin used. In the NCI trials, the goal was to maximize 
the antiproliferative effects of bryostatin by causing a profound reduction of total cellular PKC, known as 
down regulation. This was accomplished by exposure to high concentrations and prolonged exposures of 
cells to the drug. In trials designed to treat neurodegenerative (e.g., AD, MS) and neurodevelopmental (e.g., 
FXS) diseases with bryostatin, the goal is to prolong the activation or the upregulation of PKC by exposure 
to low concentrations and short exposure times.  
 
The primary objective of treatment for MS with bryostatin-1 lies in its known safety profile, anti-
inflammatory, neuroprotective, re-myelination, and neurogenesis stimulatory properties (synaptogenesis, 
anti-apoptosis), and purported ability to cross the blood-brain barrier. 
 
      Safety Profile 
       
The NCI previously held an IND for bryostatin in oncology (IND 42780). Fifty-seven 
clinical trials were conducted in patients with various solid and liquid tumors under that IND. 
Approximately 1430 oncology patients have been dosed across a wide range of doses and regimens 
(5 μg/m2 to 225 μg/m2 administered as infusions ranging from 1 to 72 hours in duration).  Those studies 
established bryostatin’s maximum tolerated dose range (25-50 μg/m2) or 45-90 μg for a standard 70 kg man. 
The predominant dose-limiting toxicity observed was myalgia, which is dose dependent and cumulative, 
thus variable in severity. Symptoms generally occurred within 24-48 hours after the second or third dose but 
resolved within a week.  In the only study in pediatric oncology where 22 children with refractory solid 
tumors were treated with rising doses of bryostatin, 3/6 patients at dose-level 57μg/m2 had a Grade 3 dose-
limiting myalgia. Grade 1 or 2 myalgia was observed at all lower dose levels except the lowest dose of 20 
μg/m2. 
In the Synaptogenix NTRP101- 201 AD study, there were no reports of myalgia after a single 25 µg/m2 
infused dose of bryostatin, administered to 6/9 patients with mild AD. The only AE reported in the 
bryostatin treatment group was headache. In NTRP101-202 in which AD patients with moderately severe to 
severe AD received 7 fixed doses of infused study drug (either 20 μg or 40 μg), bryostatin treatment was 
generally safe and well-tolerated. The 20 μg bryostatin treatment group had similar numbers of TEAEs to 
the placebo group, except in injection site reactions and diarrhea. There were no clear differences in SAEs 
between the 20 μg bryostatin treatment group and the placebo treatment group. The 40 μg treatment group 
had more TEAEs and SAEs that the 20μg or placebo treatment groups across many SOC.  The most 
common treatment related TEAEs were diarrhea, headache, fatigue and myalgia – all reported in greater 
frequency with the 40 μg dose of bryostatin. There were no dose-limiting toxicities. In its NTRP101-203 
and NTRP101-204 trials, similar safety findings were observed at the 20 μg fixed infused dose compared to 
placebo in patients with moderately-severe to severe AD. Treatment with bryostatin at the loading dose of 
24 μg and the assigned dose of 20 μg was well tolerated by all subjects. One death in NTRP101-203 was 
reported during the study in the placebo group where the cause was unknown. No other doses were 
evaluated in those two studies. 
 
Efficacy 
NTRP101-201 was a safety study that evaluated a single dose of bryostatin in nine eligible subjects with 
mild to moderate AD. The study was not powered to detect an effect; consequently, the 25 μg/m2 dose did 
not show a difference in cognitive improvement when comparing bryostatin treated patients (6/9) to 
placebo-treated patients (3/9).  
NTRP101-202 examined the efficacy of 2 doses of bryostatin in subjects with moderate to severe 
AD. The primary efficacy endpoint was the change from baseline on the SIB at Week 13, and the 
secondary efficacy endpoints were the change from baseline on the ADCS-ADL-SIV, NPI, and MMSE-2 
tests at Week 13. The primary efficacy endpoint and secondary efficacy endpoint for the ADCS-ADL-SIV 

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was met in the CAS with the 20 μg fixed dose, which was statistically significantly different from placebo at 
 these time points. The 40 μg dose was not statistically significant from the placebo. No primary or 
secondary endpoints were met in the FAS. Multiple exploratory analyses in the FAS for covariates in the 
primary and secondary endpoints revealed additional significant differences that occurred 
predominantly at the Week 5 time point. 
 
In NTRP101-203 and NTRP101-204, as described above in Section 3.2.2 and 3.2.1, respectively, the 
primary efficacy endpoints were not met. Exploratory, post hoc analyses of a subgroup of subjects with 
moderately severe AD suggest that those patients may derive some improvement on an SIB score with a 
fixed dose of 20 μg bryostatin. No other dose was evaluated. 
      Bryostatin, delivered intraperitoneally (IP) at a dose of 30 μg/kg x 3 days/week, provided a noticeable 
benefit in mice with experimental autoimmune encephalomyelitis (EAE).21 A drug administered IP, is 
absorbed more slowly than intravenous (IV) absorption, as the primary route of IP absorption is into the 
mesenteric vessels which drain into the portal vein and pass through the liver where it undergoes first pass 
hepatic metabolism before reaching the systemic circulation. When 40 μg/kg bryostatin was administered 
IV and IP to mice, the Cmax was shown to be 92.94 ng/ml and 13.52 ng/ml, respectively, albeit at different 
times.43 This suggests that only 14.5 % of the administered IP dose of bryostatin reached the systemic 
circulation. Thus, in the EAE mouse model, one may surmise that only 4.35 μg/kg/30μg/kg administered 
reached the systemic circulation. That being the case, the estimated human equivalent dose (HED) is 
determined to be 0.35μg/kg.44 For a 70-kg man, the fixed dose is 24.7 μg.  
Based on the above, a fixed dose of 20 μg bryostatin will be administered to eligible MS patients with a 
primary focus on safety; however, exploratory outcome measures will be captured that represent signals of 
efficacy, such as evidence of improved cognition or remyelination. 
The introduction of a rest between doses at Week 13 stems from concern about tachyphylaxis, or a 
reduced response to bryostatin after successive doses favoring down-regulation of PKC. A drug holiday 
followed by loading doses of bryostatin should refresh the response to bryostatin administration and 
enhance possible effects on exploratory endpoints. 
5.3 Risk/Benefit 
 
It is anticipated that the risk to subjects enrolled in NTRP103-301 will be minimal, based on prior use of 
bryostatin studied in over 1500 cancer and AD patients. 
 
Participants in this study with MS will have been stable on their current DMT for at least 1 year.  
 
Participants will also be identified with mild to moderate cognitive deficits as defined by a pre-study PST26 
with a z-score falling between -1.0 and -2.5 of the normal population. 
 
As reproductive risks with bryostatin are unknown, females participating in the study must be surgically 
sterilized for at least 6 months, post-menopausal, or 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. Contraception methods resulting in an overall failure rate of <1 % per year are 
required for women of childbearing potential. 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.  
 
Sperm and egg donation are not permitted during the study and for at least 30 days after the last dose of 
study treatment. 
 

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The potential anti-inflammatory, neuroprotective, re-myelinating, and neurogenesis stimulatory 
(synaptogenic, anti-apoptotic) properties, and the positive safety profile observed in adult patients with AD 
suggest that the potential clinical benefits of treatment with bryostatin at the proposed fixed dose of 20 μg in 
the protocol outweigh the risks.  
 
5.4 Study Endpoints 
Safety Assessments 
Safety and Tolerability Primary Outcomes 
• Frequency of Adverse Events [Treatment Emergent AEs (TEAEs), Serious Adverse Events (SAEs), 
and Suspected Unexpected Serious Adverse Reactions (SUSARS)] 
• Frequency of study medication discontinuation and reason thereof  
• 
Potential CNS inflammatory effects as captured by clinical monitoring and MRI  
 
Exploratory Outcomes 
Changes from baseline to Week 11, Week 28, and Week 40 in the following: 
• 
MRI biomarkers   
- lesion volume and brain parenchymal fraction 
- default mode network node connectivity 
- diffusion MRI measures of tissue integrity 
- anatomical connectivity of transcallosal motor pathway 
- myelin water fraction 
- measures of myelination derived from magnetization transfer ratio, quantitative T2* and quantitative 
susceptibility mapping 
- grey matter atrophy, including grey matter fraction, white matter fraction, and cortical atrophy as measured 
by CLADA 
• 
Expanded Disability Status Scale (EDSS) 
• 
Montreal Cognitive Assessment (MoCA) test 
• 
Controlled Oral Word Association Test (COWAT) 
• 
MS Performance Test Domains 
- lower extremity function 
- upper extremity function 
- cognition 
• 
Quality of Life in Neurological Disorders (Neuro-QoL) 
 
Change from baseline to Week 28 and Week 40 in the following: 
• 
California Verbal Learning Test- 3rd Edition (CVLT 3) 
• 
Brief Visuospatial Memory Test - Revised (BVMT-R) 
• 
Judgement of Line Orientation (JOLO) 
• 
Boston Naming Test (BNT) 
• 
Delis–Kaplan Executive Function System (D-KEFS) Sorting Test 
 
 The time-course of changes will be assessed for those outcomes with more frequent assessments (i.e. 
COWAT, MoCA, and MSPT) 
5.5 Study Population – Eligibility Requirements 
Participants with MS are eligible to enroll. Participant will be permitted to continue current DMTs, as long 
as they have been stable for 1 year and a change in DMT is not anticipated over the course of this study, but 

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no new treatments can be initiated unless clinically necessary due to safety concerns or significant change in 
the participant's status.  
 
