Clinical trial NCT04225533
Conditions: Myocardial Infarction Inflammation
Sponsor: Serpin Pharma, LLC
Start date: 2020-02-24; Completion date: 2021-12-21
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will evaluate the potential benefit of blocking inflammation during a heart attack using an investigational anti-inflammatory medicine called SP16. The study will enroll 10 patients and all 10 patients will receive a standard dose of SP16.

Detailed description:
The main hypothesis of this study is that a single subcutaneous administration of SP16 0.2 mg/kg is safe and well tolerated in patients with ST segment elevation myocardial infarction (STEMI) and associated with a reduction in the acute inflammatory response to STEMI, as measured as area-under-the-curve (AUC) for C reactive protein (CRP), the preferred inflammatory marker for cardiovascular risk prognostication.

SP16 will be administered subcutaneously as this route has greater ease of administration than intravenous injection. A single dose administration has been selected based upon pre-clinical data and expected clinical use of SP16.

Arms: arm 1: Patients will receive a single dose of SP16 0.2 mg/kg by subcutaneous injection
Interventions: intervention 1: SP16
Intervention descriptions: intervention 1: All patients will receive a single dose of SP16

Protocol documents:
Prot_SAP_000.pdf: 
 
 
Title: Safety, Tolerability and Effects of a Single Subcutaneous Administration of SP16–a 
SERPIN-like, Small Peptide Agonist of the Low Density Lipoprotein-like Receptor 1 –on the 
Acute Inflammatory Response in Patients with ST-segment Elevation Myocardial Infarction 
(STEMI) 
 
NCT #: 04225533 
 
Document date: August 21,2020 
 
Document Type: Protocol 
 
 
 


Safety, Tolerability, and Efficacy of SP16 in STEMI 
Protocol Number 02-SP16 
Version 2
August 21, 2020
 
 
Confidential 
 
 
Safety, Tolerability and Effects of a Single 
Subcutaneous Administration of SP16–a SERPIN-
like, Small Peptide Agonist of the Low Density 
Lipoprotein-like Receptor 1 –on the Acute 
Inflammatory Response in Patients with ST-segment 
Elevation Myocardial Infarction (STEMI) 
 
Protocol Identifying Number: 02-SP16 
 
SP16 Inflammatory Response Inhibition Trial 
(SPIRIT) 
 
 Principal Investigators: 
Antonio Abbate, MD, PhD 
Benjamin W. Van Tassell, PharmD 
 
 IND/IDE Sponsor: Serpin Pharma, LLC 
 
Version Number: v.2 
21 August 2020 


Safety, Tolerability, and Efficacy of SP16 in STEMI 
Protocol Number 02-SP16 
Version 2
August 21, 2020
 