Inclusion 
1. Written informed consent signed by participant 
2. English-speaking 
3. Hospital Anxiety and Depression Scale <11 
4. Male and female participants, 18-65 years of age inclusive 
5. Established diagnosis of MS, as defined by the 2017 revision of McDonald Diagnostic Criteria (any form 
of MS).14 A diagnosis of MS must be confirmed at the time of the screening visit. 
6. Processing Speed Test (PST) z-score between -1.0 and -2.527  
7. EDSS between 0.0 and 7.0, inclusive 
8. Adequate vision and motor function to participate in assessment procedures 
9. Participants must be off of a DMT or on a stable dose of a DMT for at least 1 year prior to entry into the 
study, and the dose should not change during the study unless a change is required by a clinically 
significant change in the participant’s status. 
10. 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. Contraception methods resulting in an overall failure rate of <1 % per year 
are required for women of childbearing potential. 
11. 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 
12. Participants should be in reasonably good health over the last 6 months and any chronic disease should 
be stable. 
 
Exclusion 
1. Evidence of significant CNS vascular disease on previous neuroimaging, including but not limited to 
cortical stroke, multiple infarcts, localized single infarcts in the thalamus, angular gyrus, multiple lacunar 
infarcts, or extensive white matter injury 
2. Clinically significant neurologic disease or condition other than MS, 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 
3. Previous history of seizures or seizure disorders 
4. Evidence of clinically significant unstable cardiovascular, pulmonary, renal, hepatic, gastrointestinal, 
neurologic, or metabolic disease within the 6 months prior to enrollment. If there is a history of cancer, 
the participant should be clear of cancer for at least 2 years prior to screening. More recent history of 
basal cell or squamous cell carcinoma and melanoma in situ (Stage 0) may be acceptable after review by 
the Medical Monitor. 
5. Estimated Glomerular Filtration Rate (eGFR) 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 screening43  
8. Use of valproic acid and/or lithium within 14 days prior to screening 
9. Use of carbamazepine within 7 days prior to screening  
10. Use of teriflunomide within 90 days prior to screening  

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11. Use of dalfampridine within 7 days of screening.  
12. Current use of acetaminophen, ciprofloxacin, and/or trimethoprim/sulfamethoxazole 
13. Use of any potent or moderate, inhibitor or inducer, of CYP3A4, CYP2C8, or CYP2C9. Concomitant 
medicines will be examined on a case by case basis against the Flockhart Table by Sponsor-Investigator, 
and if needed, the Medical Monitor, to determine allowability 
14. Current use of St. John’s Wort, within 2 weeks prior to screening 
15. Consumption of grapefruit juice from screening until end of study 
16. At the discretion of the PI, any medical or psychiatric condition that is unstable or may require the 
initiation of additional medication or surgical intervention during the course of the study 
17. Any screening laboratory values outside the laboratory reference ranges that are deemed clinically 
significant by the PI 
18. Use of an investigational drug within 30 days prior to screening 
19. Suicidality defined as active suicidal thoughts during the 6 months prior to screening or at Baseline 
[SBQ-R], or history of suicide attempt in previous 2 years, or at serious suicide risk in PI’s judgment 
20. Major psychiatric illness such as currently uncontrolled major depression according to Diagnostic and 
Statistical Manual of Mental Disorders, 5th Edition 45, 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 
21. Diagnosis of alcohol or drug abuse within the last 2 years 
22. History of prolonged QT or prolonged QT on screening ECG [QT correction with Bazett formula 
(QTcB) or QT correction by Fridericia (QTcF)>499 per central reader]46  
23. 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] 
24. Known to be seropositive for Hepatitis B or C, unless successful curative treatment for Hepatitis C (e.g., 
Harvoni) has been received, and there is documentation that there is no Hepatitis B/C virus detected 3 
months after completion of treatment 
25. Known to be seropositive for human immunodeficiency virus (HIV) 
26. Pregnancy or breastfeeding during the study. A β-hCG serum pregnancy test will be performed at 
Screening for female patients of child-bearing potential.  
27. Aspartate Amino Transferase (AST) or Alanine Aminotransferase (ALT) >3x upper limit of normal 
(ULN) and total bilirubin >2x ULN or International Normalized Ratio (INR) >1.5 
28. History of significant bleeding disorders 
29. Moderate baseline thrombocytopenia (platelets <100K/uL) 
30. Elevated INR (>2.0) 
31. Prior exposure to bryostatin, or known sensitivity to bryostatin or any ingredient in the study drug 
32. Any other concurrent medical condition, which in the opinion of the PI makes the participant unsuitable 
for the clinical study 
 
6.0. PRODUCTS USED IN THIS STUDY 
Active study drug, bryostatin, will be provided as described below. 
6.1 Bryostatin 
The investigational drug product, bryostatin for Infusion, 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 0.025 mg bryostatin, 2.5 mg povidone lyophilized from 40% t-butanol. Accompanying each vial 
of bryostatin will be a 10 mL vial containing 2 mL of sterile PET diluent [60% v/v polyethylene glycol 400, 
30% v/v dehydrated ethyl alcohol, and 10% v/v Tween-80 (polysorbate 80)] for reconstitution of the 
lyophilized bryostatin for Infusion.  

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6.2 Packaging and Labeling of Study Drug 
Vials of bryostatin for Infusion and vials of PET diluent will be batch shipped to the site.  
 
Study drug vials will be labeled in English according to US FDA’s current Good Manufacturing Practice 
(GMP) and local regulations. 
 
Bryostatin for Injection vial label will contain the following information:  
1. Bryostatin for Infusion  
2. Lot # XXXXX 
3. Store refrigerated at 2-8°C 
4. Caution New Drug - - Limited by Federal Law (US) to Investigational use. 
5. Each vial contains 0.025 mg bryostatin and 2.5 mg povidone C-17. Contains no antibacterial 
preservatives 
6. Reconstitute with 1 mL PET Diluent. Swirl to dissolve.  
7. Further dilute with 9 mL sodium chloride for injection 
8. Manufactured for Synaptogenix by Lyophilization Technology, Inc.  
 
PET Diluent vial label will contain the following information: 
1. PET Diluent for Reconstitution of bryostatin for Infusion 
2. Lot #: XXXX 
3. Volume: 2 mL 
4. Caution New Drug - - Limited by Federal Law (US) to Investigational use 
5. Contains Polyethylene Glycol 400 (60%), dehydrated Ethyl Alcohol (30%) and Polysorbate 80 
(10%). 
6. For Single Use Only 
7. Manufactured for Synaptogenix by Lyophilization Technology, Inc. 
6.3 Storage and Preparation of Study Drug 
The study drug will be stored under refrigeration (2-8°C), in a refrigerator that is securely locked and 
continuously temperature monitored. Access to the stored study drug will be restricted to the investigational 
site pharmacy or designated staff member. 
 
Study drug will be prepared and dispensed for administration by a qualified member of site pharmacy 
staff. This individual will be responsible for reconstitution, dilution, and preparation of study drug. The 
investigational drug is to be administered only according to the conditions of this protocol. 
 
Study drug will be administered by the study PI or his/her designees. Study drug should be allowed to 
come to room temperature prior to administration. The study drug contains no antibacterial preservatives 
and must be used within 8 hours of reconstitution. Study drug should be reconstituted with 1 mL of PET 
diluent. After swirling the 10 mL 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 (a 9.6 mL loading dose for the first two 
doses and an 8.0 mL maintenance dose for the remaining 5 doses) should then be added to an IV infusion 
bag containing 50 mL of NS. Once the infusion bag is filled with the assigned dose, the 45±5 minute 
continuous infusion must be completed within 3 hours of the IV infusion bag fill. 
 
The infusion system (IV infusion bag and tubing) should be made of a polyolefin plastic, such as 
polypropylene or polyethylene, or a combination of both. The use of polyvinylchloride (PVC) plastic bags 
and tubing is NOT to be used as plasticizer from the PVC is leached, and there is absorption of bryostatin to 

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PVC plastics. 
 
The prepared infusion bag containing study drug should be labeled with the following information:  
1. Protocol number 
2. Participant number Date and time prepared 
3. Instructions for dosing (e.g., entire contents of IV infusion bag infused within 45 ±5 minutes) 
6.4 Study Drug Accountability and Disposal 
Neither the Investigational Pharmacy, designated drug preparer, the PI, nor any of his/her designees may 
provide drug to any person not enrolled in this study. Adequate records of study drug receipt and use must 
be maintained in order to comply with governmental regulations and with the protocol in addition to 
preventing unauthorized distribution. 
Study drug orders, records of receipts, dispensing records, and inventory forms will be examined and 
reconciled throughout the study. All study drug that is used during the course of the study must be 
accounted for on a drug accountability form. 
Unless otherwise directed at the end of the study all unused study medication must be destroyed onsite 
following the site’s specific standard operating procedures (SOPs) after drug accountability has been 
verified by the monitor. If destruction on site is not possible, study medication should be retained and 
returned to the drug vendor 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.  
6.5 Blinding 
The study is open-label. 
6.6 Study Drug Administration 
Study drug is scheduled to be administered by continuous intravenous infusion only, via a pump, at the 
same rate over 45 minutes (±5 min) once a week for 2 weeks and then every 14 days ±2 days thereafter. The 
entire volume of study drug in the infusion bag is to be administered. Infusion times should not be extended 
or shortened. If a participant misses a dose, the dose should be administered as soon as possible.  The 
participant should then continue on the original dosing schedule. 
Bryostatin absorbs PVC plastics. Infusion bags and sets (e.g., tubing) used in the delivery of the study 
drug must be made of a polyolefin plastic, such as polyethylene or polypropylene or a combination of both.  
 
7. STUDY PROCEDURES AND ASSESSMENTS 
All participants will be treated with the study drug bryostatin 1. A follow-up visit will take place 30 days 
after the last full assessment (Week 28) for all participants, including participants that have discontinued 
treatment before completion of the study. Assessments will be performed according to the Schedule of 
Activities (Table 1). 
7.1 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 participant. When a protocol required test cannot be performed, the 
PI will document the reason for the missed test and any corrective and preventative actions 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. 
 

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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 SBQ-R, 
clinical chemistry, hematology, coagulation lab tests, and MRI. 
 
Laboratory 
Blood samples will be obtained for routine laboratory tests, if indicated as outlined in the Schedule of 
Activities (Table 1). Laboratory tests will be run at the Cleveland Clinic Laboratories and processed 
routinely. Lab normal will be listed with results at the time of the report.  
 
Hematology tests will include CBC with differential, platelet count and coagulation (prothrombin time 
(PT) and partial thromboplastin time (PTT)) studies. 
 
Clinical chemistry tests will include comprehensive metabolic panel (sodium, potassium, chloride, blood 
urea nitrogen (BUN), creatinine, estimated glomerular filtration rate (eGFR), glucose, calcium, CO2, 
total protein, albumin, ALT, and AST). 
 
Screening blood tests will include hematology, clinical chemistry, βhCG serum pregnancy for females 
of child-bearing potential, TSH, B12, creatinine phosphokinase (CK), gamma glutamyl transferase 
(GGT), lactate dehydrogenase (LDH), uric acid, and bilirubin. 
 
Routine laboratory tests after screening will include Hematology, Clinical Chemistry, GGT, LDH, uric 
acid, and bilirubin. Additionally, serum samples will be collected at screening, Week 11, and Week 28 
for future biomarker analysis. 
 
Urine pregnancy tests will be performed prior to study drug administration at Day 0, Day 21, Day 49, 
Day 105, Day 126, Day 154, and Day 182. If pregnancy test is positive, study drug will not be 
administered.  
 
In order to monitor for weight loss potentially related to study drug, weight will be monitored at 
screening and on Day 35, Day 77, Day 140, and Day 196. If at any time a clinically significant weight 
loss is observed, study drug will be permanently discontinued. A clinically significant weight loss is 
defined as a loss of more than 5% of usual body weight.  
 
In the event of any reported myalgia, additional serum CK and B12 tests will be performed.   
 
Some non-clinical data described in the Investigator’s Brochure suggest a potential risk of bleeding 
associated with bryostatin. Therefore, at study visits, participants will be evaluated for clinical signs and 
symptoms of bleeding. If evidence of increased and/or unexpected bleeding is noted, the Principal 
Investigator will be contacted for further evaluation of the participant and possible study 
discontinuation.  
 
Physical Examination 
All PEs must be performed by the PI or qualified designee (physician, physician’s assistant, or nurse 
practitioner). The complete PE conducted during the screening period and at designated subsequent time 
points should include, but is not limited to the following: 
1. General appearance 
2. Weight 
3. Height (screening only) 

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4. Ears 
5. Eyes 
6. Nose 
7. Throat 
8. Neck 
9. Respiratory system 
10. Cardiovascular system 
11. Abdomen 
12. Musculoskeletal /Neurologic 
13. Extremities 
14. Skin 
15. Lymph nodes 
 
Examination of other systems as needed to explore reports of AEs should be conducted as needed by the 
PI, or designee. Any clinically significant physical findings that were not present on the initial PE will 
be considered AEs and documented on the AE electronic case report form (eCRF), as well as in the 
participant’s source documentation and on the physical examination eCRFs. 
 
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 (Table 1). Vital signs will include: blood pressure, heartrate, and 
temperature. 
 
Electrocardiogram 
A 12-lead ECG will be collected at screening and at time points specified in the Schedule of Activities. 
 
Suicide Behaviors Questionnaire Revised (SBQ-R) 
The 4-item SBQ-R is a measure of past suicidal thoughts and attempts, which have proved to be 
significant predictors of future suicidality.47 The items ask if the respondent has ever thought about or 
attempted suicide, how frequent was suicidal thoughts in the past year, have they told someone about 
such thoughts, and what is the likelihood of attempting suicide in the future. 
Suicide Behaviors Questionnaire-Revised (SBQ-R) scale will be obtained and reviewed at each study 
visit and for any participant with SBQ-R score ≥7, the study neurologist will be notified to immediately 
assess and manage suicidality. 
Magnetic Resonance Imaging (MRI) 
Potential pro-inflammatory effects will be evaluated through the presence of abnormal post-Gd T1 
enhancement. A clinical read of all scans will be performed by a board-certified neuroradiologist and 
results recorded. 
 
Exploratory Efficacy Assessments 
Magnetic Resonance Imaging (MRI) 
Participants will be scanned on a 7T scanner (Terra; SIEMENS) as follows: 
• MRI will include the following:  
o Prescans (localizer, etc.) 
o T1-weighted (MP2RAGE) 
o Fluid-Attenuated Inversion Recovery (FLAIR) 
o Resting State-Functional MRI (rs-fMRI) 

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o Diffusion Tensor Imaging (DTI) 
o Visualization of Short Transverse (ViSTa) 
o Magnetization Transfer Ratio (MTR) 
o Multi-echo gradient recalled echo (mGRE) 
o T1-weighted post-gadolinium (MP2RAGE) 
• T1-weighted and FLAIR imaging will be used for volumetric measures and lesion measures.  
• rs-fMRI will be used to assess inter-node functional connectivity within the default mode 
network including a reverse phase encode scan to correct for image distortion.  
• DTI will be used to assess tissue integrity.48 This scan is combined with rs-fMRI to derive the 
Structural and Functional Connectivity Index (SFCI).49  
• ViSTa is a novel approach to measuring myelin water fraction that can be performed across the 
entire brain quickly and without the numerical instability associated with alternative methods 
like multi-echo imaging or multicomponent driven equilibrium single pulse observation of T1 
and T2 (mcDESPOT).50 ViSTa will provide measures of myelin water fraction in normal-
appearing white matter and in white matter lesions.  
• MTR will provide measures of myelination in normal-appearing white matter and in white 
matter lesions and has been adapted for 7T imaging.51  
• Multi-echo gradient recalled echo (mGRE) is a single imaging acquisition that can be analyzed 
to generate maps of quantitative T2* (qT2*) and quantitative susceptibility maps (QSM). qT2* 
has been found correlate with myelination.52 QSM has been found to correlate with myelination 
and with iron.53 The sensitivity of the mGRE sequence to iron makes it a candidate for 
identifying paramagnetic rim lesions.54 The mGRE acquisition can also be used to generate 
susceptibility-weighted imaging (SWI) for detection of paramagnetic rim lesions.55 
• Grey matter atrophy assesses the specific impact of treatment on grey matter structures. In this 
study, this will include grey matter atrophy, including grey matter fraction, white matter fraction, 
and cortical atrophy as measured by CLADA  
 
Expanded Disability Status Scale (EDSS): The EDSS was developed to quantify disability based on the 
neurological exam, ambulatory capacity, and ability to carry out activities of daily living.56 The scale 
takes into account a wide range of neurological functions relevant to MS. The EDSS has several 
advantages. It is accepted by regulators for disability measurement. It is familiar to MS clinicians and 
allows comparison of participants on a 0-10 scale. However, several limitations to the EDSS have been 
widely discussed.57 The scale is an ordinal measure, where changes between scores at different points 
are not necessarily of the same clinical meaning. Despite these limitations, the EDSS remains a widely 
used measure in clinical trials, MS registries, and clinical practice.  
 