Confidential 
2 
Table of Contents 
LIST OF ABBREVIATIONS ............................................................................................................................. 4 
STATEMENT OF COMPLIANCE ..................................................................................................................... 7 
PROTOCOL SUMMARY .................................................................................................................................. 8 
1 
KEY ROLES ........................................................................................................................................... 10 
2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................ 11 
2.1 
BACKGROUND INFORMATION ................................................................................................... 11 
2.2 
RATIONALE .................................................................................................................................. 13 
2.3 
POTENTIAL RISKS AND BENEFITS ............................................................................................ 14 
2.3.1 
KNOWN POTENTIAL RISKS .................................................................................................... 14 
2.3.2 
KNOWN POTENTIAL BENEFITS ............................................................................................. 14 
3 
OBJECTIVES AND PURPOSE ............................................................................................................. 15 
4 
STUDY DESIGN AND ENDPOINTS ..................................................................................................... 15 
4.1 
DESCRIPTION OF THE STUDY DESIGN .................................................................................... 15 
4.2 
STUDY ENDPOINTS ..................................................................................................................... 15 
4.2.1  PRIMARY ENDPOINT .............................................................................................................. 15 
4.2.2 
SECONDARY ENDPOINTS ..................................................................................................... 15 
4.2.3 
PHARMACOKINETIC ASSESSMENT...................................................................................... 16 
5 
STUDY ENROLLMENT AND WITHDRAWAL ...................................................................................... 16 
5.1 
PARTICIPANT INCLUSION CRITERIA ......................................................................................... 16 
5.2 
PARTICIPANT EXCLUSION CRITERIA ....................................................................................... 16 
5.3 
STRATEGIES FOR RECRUITMENT AND RETENTION .............................................................. 17 
5.3.1 
SCREENING ............................................................................................................................. 17 
5.3.2  CONSENTING .......................................................................................................................... 17 
5.3.3 
STUDY DRUG ADMINISTRATION ........................................................................................... 17 
5.4 
PARTICIPANT WITHDRAWAL OR TERMINATION ..................................................................... 17 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION .............................................................. 18 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION .................................... 18 
5.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY ..................................................... 18 
6 
STUDY AGENT ...................................................................................................................................... 18 
6.1 
STUDY AGENT(S) AND CONTROL DESCRIPTION .................................................................... 18 
6.1.1 
ACQUISITION ........................................................................................................................... 18 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING ......................................... 19 
6.1.3 
PRODUCT STORAGE AND STABILITY .................................................................................. 19 
6.1.4 
PREPARATION ......................................................................................................................... 19 
6.1.5 
DOSING AND ADMINISTRATION ............................................................................................ 19 
6.1.6 
ROUTE OF ADMINISTRATION ................................................................................................ 19 
6.1.7 
DOSE ........................................................................................................................................ 19 
6.1.8 
DURATION OF THERAPY ....................................................................................................... 20 
6.1.9 
TRACKING OF DOSE .............................................................................................................. 20 
6.2 
STUDY AGENT ACCOUNTABILITY PROCEDURES ................................................................... 20 
7 
STUDY PROCEDURES AND SCHEDULE ........................................................................................... 20 
7.1 
STUDY PROCEDURES/EVALUATIONS ...................................................................................... 20 
7.1.1 
STUDY SPECIFIC PROCEDURES .......................................................................................... 20 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES ................................................................. 20 
7.2 
LABORATORY PROCEDURES/EVALUATIONS ....................................................................... 21 
7.2.1 
CLINICAL LABORATORY EVALUATIONS .............................................................................. 21 


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7.2.2 
OTHER ASSAYS OR PROCEDURES ................................................................................... 21 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE ................................................... 21 
7.2.4 
SPECIMEN SHIPMENT ............................................................................................................ 21 
7.3 
STUDY SCHEDULE ...................................................................................................................... 22 
7.3.1 
SCREENING ............................................................................................................................. 22 
7.3.2 
DOSING (after PCI)................................................................................................................... 22 
7.3.3 
DISCHARGE (or 72 hours, whichever comes first) .................................................................. 22 
7.3.4 
VISIT 4: FOLLOW-UP VISIT (Day 14+/- 2) ............................................................................... 22 
7.3.4 
VISIT 5: FOLLOW-UP VISIT 2 (Day 90+/-14) ........................................................................... 23 
7.3.5 
VISIT 6: FOLLOW-UP VISIT 3 (Day 365 +/- 30)....................................................................... 23 
7.3.6 
SCHEDULE OF EVENTS TABLE ............................................................................................. 23 
7.4 
CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES .................................... 24 
7.5 
JUSTIFICATION FOR USE OF PLACEBO ................................................................................... 24 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES .......................... 24 
7.6 
PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES......................................... 24 
7.7 
PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES .................................. 24 
7.8 
RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES ................................................ 24 
7.9 
PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE .......................................... 24 
8 
ASSESSMENTS OF SAFETY ............................................................................................................... 24 
8.1 
SPECIFICATION OF SAFETY PARAMETERS ............................................................................. 24 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) .............................................................................. 24 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) .......................................................... 25 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) ............................................................ 25 
8.2 
CLASSIFICATION OF AN ADVERSE EVENT .............................................................................. 25 
8.2.1 
SEVERITY OF EVENT ............................................................................................................. 25 
8.2.2 
RELATIONSHIP TO STUDY AGENT ....................................................................................... 26 
8.2.3 
EXPECTEDNESS ..................................................................................................................... 26 
8.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP .................. 26 
8.4 
REPORTING PROCEDURES ....................................................................................................... 27 
8.4.1 
ADVERSE EVENT REPORTING .............................................................................................. 27 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING ............................................................................ 27 
8.4.3 
UNANTICIPATED PROBLEM REPORTING ............................................................................ 28 
8.4.4 
EVENTS OF SPECIAL INTEREST ........................................................................................... 28 
8.4.5 
REPORTING OF PREGNANCY ............................................................................................... 28 
8.5 
STUDY HALTING RULES ............................................................................................................. 28 
8.6 
SAFETY OVERSIGHT ................................................................................................................... 29 
8.7  
 ADJUDICATION OF CLINICAL EVENTS ..................................................................................... 29 
8.7.1 
Event-adjudicating committee ................................................................................................... 29 
8.7.2 
Definition of the events .............................................................................................................. 29 
8.7.3 
Implications of the findings of the event-adjudicating committee .............................................. 30 
9 
CLINICAL MONITORING ...................................................................................................................... 30 
10  
STATISTICAL CONSIDERATIONS .................................................................................................. 30 
10.1 
ANALYSIS DATASETS ................................................................................................................. 30 
10.2 
DESCRIPTION OF STATISTICAL METHODS .............................................................................. 30 
10.2.1 
GENERAL APPROACH........................................................................................................ 30 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS ..................................... 31 
12 
QUALITY ASSURANCE AND QUALITY CONTROL ........................................................................... 31 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................................. 31 
13.1 
ETHICAL STANDARD ................................................................................................................... 31 
13.2 
INSTITUTIONAL REVIEW BOARD ............................................................................................... 31 
13.3 
INFORMATED CONSENT PROCESS .......................................................................................... 31 