Quality of Life in Neurological Disorders (Neuro-QoL): The Neuro-QoL assessment is a survey 
consisting of a series of “life item banks” related to different domains which affect an individual’s 
quality of life.58 Answers given to series of questions within each domain determine a numerical score 
indicating the level of functioning for that individual at that time. A computer adapted version was 
developed and assessed in an MS population and was shown to provide similar results as the full 
battery.59  
 
Short Cognitive Battery and Performance Test: 
• Montreal Cognitive Assessment (MoCA) – MoCA is a brief, 30-question assessment of cognitive 
impairments for detecting early AD, measuring executive functions, and multiple cognitive 
domains which are important components not measured by the MMSE.60 
• Controlled Oral Word Association Test (COWAT) – The COWAT consists of three word 

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conditions. The participants’ task is to produce as many words as he can that begin with the given 
letter (C, F, or L;P, R, or W) within a 1-min time period. The COWAT and other measures of verbal 
fluency have proven to be sensitive indicators of frontal lobe dysfunction.61 
• 
Multiple Sclerosis Performance Test (MSPT) – The MSPT was developed as an iPAD based version 
of the Multiple Sclerosis Functional Composite (MSFC),62 which allows administration to take 
place independently, without the use of a study coordinator. The MSFC is an alternative approach 
to address some of the shortcomings of the EDSS.63 The MSFC is based on quantitative 
neuroperformance tasks that were selected after extensive analysis of a collection of clinical 
datasets. The original MSFC was manually administered by trained personnel and contained the 
following three domains: lower extremity function [timed 25-foot walk (T25FW)], upper extremity 
function [9-hole Peg Test (9HPT)], and cognition [Paced Auditory Serial Addition Test (PASAT)]. 
Psychometrically, the measurement is favorable as each domain yields a single continuous score of 
function relevant to MS. Although practice effects can occur, these can be mitigated with pre-
baseline run-in testing. The MSPT adapted the key elements of the MSFC into an electronic 
format. In the current version of the MSPT, the Walking Speed Test (WST) replaces the T25FW, 
the Manual Dexterity Test (MDT) replaces the 9-HPT, the Processing Speed Test (PST) replaces 
the PASAT. A vision measure – the Low-contrast Letter Acuity (LCLA) test – has been added, to 
form a 4-domain measure of neurologic function relevant to MS, but will not be utilized in this 
trial. The MSPT has been validated for use in the MS population.64  
 
Extensive Cognitive Battery: 
• California Verbal Learning Test- 3rd Edition (CVLT 3) – is a comprehensive, detailed assessment 
of verbal learning and memory deficits.65 
• Brief Visuospatial Memory Test - Revised (BVMT-R)- The BVMT-R assesses visuospatial 
learning and memory abilities in research and clinical settings.66 
• Judgement of Line Orientation (JOLO) – JOLO is a widely used measure of visuospatial 
judgment that measures accuracy of angular orientation based on judgments about a pair of 
angled lines that visually match an identical pair immersed within a semicircular array of 11 
lines.67 
• Boston Naming Test (BNT)– BNT is a test of word retrieval used to evaluate aphasia. Drawings of 
objects are presented, and the participant provides the name of each object.68 
• 
Delis–Kaplan Executive Function System (D-KEFS) Sorting Test– The Sorting Test explores 
executive abilities by measuring concept-formation skills, modality-specific problem-solving skills 
(verbal/nonverbal), and the ability to explain sorting concepts abstractly.69 
7.2 Visit Procedures 
Screening (Days -28 to -2) 
In order to avoid unnecessary screen failures, a prescreening telephone call to rule out clearly 
exclusionary conditions is advised prior to scheduling a screening visit. Informed Consent must be 
obtained before any study related procedures are performed. Screening procedures will take place within 
an approximate 4-week period prior to first dose administration (Days -28 to -2). 
Participants who are screen-failed (e.g., due to clinically significant laboratory abnormality or an 
active medical condition) may be re-screened if the laboratory abnormality or medical condition 
stabilizes or improves as assessed by the PI. The Study Administration should be consulted prior to re-
screening. Participants who are Screen Failures may be rescreened only once. 
 
 
 
 

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The following procedures should be performed first to avoid unnecessary procedures for ineligible 
participants: 
Study Nurse: 
• Informed Consent 
• Collection of participant demographic data 
• Review of concomitant medications 
• Review of medical history 
• Lab- Blood samples for initial Safety Monitoring 
• Biobank samples  
• Vital signs 
• Weight 
 
Study Coordinator:  
• ECG 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
• Neuro-QoL 
• Schedule MRI 
• Hospital Anxiety and Disability Scale 
 
Study Neurologist: 
• EDSS 
• Complete PE 
 
Neuropsychologist: 
• Extensive Cognitive Battery 
 
If changes in the participant’s health or mental status occur during the screening period, including 
changes in medication affecting the mental status, the Study Administration should be notified. The 
Study Administration will advise the PI regarding any assessments that should be repeated to ensure 
eligibility requirements are met.  
 
At weeks 0, 1, 15, and 16, the dose of study drug will be a loading dose 20% higher (i.e., 24 µg/m2) than 
the assigned dose and will be administered one week apart. For all other weeks of treatment, except for 
Week 13 when no dose is administered, the assigned dose will be 20 µg/m2 and will be administered 
every other week. 
 
Week 0 (Day 0/Dose 1) (Bryostatin loading Dose, 24 µg) 
A final assessment of the inclusion/exclusion criteria, including any changes in medications or health 
status will be done before dosing to confirm the participant’s eligibility. 
The following procedures will be done on Day 0: 
Study Nurse: 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration 
• 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 
• AEs 

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• Concomitant medications 
 
Week 1 (Day 7 ±3 days/Dose 2) (Bryostatin loading Dose, 24 µg) 
One week after the first dose of study drug, participants will return for a second infusion. The following 
procedures will be performed: 
Study Nurse: 
• 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  
• Concomitant medications 
 
Week 3 (Day 21 ±3 days/ Dose 3) (Bryostatin Dose, 20 µg) 
Study Nurse: 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• Vital signs prior to infusion, then at 30 (±5), 60 (±5), and 90 (±5) minutes from start of the 
infusion  
• Routine Labs 
• Dosing by IV infusion 
• AEs 
• Concomitant medications 
 
Study Coordinator: 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
 
Week 5 (Day 35 ±3 days/ Dose 4) (Bryostatin Dose, 20 µg) 
Study Nurse: 
• Vital signs prior to infusion, then at 30(±5), 60(±5), and 90(±5) minutes from start of the 
infusion 
• Dosing by IV infusion 
• Weight 
• AEs 
• Concomitant medications 
 
Study Neurologist: 
• PE 
 
Week 7 (Day 49 ±3 days/ Dose 5) (Bryostatin Dose, 20 µg) 
Study Nurse: 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• 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 
• Concomitant medications 
 

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Study Coordinator: 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
 
Week 9 (Day 63 ±3 days/ Dose 6) (Bryostatin Dose, 20 µg) 
Study Nurse: 
• 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 
• Concomitant medications 
 
Week 11 (Day 77±2 days/ Dose 7) (Bryostatin Dose, 20 µg) 
Prior to dosing: 
Study Nurse: 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• Routine Labs 
• Weight 
• Biobank sample 
• Vital signs prior to infusion, then at 30(±5), 60(±5), and 90(±5) minutes from start of the 
infusion 
 
Study Coordinator: 
• ECG 
 
After dosing: 
Study Nurse: 
• AEs 
• Concomitant medications 
 
Study Neurologist: 
• PE 
• EDSS 
 
Study Coordinator: 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
• Neuro-QoL 
• Schedule MRI 
 
Week 13 (Day 91) No clinical visit 
 
Week 15 (Day 105 ±3 days/ Dose 8) (Bryostatin loading Dose, 24 µg) 
Study Nurse: 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• Vital signs prior to infusion, then at 30(±5), 60(±5), and 90(±5) minutes from start of the 
infusion 

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• Dosing by IV infusion 
• AEs 
• Concomitant medications 
 
Week 16 (Day 112 ±3 days/Dose 9) (Bryostatin loading Dose, 24 µg) 
Study Nurse: 
• 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 
• Concomitant medications 
 
Study Coordinator: 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
 
Week 18 (Day 126 ±3 days/Dose 10) (Bryostatin Dose, 20 µg) 
Study Nurse: 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• Vital signs prior to infusion, then at 30(±5), 60(±5), and 90(±5) minutes from start of the 
infusion 
• Routine Labs 
• Dosing by IV infusion 
• AEs 
• Concomitant medications 
 
Week 20 (Day 140 ±3 days/Dose 11) (Bryostatin Dose, 20 µg) 
Study Nurse: 
• Vital signs prior to infusion, then at 30(±5), 60(±5), and 90(±5) minutes from start of the 
infusion 
• Weight 
• Dosing by IV infusion 
• AEs 
• Concomitant medications 
 
Study Coordinator: 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
 
Study Neurologist: 
• PE 
 
Week 22 (Day 154 ±3 days/Dose 12) (Bryostatin Dose, 20 µg) 
Study Nurse 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• Vital signs prior to infusion, then at 30 (±5), 60 (±5), and 90 (±5) minutes from start of the 
infusion  

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• Dosing by IV infusion 
• AEs  
• Concomitant medications 
 
Week 24 (Day 168 ±3 days/Dose 13) (Bryostatin Dose, 20 µg) 
Study Nurse 
• 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 
• Concomitant medications 
 
Study Coordinator 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
 
Week 26 (Day 182 ±3 days/Dose 14) (Bryostatin Dose, 20 µg) 
Study Nurse 
• Urine pregnancy test for women of childbearing potential, prior to study drug administration  
• Routine Labs 
• Vital signs prior to infusion, then at 30(±5), 60(±5), and 90(±5) minutes from start of the 
infusion 
• AEs 
• Concomitant medications 
 
Week 28 (Day 196 ±3 days) 
Study Nurse 
• Routine Labs 
• Biobank sample 
• Vital signs  
• Weight 
• AEs 
• Concomitant medications 
 
Study Coordinator 
• SBQ-R 
• Short Cognitive Battery and Performance Test 
• Neuro-QoL 
• Schedule MRI 
• ECG 
 
Study Neurologist 
• EDSS 
• PE 
 
Neuropsychologist 
• Extensive Cognitive Battery 

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Week 32 (Day 224 ±3 days; 30-day follow up) 
Study Nurse 
• AEs 
• Concomitant medications 
 
Week 40 (Day 280 ±3 days; 3-month follow up) 
Study Nurse 
• Concomitant medications 
 
Study Coordinator 
• Short Cognitive Battery and Performance Test 
• Neuro-QoL 
• Schedule MRI 
 
Study Neurologist 
• EDSS 
 
Neuropsychologist 
• Extensive Cognitive Battery 
 
Early Termination 
Study Nurse 
• Routine Labs 
• Vital signs  
• AEs 
• Concomitant medications 
 
Study Coordinator 
• Short Cognitive Battery and Performance Test 
• SBQ-R 
• ECG 
• Neuro-QoL 
• Schedule MRI 
 
Study Neurologist 
• EDSS 
• PE 
 
Neuropsychologist 
• Extensive Cognitive Battery 
 
7.3 Concomitant Medications 
During the screening visit, the participant will provide a list of currently used medications. All 
concomitant medications used should be recorded on the source documents and also in the eCRF 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. 

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Participants 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. 
 
Medications for MS 
Participants either off MS DMT or currently taking Food and Drug Administration (FDA) approved 
DMT (as well as rituximab) for the treatment of MS may be enrolled in the study. For those taking disease 
modifying therapy, the participant must be on a stable dose for at least 1 year prior to entry into the study 
(see 4.5 Inclusion Criteria). Participants should not be anticipated to change MS DMT over the course of the 
study.  
Administration of MS DMTs, whether by injection or infusion, must occur on days that the participant 
is not receiving a bryostatin administration. To decrease IFN-1 site reactions, it is recommended that 
bryostatin infusions occur in a different limb than was used for the most recent IFN-1 injection, if possible.   
 
Concomitant Medications for Management of Myalgia 
Non-steroidal anti-inflammatory drugs such as ibuprofen and naproxen sodium are permitted. Use of 
acetaminophen as an analgesic is not allowed as it has the ability to inhibit PKC activation. 
 
Prohibited Medications 
High dose Vitamin E (> 400 IU / day), Valproic Acid, lithium, and divalproex sodium are prohibited. 
If the PI determines that initiation of any of the prohibited medications is required to ensure the 
participant’s safety, the medication may be initiated with the notification of the Medical Monitor and proper 
documentation of a protocol deviation.  
 
A full list of restricted concomitant medications is shown in Appendix 1. 
 
8. ADVERSE EVENTS AND OTHER SAFETY EVALUATIONS 
8.1 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 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 participants 
will be encouraged to contact the PI or clinical site personnel during any clinical study-related emergency. 
All AEs spontaneously reported by the participant 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. 
8.2 Adverse Events of Special Interest (AESI) 
8.2.1 Myalgia 
Myalgia has been reported as the predominant dose limiting toxicity across oncology studies. The 
incidence of myalgia appears to be dose dependent and cumulative. In the AD studies, subjects who 
received a fixed dose of 20 μg, the proposed dose in this study (NTRP103-301), did not experience myalgia. 

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However, it has been reported in participants receiving doses as low as 5 μg/m2.  
Myalgia has been investigated in some studies but not all. No increase in muscle enzymes were found in 
the cases investigated. Electromyography (EMG) was abnormal in one participant who received 65 µg/m2 
and suggested a patchy myositis. An MRI done in another participant was normal. 
For all cases of myalgia (regardless of severity), a narrative will be created documenting onset, severity, 
treatment, and outcome. CK and B12 tests will be collected for all cases of myalgia.  Additional 
investigations are at the discretion of the investigator.  
To reduce the effects of myalgia, an analgesic such as ibuprofen may be administered. Acetaminophen 
as an analgesic is not allowed as it has the ability to inhibit PKC activation. 
Participants taking interferon-1 will be counseled to receive bryostatin infusions on a different day than 
interferon-1 injection to decrease the likelihood of myalgia side effects.  
8.2.2 Systemic Infusion Related Reactions 
Bryostatin 1 is administered through IV infusion. Infusion-site reactions, including cellulitis, and 
generalized infusion reactions occurred in previous human trials. As a result, a guide for preventing, 
recognizing, and treating these issues is outlined. All necessary supplies to treat infusion-related 
complications should be on-site during all infusions. 
 
Complication  
Signs/Symptoms 
Management 
Prevention 
Systemic infusion 
reaction 
• Dyspnea 
• Flushing 
• Bradycardia/tachyc
ardia 
• Chest pain 
• Fever 
• Chills 
• Generalized 
itching/hives 
• Flushing 
• Rash 
• Dizziness or 
lightheadedness 
• Abdominal cramps 
• Slow infusion rate or 
temporarily hold 
infusion 
• H1 blocker (i.e. 
diphenhydramine) 
• H2 blocker (i.e. 
ranitidine or 
famotidine) 
• IV fluids 
• Methylprednisolone 
(none) 
Anaplylaxis/ 
anaphylaxoid 
  
The same as for systemic 
infusion reaction, plus: 
• Laryngeal edema 
• Bronchospasm 
• Diaphoresis 
• Hypoxia 
• Hypotension 
• Angioedema 
• Cyanosis 
• Loss of 
consciousness, 
seizure 
• Vomiting/diarrhea 
Stop infusion immediately 
  
Medications as for systemic 
infusion reaction, plus: 
• Oxygen 
• Epinephrine 
• Trendelenberg 
positioning 
• Assess airway, 
breathing, 
circulation, vital 
signs, mental status  
• Consider transfer to 
ER 
Do not infuse if 
patient has prior 
allergic reaction to 
bryostatin or similar 
agents 

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8.2.3 Infusion Site Reactions 
Injection site reactions are seen with IFN-β1, glatiramer acetate, and ofatumumab medications. These 
reactions are typically mild and self-limiting but can occasionally be associated with serious skin infection 
or damage. 
 