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13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS .................................................................................................................... 31 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION ........................................................ 32 
13.4 
PARTICIPANT AND DATA CONFIDENTIALITY ........................................................................... 32 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA ................... 32 
13.5 
FUTURE USE OF STORED SPECIMENS .................................................................................... 32 
14 
DATA HANDLING AND RECORD KEEPING....................................................................................... 33 
14.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES ................................................ 33 
14.2 
STUDY RECORDS RETENTION .................................................................................................. 33 
14.3 
PROTOCOL DEVIATIONS ............................................................................................................ 33 
14.4 
PUBLICATION AND DATA SHARING POLICY ............................................................................ 33 
15 
STUDY ADMINISTRATION ................................................................................................................... 34 
15.1 
STUDY LEADERSHIP ................................................................................................................... 34 
16 
CONFLICT OF INTEREST POLICY ...................................................................................................... 34 
18 
LITERATURE REFERENCES ............................................................................................................... 35 
 


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SUMMARY OF CHANGES 
 
Changes to prior version 27 March 2020 
 
Changes necessary to address COVID19 Pandemic Risk. Enrollment to resume when IRB approval 
obtained. 
 
 
Section 
Change 
Rationale 
Section 5.2 
Updated exclusion criteria to include 
COVID-19. 
Specify criteria for COVID-19 
exclusion. 
Section 7.3.6 
New section  
Need to explain need to comply with 
SARS-CoV2 screening and testing 
practice at VCU Health 
Section 7.3.7 
Table of events updated 
Updated with changes 
Figure 1 
Updated PK times to 0, 30, 60 & 180 
minutes 
Updated with changes 
Section 4.2.3 
Updated PK times to 0, 30, 60 & 180 
minutes 
Updated with changes 
Section 7.3.2 
Updated PK times to 0, 30, 60 & 180 
minutes 
Updated with changes 
Schedule of 
Events Table 
Updated PK times to 0, 30, 60 & 180 
minutes 
Updated with changes 
 
 
Changes to prior version 13 December 2019 
 
Changes in response to COVID19 Pandemic Emergency – All changes planned to revert when 
emergency resolved. 
 
Enrollment has been halted on 3/23/2020. 
 
Section 
Change 
Rationale 
Sections 4.2.2, 7.3.5, 7.3.7 
Visits changed to virtual. 
Echocardiogram postponed 
from 90 days to 365 days.  
To limit in-person visits 
during this pandemic. 
 