Complication 
Signs/Symptoms 
Management 
Prevention 
Phlebitis 
• Redness 
• Pain 
• Tenderness 
• Swelling  
• Re-site canula 
• Elevate limb 
• Topical anti-
inflammatory gel or 
cream 
• Anti-inflammatory 
analgesics 
• Consider infection 
as cause and treat as 
cellulitis 
• Universal infection 
control  
• Use smaller cannula 
• Avoid insertion near 
bony prominence or 
venous valve 
• Slow infusion rate 
  
Extravasation 
• Pain 
• Redness 
• Burning 
• Skin pallor 
• Edema 
• Decreased IV flow or 
flush 
• Skin blistering 
• Necrosis 
• Stop infusion  
• Remove cannula 
• Elevate limb 
• If severe, consider 
irrigation with 0.9% 
saline 
• Localized supportive 
treatment  
• Careful insertion of 
cannula 
• Careful monitoring for 
extravasation 
Hematoma 
• Skin discoloration 
bruising 
• Swelling 
• pain/discomfort, 
tenderness to touch 
• Apply ice with light 
pressure 
• Elevate limb 
• Careful insertion of 
cannula 
• Consistent pressure 
after removing 
cannula  
Cellulitis  
4 cardinal signs 
• Localized 
• pain/tenderness 
• Swelling 
• Erythema, warmth 
Additionally: 
• Borders are typically 
not elevated 
• Regional lymphaden-
opathy 
• Systemic signs 
including malaise, 
chills, fever 
Needs immediate medical 
evaluation and management, 
including consideration of 
antibiotics 
 
 
• Universal precautions 
• Diligent skin 
preparation and post-
infusion skin care 
• Infusion staff wash 
hands frequently 
 

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8.3 Definition of Serious Adverse Event 
An SAE is any untoward medical occurrence that fulfills any of the following criteria: 
1. Results in death (fatal) 
2. Is life threatening (an event is considered “life threatening” if, in the view of either the 
investigator or sponsor-investigator, its occurrence placed the participant at immediate risk of 
death. It does not include an AE that, had it occurred in a more severe form, might have caused 
death). 
3. Requires in-patient hospitalization or prolongation of existing hospitalization 
4. Results in a persistent or significant disability/incapacity 
5. Is a congenital anomaly/birth defect  
6. Is an important medical event that may not result in death, may be immediately life threatening 
or require hospitalization, may be considered serious when based upon appropriate medical 
judgment, may jeopardize the participant, or 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. 
7. The following situations may not, by themselves, constitute sufficient grounds to be considered 
as an SAE: 
a. Hospitalization solely for a diagnostic purpose, even if related to an AE, 
b. Elective hospitalization for an intervention planned before the participant enrollment in the 
study 
c. Admission to a day care facility or sleep laboratory 
8.4 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. 
8.5 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, 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 
are listed in the following Table 2. 
 
 
 
 
 
 
 
 
 

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8.6 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 participant’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 participant’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. 
 
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. 
8.7 Reporting Adverse Events 
The PI should instruct all participants on the procedure for reporting AEs/SAEs to the appropriate 
clinical site personnel. For each AE reported, clinical site personnel should obtain all required information 
to complete the source document and eCRF. 
The PI or designee should document all AEs/SAEs in participant’s source documentation, on the AE 
Source Document and in the eCRF. 
In addition to standardized reporting procedures, worsening or exacerbation of concurrent conditions in 
participants will also be reported as AEs, and will follow the designated reporting format. 
 
The following should be recorded with each SAE/AE: 
1. The nature of the AE, with a diagnosis wherever possible 
2. Date of event 
3. Assessment of intensity 
4. Whether the event is an SAE 

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5. Relationship to study drug or trial-related procedures 
6. Action taken regarding study drug treatment 
7. 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-investigator. An SAE that occurs after the Week 40 (3-month follow up) visit 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 participant completes the study. 
 
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 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 Medical Monitor or designee will review the SAE including the SAE criteria, 
the relationship to study medication, the expected or unexpected assessment, and inform the sponsor-
investigator by phone and e-mail immediately. 
 
The following AEs should also be reported to the sponsor-investigator’s designated Medical Monitor 
immediately: 
1. severe injection/infusion site reactions (ulceration or necrosis that is severe; operative intervention 
indicated) 
2. systemic hypersensitivity reactions 
 
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 Week 40 (3-month follow up) visit will NOT be collected unless the PI 
determines that the event is related to the investigational drug product. 
 
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 
(Suspected Unexpected Serious Adverse Reaction; SUSAR) will be promptly reported to regulatory 
authorities by the sponsor-investigator 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-investigator. 

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8.8 Criteria for Withdrawal of Participants 
Participants may be withdrawn from the clinical study for the following reasons: 
1. The PI believes withdrawal to be medically necessary or in the best interest of the participant 
2. Noncompliance with the protocol as judged by the sponsor-investigator/PI  
3. Participants who are enrolled in violation of inclusion and/or exclusion criteria 
4. An AE that presents an unacceptable consequence or risk to the participant as judged by the PI, 
sponsor-investigator, sponsor, or Medical Monitor 
5. Lost to follow up 
6. Withdrawal of consent 
 
Participants may voluntarily discontinue their participation in the study at any time without prejudice to 
further treatment. 
8.9 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 sponsor-investigator/PI believes that discontinuing treatment is in the best interest of the 
participant 
 
Participants will stop study medication if they experience any of the following serious adverse events: 
• Pregnancy 
• Systemic infusion-related reactions which are categorized as moderate or severe 
• Infusion site reactions which are categorized as moderate or severe 
• One or more seizure 
• Clinically significant weight loss as defined as 5% or more of baseline body weight 
• Myalgias which are categorized as moderate or severe 
8.10 Study Discontinuation 
The sponsor-investigator in collaboration with the sponsor (Synaptogenix) has the right to discontinue 
this clinical study at any time.  
The PI has the right to discontinue participation in this clinical study at any time for any reason.  
 
Should the clinical study be discontinued prematurely, all participants should be brought in for Early 
Termination procedures as outlined in Table 1. All clinical study materials should be returned to 
Synaptogenix or designee. 
 
A low frequency of AEs is anticipated for this study based on accumulating experience with prior 
bryostatin clinical trials. While a number of infusions have been performed, little information can be 
considered directly applicable to participants with MS. We anticipate a reasonable chance of 
statistically distinguishing a relatively low toxicity rate (AEs occurring in 1 of 20 participants) from a 
rate of 4-5/20 participants, while at the same time giving good protection against rejecting this 
therapeutic approach prematurely due to a sample with uncharacteristically frequent AEs. Early study 
discontinuation will be considered for accumulating evidence of toxicity, but not for results relating to 
efficacy. 
 
 
 

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Stopping Rules: 
Results will be examined for potential early stopping at every DSMB meeting. DSMB meetings will be 
held as outlined in the DSMP. Additional DSMB meetings may be convened any time the Medical Safety 
Monitor or Study PI requests a DSMB meeting due to safety concerns.. Additionally, discontinuation of the 
trial will be considered by the DSMB if 2 participants within the first 6 of 20 planned experience 
significant AEs classified as a SUSAR (Suspected Unexpected Serious Adverse Reaction) or if 3 
participants experience significant AEs classified as a SUSAR (Suspected Unexpected Serious Adverse 
Reaction) at any time.  
 
9. CLINICAL DATA AND SAFETY MONITORING 
 
9.1 Clinical Monitor 
A Clinical Monitor will assess the implementation and progress of study, NTRP103-301, and will 
review accumulating trial data to monitor the safety of bryostatin administered to participants and to assure 
that the data collected and recorded is complete and accurate. This is done through independent verification 
of study data with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse event monitoring 
• Source data verification 
• Response assessment  
 
Clinical monitoring activities will be performed by a CRO to be contracted specifically for this purpose, so 
that independence is maintained.  
 
9.2 Medical Safety Monitor 
 
A Medical Safety Monitor will be appointed who will review safety data on an ongoing basis and report 
any concerns to the Treating Neurologist, Principal Investigator, or DSMB as appropriate. This Medical 
Safety Monitor will be independent from the Institution running the study and will not be located at the 
clinical site.  
 
The Medical Safety Monitor (MSM) serves two major roles in the evaluation of AEs and SAEs for the trial:  
 
1. They perform ongoing, real-time reviews of all individual SAE reports  
2. They perform quarterly reviews of cumulative AE (serious and non-serious) data to judge 
whether there are concerning trends in the occurrence of events, and the possible relationship 
of those trends to the trial. 
 
AEs for which the significance for potential stopping of the trial is ambiguous will be preliminarily reviewed by the 
Medical Monitor and confirmed by the DSMB. 
 
The Medical Safety Monitor evaluates each SAE and completes a review within three (3) business days of 
receipt. The Medical Safety Monitor will use the detail, when needed, to clarify the context or assumptions 
used in the evaluation. 
 
 9.3 Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be established to serve as the primary 
data and safety monitoring group for the trial.  The monitoring of subject safety and data quality will follow 

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the Guidelines for Data and Safety Monitoring in Clinical Trials. A DSMB will be appointed by the 
sponsor-investigator to review study data provided by the study statistician. This committee will monitor 
rates of AEs and safety endpoints in the trial.  The DSMB will review interim safety data, evaluate whether 
the study should be stopped or amended for safety or other reasons, and make such recommendations to the 
Steering Committee.  In addition, the DSMB will provide input to the Steering Committee concerning the 
study protocol.  The membership, responsibilities, and procedures of the DSMB are outlined in detail in the 
DSMB Operating Guidelines. 
 
10. 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 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. 
 
Adverse event and other safety data will be analyzed descriptively in all participants who received any 
dose of study drug (including partial infusions). These data will be summarized by time in study. 
 