 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Expanded Term 
λ 
Terminal rate constant 
AAT 
ACC 
AHA 
α1-Anti-Trypsin 
American College of Cardiology 
American Heart Association 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AMI 
Acute myocardial infarction 
AST 
Aspartate aminotransferase 
AUC∞ 
Total area-under-the-curve 
CFR 
CRF 
Code of Federal Regulations 
Case Report Forms 
CK-MB 
Creatine Kinase-Myocardial Band 
CLtot 
Total clearance 
cmax 
CRP 
Maximum concentration 
C-Reactive Protein 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GMP 
ICH 
IDS 
IND 
   Good Manufacturing Practice 
   International Council of Harmonisation 
Investigational Drug Services 
Investigational New Drug 
IRB 
Institutional Review Board 
LAD 
LRP1 
MOP 
Left Anterior Descending artery 
Low Density Lipoprotein Receptor-like Protein 1 
Manual of Procedures 
MSRD 
Maximum Recommended Starting Dose 
MRTsys 
OHRP 
NIH 
Mean resident time 
Office of Human Research Protection National Institute of Health 
National Institutes of Health 
NSAIDs 
PCI 
PI 
   Nonsteroidal anti-inflammatory drugs 
Percutaneous Coronary Intervention 
Principle Investigator 
SAE 
Serious adverse event 
SERPINS 
Serine protease inhibitors 
SP16 
SQ 
Serpin peptide 16 
Subcutaneous 
STEMI 
ST-segment Elevation Myocardial Infarction 
t1/2 
Half-life 
tmax 
TIMI 
Time to Cmax 
Thrombolysis in Myocardial Infarction 
TNF 
Tumor necrosis factor 
UK 
UP 
United Kingdom 
Unanticipated problems 


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US 
United States 
VCU 
Virginia Commonwealth University 
Vdcc 
Volume of distribution of the central compartment 
Vdss 
Volume of distribution at steady-state 
WBC 
White blood cell 
 
 
 


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STATEMENT OF COMPLIANCE 
 
The trial will be carried out in accordance with Good Clinical Practice (GCP) as required by 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812) and 
International Conference on Harmonisation Guidance for Industry, Good Clinical Practice: 
Consolidated Guidance.  
 
All key personnel (all individuals responsible for the design and conduct of this trial) have 
completed Human Subjects Protection Training. 
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments. 
 
 
Principal Investigator:  Antonio Abbate, MD, PhD 
 
  Print/Type Name 
 
 
Principal Investigator: Benjamin Van Tassell, PharmD 
 
Print/Type Name 
 
 
Signed:  
 
 
   
Date/Signature 
 
 
 
   
Date/Signature 


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PROTOCOL SUMMARY 
 
 
Title: 
Safety, Tolerability and Effects of a Single Subcutaneous Administration of 
SP16–a SERPIN-like, Small Peptide Agonist of the Low Density Lipoprotein-
like Receptor 1–on the Acute Inflammatory Response in Patients with ST-
segment Elevation Myocardial Infarction (STEMI) 
 
Design: 
Single-center, single-arm, open-label, clinical trial of SP16 0.2 mg/Kg 
administered within 6 hours of reperfusion.  
 
Objectives:           The primary objective is to determine the effects of SP16 on the area-under-
the-curve (AUC) for C-reactive protein (CRP) at 14 days as compared with 
historical controls treated with placebo in the VCUART, VCUART2, and 
VCUART3 studies. Secondary objectives include the assessment of the effects 
of SP16 on AUC for creatine kinase myocardial band (CK-MB) at 72 hours.  
 
Study 
Endpoints: 
 
• AUC for CRP at 14 days [primary endpoint] 
• AUC for CK-MB at 72 hours 
• Pharmacokinetics 
• Safety assessments 
• Echocardiography at 365 days 
• Incidence of heart failure at 365 days 
 
Safety 
Monitoring: 
Subjects will be monitored directly for at least 12-hours after administration of 
investigational medication and then have repeated follow-up at 72 hours, 14 
days, and 365 days.  
 
Population: 
 
Adult (>21 years of age) individuals (N=10) with acute ST-segment elevation 
myocardial infarction (within 12 hours of symptom onset).  
 
Phase: 
1B/2A 
 
Number of Sites 
Enrolling 
Participants 
1 (Virginia Commonwealth University) 
 
 
 
Description of 
Study Agent: 
SP16 is a synthetic oligopeptide based upon the structure of human alpha-1 
antitrypsin. SP16 exhibits high affinity for the LRP1. 
 
Study Duration: 
Primary Endpoint: 14 days 
Safety Endpoint: 14 days 
Long-term Follow-up: 365 days from last patient enrolled 
 
Participant 
Duration: 
365 days 
 
    
 


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Figure 1: 
Schematic of the Study Design 
 
  
 
 
 
 
 
 
 
 
 


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1 
KEY ROLES 
 
Principal Investigators: 
 
Antonio Abbate, MD, PhD 
James C. Roberts, Esq., Professor in Cardiology  
Department of Internal Medicine 
Virginia Commonwealth University 
1200 E Broad Street 
Richmond, VA 23298 
 
Benjamin Van Tassell, PharmD 
Professor and Vice Chair for Clinical Research  
Department of Pharmacotherapy & Outcomes Science 
Virginia Commonwealth University 
410 North 12th Street, Rm 636 
Richmond, VA 23298 
 
 


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2 
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE 
 
2.1 BACKGROUND INFORMATION 
 
Acute myocardial infarction remains a major cause of morbidity and mortality in the US and 
worldwide.1 Despite current strategies for early reperfusion, many patients die early during the 
course, and those who survive are at risk for dying late from adverse cardiac remodeling, heart 
failure, and sudden death. 
 
Patients presenting with ST-segment elevation (STEMI) are at particularly high risk for adverse 
cardiac remodeling, heart failure, and mortality.1,2 Although there have been considerable 
improvements in the treatment of STEMI, the reduction in early mortality has been associated with 
an increasing incidence of heart failure after STEMI.1 This likely reflects more high-risk patients 
surviving the index event as well as the aging of the population and the epidemics of hypertension 
and diabetes. Within 1 year of STEMI, more than 20% of survivors are diagnosed with heart 
failure, a disease associated with high morbidity, disability, and mortality.1 Heart failure is indeed 
a major public health problem affecting approximately 5 million Americans with 500,000 new 
cases per year. In contrast to other cardiovascular disease, the incidence and prevalence of heart 
failure continue to increase and heart failure is now the leading cause of hospitalization for people 
aged ≥65 years, a segment of the population that is also rapidly growing.1 Although survival after 
the onset of heart failure is also improved, current therapies may slow but not halt the progression 
of the disease. With the limitations to functional capacity, the progressive symptoms of dyspnea 
and fatigue, the frequent hospital admissions and the economic consequences of lost productivity 
and increasing costs of medical care, heart failure imposes a significant burden on healthcare. 
 
There is an urgent need to develop additional treatments to prevent heart failure after AMI.2 The 
current treatment in STEMI includes prompt reperfusion of the ischemic myocardium by 
restoration of the coronary artery patency (i.e. angioplasty or fibrinolysis), prevention of re-
occlusion (i.e. antiplatelet and anticoagulants), and neurohormonal blockade (i.e. renin-
angiotensin-aldosterone and adrenergic blockers). While each of these interventions provide 
incremental benefit and significantly reduce morbidity and mortality, the incidence of heart failure 
after STEMI has continued to rise, implying that the current treatment paradigm still misses one or 
more key pathophysiologic mechanisms. Determining the mechanisms by which unfavorable 
cardiac remodeling and heart failure progress despite optimal treatment is thus a critical step in the 
search for novel interventions, with the ultimate goal of reducing the incidence, burden, and 
mortality of heart failure after STEMI.2 
 
A close interplay exists between inflammation, adverse cardiac remodeling and heart failure after 
AMI. Acute myocardial ischemia and infarction initiate an intense inflammatory response within 
the myocardium.3 Leukocytes infiltrate the damaged myocardium to coordinate tissue repair and 
infarct healing, leading to newly formed vessels and reparative fibrosis. Thus, inflammation is 
necessary for infarct healing, but uncontrolled inflammation is responsible for further damage to 
the heart and non-functional healing which are the basis for adverse cardiac remodeling and heart 
failure. In experimental animal models, the degree of the inflammatory response determines 
adverse cardiac remodeling, independent of infarct size.3 In patients with AMI, the intensity of the 
inflammatory response, reflected in levels of circulating biomarkers, predicts adverse cardiac 
remodeling, heart failure and death.4 Modulation of the inflammatory response therefore represents 


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a target for intervention. While previous attempts to modulate the inflammatory response have 
failed, we propose a novel and substantially different approach to modulating the inflammatory 
response based upon the anti-inflammatory and cytoprotective properties of alpha-1 antitrypsin 
(AAT).5  
 
AAT is a naturally occurring anti-inflammatory protein that is abundant in the plasma and exerts 
powerful cytoprotective effects in endothelial cells, cardiomyocytes and fibroblasts.5 In an 
experimental model of acute myocardial infarction (AMI), AAT administered at the onset of 
ischemia or at time of reperfusion led to a significantly smaller infarct size and more favorable 
cardiac healing and remodeling.6  
 