Descriptive summaries of safety and exploratory data including number of evaluable participants, mean, 
median, SD, maximum, and minimum for continuous variables will be provided by 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 safety and efficacy endpoints will be conducted on data collected 
through Week 40. 
10.1 Sample Size Determination 
This is an open label, single-arm, single-dose, Phase 1 study of the safety of bryostatin for the treatment 
of MS in participants receiving any DMT. No formal power analyses were performed. 
10.2 Statistical Methods 
The Safety Analysis Set (SAS) is defined as all participants who received one of more doses of study 
medication. 
Demographics including age, sex, race, ethnicity, height, and body weight will be summarized using 
descriptive statistics. 
Medical history, neuroimaging, prior and concomitant medications, existing disease, years since MS 
onset and diagnosis, baseline medical conditions, and baseline safety and neuropsychological assessments 
will be summarized. 
Trajectories over time for exploratory efficacy assessments including neuroimaging outcomes, MRI 
biomarkers, EDSS, cognitive assessments, MS Performance tests, and PROs will be modeled using mixed-
effects models. Random effects will include intercept and fixed effects will include time and additional 
growth terms, as appropriate. Change over time will be calculated and graphically presented along with 
measures of variability at each time point. Contrasts will estimate the change from baseline to follow-up 
time points, and sustainability between Week 28 and Week 40, for applicable endpoints. 
Participant disposition will be summarized and will include numbers screened, dosed, and withdrawn 
with reason for withdrawal. 
 

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10.3 Safety and Tolerability Outcomes 
AEs, safety laboratory, ECGs, physical exam, vital signs, and MRI data will be presented in tabular 
format and summarized descriptively. Incidence and severity of AEs will be summarized using System 
Organ Class (SOC). AEs will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA).  
Participant disposition will be summarized by numbers screened, dosed and withdrawn with reason for 
withdrawal.  
10.4 Safety Assessments 
Summaries and listings of safety data will be provided to the Data Safety Monitoring Board as described 
in Section 9.3. Analyses will be performed by an independent statistician.  
10.5 Analysis of Safety Data 
For continuous variables, data will be summarized by treatment using n, mean, SD, minimum, and 
maximum values. For categorical variables, data will be summarized by treatment using frequency and 
percentage. 
 
Adverse Events 
AEs will be coded using standard guidelines determined by the sponsor-investigator and are defined as 
events with an onset on or after the first treatment. TEAEs will be summarized by System Organ Class, 
and preferred term. The following TEAE summaries will be provided: 
1. Overall (i.e., regardless of severity or relationship to treatment) 
2. By severity grade (mild, moderate, severe, life threatening or death for SAEs) 
3. By relationship to clinical trial treatment (definitely related, probably related, possibly related, 
unlikely related, unrelated) 
 
Unless otherwise specified, at each level of participant summarization, a participant will be counted 
only once. If there is more than one occurrence of an event, the event of the worst severity or the worst-
case relationship category will be summarized. 
 
In addition, separate summaries of serious adverse events, and adverse events resulting in 
discontinuation of study treatment will be presented. 
 
AEs leading to premature discontinuation of clinical trial treatment, AEs that lead to study 
discontinuation, AEs that lead to death and SAEs will also be summarized. 
 
Clinical Laboratory Evaluations 
All available results of the clinical laboratory evaluations will be listed and summarized as follows: 
 
Laboratory Values over Time 
Summary statistics of raw data and change from baseline values for each laboratory parameter will 
be presented by time point. Data will be summarized as appropriate for the variable type. 
For continuous data, summaries will include the number of observations, mean, SD, median, 
minimum, and maximum values. 
For categorical data, frequency counts and percentages will be used. 
 
For change from baseline summaries, participants with an undefined change from baseline, 
because of missing data, will be excluded. 
 

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Individual Participant Changes (Shift Tables) 
Individual participant changes will be identified through shift tables. Shift tables will be presented 
for each laboratory parameter with counts and percentages of participants, by time point, for shift 
(change) from baseline, using the normal ranges from the laboratory. 
 
Individual Clinically Significant Abnormalities 
Clinically significant laboratory abnormalities (i.e., those laboratory abnormalities recorded as 
AEs) will be listed. 
 
All results of laboratory evaluations will be presented as by- participant listings. 
10.6 Physical Examination 
All PE findings will be listed and/or summarized. Shift tables will also be presented to show any 
abnormality shifts from baseline to post-baseline visits. 
10.7 Vital Signs 
Tabulations of raw data and change from baseline values will be presented by time point for each vital 
sign parameter. Tabulations will include the number of observations, mean, standard deviation, median, and 
minimum and maximum values. For change from baseline summaries, participants with an undefined 
change from baseline, because of missing data, will be excluded. 
10.8 ECG 
All ECG findings will be listed and/or summarized. Shift tables will also be presented to show any 
abnormality shifts from baseline to post baseline visits. 
 
10.9 The Suicide Behaviors Questionnaire-Revised (SBQ-R)  
The 4-item SBQ-R is a measure of past suicidal thoughts and attempts which have proved to be 
significant predictors of future suicidality.47 The items ask if the respondent has ever thought about or 
attempted suicide, how frequent was suicidal thoughts in the past year, have they told someone about such 
thoughts, and what is the likelihood of attempting suicide in the future. 
 
10.10 Patient-Reported Outcomes (PROs) 
PROs will be summarized using descriptive statistics by visit, including mean, SD, median, maximum, 
and minimum, as appropriate. A responder analysis will be conducted by summarizing meaningful change 
at the individual level.70 The percentage of participants who meet the minimum clinically important 
difference of +3.5 T-score points at each visit after baseline will be summarized using frequency count and 
percentage.71 
 
10.11 Magnetic Resonance Imaging (MRI) 
All MRI findings will be listed and/or summarized.  
10.12 Exploratory Outcomes 
Descriptive statistics by visit will be provided for all exploratory data, where applicable. These 
descriptive statistics will include the mean, median, SD, maximum and minimum for continuous variables, 
and frequencies, percentage, and tabulations for categorical variables. 
 
Durability of bryostatin activity in MS participants 
Durability of a drug is its ability to delay progression of disease, in a safe and well tolerated manner. 
Here, the durability of bryostatin in improving cognitive function, neurologic function, and MRI biomarkers 
will be assessed. The durability of changes in Exploratory efficacy data (cognitive and MRI) will be 

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analyzed and summarized from baseline to Week 28 and Week 40 using mixed effects models, as described 
above.     
Summary statistics will also be performed on both the participant demographics and participant clinical 
characteristics. Exploratory plots of the data will also be created, including box plots and histograms, in 
order to determine the distribution of these data as well as to identify any unusual or outlying observations. 
 
10.13 Analysis of Exploratory Endpoints 
Exploratory endpoints for this study include the change from baseline to 28 and 40 weeks in the 
Extensive Cognitive Battery (MOCA, CVLT 3, BVMT-R, JOLO, BNT, COWAT, D-KEFS, and PST) 
scores, EDSS scores, MSPT, and MRI findings. Exploratory endpoints also include the change in the 
monthly assessment of MOCA, COWAT, and PST. All statistical tests for these efficacy signals will be 
two-sided tests, with α=0.05. Since all of the efficacy assessments are exploratory, there will be no 
adjustment for multiplicity. 
Based on the review of participants treated with bryostatin in the following AD clinical trials, NTRP 
101-202, NTRP101-203, and NTRP101-204, the expected number of participants who will drop out of the 
study prematurely will not be significant.  
 
11. DATA MONITORING 
11.1 Source Documentation 
In accordance with ICH-GCP guidelines, source documents may include, but are not limited to the 
following: 
1. Clinic, office, hospital charts 
2. Copies of transcribed health care provider notes, which have been certified for accuracy after 
production 
3. 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 
4. Records of telephone contacts 
5. Diaries, evaluation checklists, or questionnaires that are completed directly by participants and 
serve as their own source 
6. Laboratory results and other laboratory test results, urine dip-stick results 
7. Correspondence regarding a participants’ treatment between physicians or memoranda sent to the 
IRB. 
8. MSTP iPAD output data 
11.2 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. PI or designees are responsible for approval of all entered or corrected data. 
 
The medical records (source documents) upon which the eCRFs are based must be kept at the clinical 
site for at least a period of 2 years following the date a marketing application is approved for the drug for 
the indication for which it is being investigated; or, if no application is to be filed or if the application is not 
approved for such indication, until 2 years after the investigation is discontinued and the FDA is notified. 
Synaptogenix must be informed if the records are passed on to any other person or institution during this 
period. Records related to nonclinical laboratory studies will be maintained by Synaptogenix or its designee 
for a minimum of 5 years per 21 Code of Federal Regulations (CFR) 58.195 (b) (2). 
11.3 Synaptogenix Site Monitoring 

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Synaptogenix or its designee will be allowed to conduct site visits at the investigation facilities to 
monitor any aspect of the study. The PI will provide Synaptogenix, or its designee, with documentation of 
IRB approval of the Study Protocol and the Informed Consent prior to study initiation and IRB approval of 
any subsequent amendments to the protocol or revision to the Informed Consent. Before the study site can 
enter a participant into the study, the sponsor-investigator or a designee may review the study site to: 
1. Determine the adequacy of the facilities 
2. Discuss with the PI(s) and other personnel their responsibilities with regard to protocol adherence, 
and the responsibilities of Synaptogenix, or its representatives. This will be documented in a 
clinical study agreement between Synaptogenix and the sponsor-investigator. 
 
During the study, a monitor from Synaptogenix, or representative may have regular contacts with the 
investigational site, for the following: 
1. Provide information and support to the PI(s) 
2. Confirm that facilities remain acceptable 
3. 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 
4. Perform source data verification. This includes a comparison of the data in the eCRFs with the 
participant’s medical records at the hospital or practice, and other records relevant to the study.  
5. Record and report any protocol deviations not previously sent to Synaptogenix 
6. 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 Ethics 
Committee (EC)/IRB/ Independent Ethics Committee (IEC). 
 
The Synaptogenix monitor will be responsible for immediately reporting the site not adhering to the 
study protocol to the project manager and sponsor-investigator. Noncompliance may result in study 
suspension or closure. 
The monitor will be available between visits to provide information or advice.  
11.4 Quality Assurance and Quality Control 
To ensure compliance with GCP and all applicable regulatory requirements, Synaptogenix, Inc. or its 
representative may conduct a quality assurance audit. 
11.5 Audits and Inspection 
Authorized representatives of Synaptogenix, a regulatory authority, or an IRB may visit the site to 
perform audits or inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to determine whether 
these activities were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. The PI should contact 
Synaptogenix immediately if contacted by a regulatory agency about an inspection. 
 
12. ETHICS 
12.1 Institutional Review Board 
The sponsor-investigator, who is also the PI in this study, 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. Following IRB approval, the sponsor-investigator must submit written notice of approval 
to Synaptogenix or its representative, before receiving study drug from Synaptogenix and before any 
participant can be enrolled into the study. 

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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 participants for the study. 
The protocol must be re-approved by the IRB upon receipt of amendments and annually, as local regulations 
require. 
Sponsor-investigator is responsible for providing the IRB and FDA with reports of all adverse drug 
reactions (ADRs) that are both serious and unexpected. 
Progress reports will be provided to the IRB according to local regulations and guidelines. 
12.2 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 participants participating in clinical medical 
research that have their origin in the Declaration of Helsinki. The PI must agree to the direct access to 
source documents and inspection of clinical study-related records by the regulatory authority/ Synaptogenix 
representatives. 
12.3 Written Informed Consent 
Written informed consent must be witnessed, signed, dated, and obtained from the participant. 
  
The PI should confirm to the extent possible that the participant has the means to 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 participants. The 
written approval of the IRB together with the approved participant’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 participants should be 
documented in the participants’ files. 
 
13. STUDY MANAGEMENT 
13.1 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 participant’s final eCRF to signify that 
all of the information is correct and complete. 
13.2 Data Quality Control 
Periodic on-site review of communications between the PI and investigational site study monitors, and 
review of eCRF data and source documents are the responsibility of the sponsor-investigator, or designee. 
The eCRF data for each participant 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. 

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13.3 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 and Study 
Staff. 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 participant’s participation in the study 
and should clearly document the dates and details of study procedures, AEs, and participant status. 
The eCRFs will identify study participants 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 guidelines determined by the sponsor-
investigator. Medical history, concurrent medical conditions, and AEs will be coded using guidelines 
determined by the sponsor-investigator. 
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 Synaptogenix and the sponsor-investigator. 
13.4 Inspection of Records 
Synaptogenix, Inc., will be allowed to conduct site visits to the investigation facilities for the purpose of 
monitoring any aspect of the study. The PI agrees to allow the monitor to inspect the drug storage area, 
study drug stock, drug accountability records, participant charts and study source documents, and other 
records relative to study conduct. 
13.5 Retention of Records 
A searchable offline version of the eCRF will be forwarded to the sponsor-investigator for storage. A 
copy of each completed eCRF will remain in the PI’s study file on a compact disk. All source 
documentation, eCRFs and administrative records will be retained by the PI for a minimum of 2 years 
following agency approval of the medication for the indication under study or following notification that the 
investigational application is closed for this indication. However, this may be adjusted based on the 
applicable local requirements. After this time, the documentation will either be destroyed or transferred to 
Synaptogenix or designee. No study documentation should be destroyed or moved to a new location without 
prior written approval by Synaptogenix. 
13.6 Confidentiality 
All study findings and documents will be regarded as confidential. The sponsor-investigator, co-
investigators and members of their research teams must not disclose such information without prior written 
approval from Synaptogenix or its representatives. 
The anonymity of participating participants must be maintained. A Protected Health Information 
statement will be provided to each participant either as a part of the Informed Consent document or as a 
separate form. Participant will be identified on eCRFs by their participant number and on source documents 
by their initials, and participant number. A separate document linking study number to identifiable 
information of the participants will be maintained separately and kept securely. Documents that identify the 
participant by name (e.g., the signed Informed Consent Form) must be maintained in strict confidence by 
the PIs. 
13.7 Protocol Amendments 
Minimally, any change that significantly affects the safety or welfare of participants, the scope of the 

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investigation, or the scientific quality of the study will be effected by means of a protocol amendment 
approved by the sponsor-investigator and submitted to the IND and the local IRB. Protocol amendments  
submitted to the relevant (local) IRB must be 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. 
13.8 Protocol Deviations 
Should a deviation from the protocol be deemed crucial for the safety and well-being of a particular 
participant, such a deviation will be instituted for that participant 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 waivers for protocol 
deviations for any Inclusion or Exclusion criterion will be permitted in this study. 
13.9 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 participant’s final eCRF to signify that all of the 
information is correct and complete. 
13.10 Insurance 
The sponsor has taken out a liability insurance policy, which covers the liability of investigators. This 
policy is in accordance with local laws and requirements. The sponsor’s insurance does not relieve the 
investigators of any obligation to maintain their own liability insurance policy as required by the applicable 
law. 
 
14. 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-investigator, PI (if different from sponsor-
investigator), Cleveland Clinic, and Synaptogenix. 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 (Cleveland Clinic/sponsor-
investigator) and Synaptogenix. Additionally, while proprietary patent issues and competitive strategic goals 
must be considered, Cleveland Clinic investigators may publish results of this study by abstract, verbal 
presentation, invited lecture, journal article, or journal letter. Authorship and the order of authorship on 
publications reporting the results of study findings are at the discretion of the sponsor-investigator or PI, if 
different. 

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15. APPENDIX 1 - RESTRICTED CONCOMITANT MEDICATIONS 
 
Drugs Not Allowed (N) during the study. 
• Acetaminophen 
• Heparin 
• Divalproex sodium, valproic acid, and topiramate 
• Memantine 
• Lithium carbonate 
• Vitamin E > 400 International Units (IU) per day within 14 days prior to screening 
• MAO inhibitors 
• Cholinesterase inhibitors donepezil, rivastigmine, and galantamine are not restricted 
concomitant medications if at a stable dose for at least 3 months prior to screening and 
usage continued unchanged throughout the study. 
• Carbamazepine 
• Terifluonimide 
• Ciprofloxacin,prohibited for 24 hours prior to each infusion and on the day of the infusion.  
• Dalfampridine 
• Bactrim (trimethoprim/sulfamethoxazole) prohibited for 24 hours prior to each infusion and 
on the day of the infusion.   
• Use of any potent or moderate, inhibitor or inducer, of CYP3A4, CYP2C8, or CYP2C9. 
Concomitant medicines will be examined on a case by case basis against the Flockhart 
Table by Sponsor-Investigator, and if needed, the Medical Monitor, to determine 
allowability. 
• Use of St John’s Wort is prohibited starting 2 weeks prior to screening and throughout the 
study. 
 
Dietary Restrictions throughout the study: 
• Grapefruit juice 
 
 

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16. APPENDIX 2 - LIST OF REFERENCES 
 
1. 
Coetzee T, Thompson AJ. Atlas of MS 2020: Informing global policy change. Mult Scler. 
2020;26(14):1807-8. Epub 2020/11/12. doi: 10.1177/1352458520968811. PubMed PMID: 33174499. 
2. 
Alonso A, Hernan MA. Temporal trends in the incidence of multiple sclerosis: a systematic review. 
Neurology. 2008;71(2):129-35. Epub 2008/07/09. doi: 10.1212/01.wnl.0000316802.35974.34. PubMed PMID: 
18606967; PMCID: PMC4109189. 
3. 
Jobin C, Larochelle C, Parpal H, Coyle PK, Duquette P. Gender issues in multiple sclerosis: an update. 
Womens Health (Lond). 2010;6(6):797-820. Epub 2010/12/02. doi: 10.2217/whe.10.69. PubMed PMID: 
21118039. 
4. 
Tanasescu R, Ionete C, Chou IJ, Constantinescu CS. Advances in the treatment of relapsing-remitting 
multiple sclerosis. Biomed J. 2014;37(2):41-9. Epub 2014/04/16. doi: 10.4103/2319-4170.130440. PubMed 
PMID: 24732658. 
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