The mechanism by which AAT preserves cardiac function during AMI is mediated by the 
engagement of the Low Density Lipoprotein Related Protein 1 (LRP1) receptor. Serpin Peptide 16 
(SP16) is a synthetic anti-inflammatory peptide developed to reproduce the -anti-inflammatory and 
α activities of the Serine Protease Inhibitors (SERPINs or Serpins), such as AAT. Serpins are a 
family of proteins characterized by the ability to inhibit plasma serine proteases such as elastase, 
thrombin, plasmin.7 When Serpins bind to serine proteases with resulting inactivation of enzymatic 
activity, causing a conformational change by which a short peptide containing a unique motif (5-11 
amino-acids) is exposed.8,9 This motif binds to LRP1, a membrane receptor responsible for 
clearance of plasma proteins and for inducing an anti-inflammatory and cytoprotective signal.9  
Serpin Pharma has developed a synthetic anti-inflammatory peptide (SP16) that contains the 
properties of the Serpin core motif responsible for the anti-inflammatory and cyto-protective 
signaling, without inhibiting the plasma serine proteases (Issued Patent #8,975,224). SP16 is 17 
amino acids in length, derived by excision of a 36-39 amino acid long peptide fragment to yield an 
active short peptide containing the unique motif.  SP16 represents the shortest oligopeptide 
maintaining activity and a single amino acid substitution enhancing anti-inflammatory signaling 
and plasma stability. In vitro, SP16 did not exhibit meaningful affinity for receptors other than 
LRP-1.  
 
From a safety perspective, SP16 appears to bind exclusively to LRP-1. A survey of >100 kinases 
and receptors showed no cross-reactivity of SP16 with other targets. SP16 appears not to be 
immunogenic. Antibodies to SP16 have not been detected in animal models after up to 6 months of 
treatment. Furthermore, deliberate attempts to produce anti-SP16 monoclonal antibodies failed to 
provoke an immune response. 
 
In comparison with AAT, SP16 is a bio-superior- small peptide which retains the anti-
inflammatory and cytoprotective properties of Serpins. SP16 only contains the LRP-1 binding 
motif, thus providing specific anti-inflammatory actions without serine protease inhibition. 
SP16 has demonstrated anti-inflammatory properties in several pre-clinical models. In ex vivo 
peripheral blood mononuclear cells derived from a collagen antibody induced arthritis mouse 
model, SP16 significantly reduced LPS-stimulated tumor necrosis factor (TNF)-α and Interleukin 
(IL)-6 production compared to vehicle and no treatment. SP16 has also been tested in db-/db 
diabetic mice, in which it significantly reduces serum amyloid A, an acute phase reactant, and 
monocyte chemotactic protein-1. Moreover, SP16 reduced IL-6 concentrations through inhibition 
of Myd88-mediated NF-κB activation, a key inflammatory signaling pathway. In vitro experiments 
have also demonstrated that SP16 inhibits NFκB activation.10 
 
In an experimental reperfused AMI model in the mouse, SP16 was shown to provide a strong 


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cardioprotective signaling.10 SP16 has been tested as treatment for acute myocardial infarction in 
the mouse. AMI was induced by temporary ligation of the proximal left coronary artery for 30 
minutes. Mice which had received a single administration of SP16 immediately at reperfusion or 
within 30 minutes of reperfusion had smaller infarct sizes and better left ventricular systolic 
function at 24 hours and 7 days. 
 
SP16 has been studied extensively in non-clinical toxicology studies. A single subcutaneous 
administration of SP16 at doses up to 60 mg/kg in Sprague-Dawley rats with a 14-day recovery 
period was well tolerated. There were no test article-related findings on clinical observation, body 
weights, body weight changes, food consumption and ophthalmology. There were no test article-
related findings on hematology, coagulation, urinalysis, absolute and relative organ weights or 
macroscopic examinations. Test article- related findings were limited to increased incidence of 
slight edema injection site in males given 60 mg/kg, minimal decreases in albumin in males given 
60 mg/kg, minimal increases in total cholesterol and triglycerides in females given ≥ 20 mg/kg, and 
microscopic changes at the injection site -a mild but increased severity of inflammation occurred in 
animals given 60 mg/kg, eosinophilic material and mild necrosis in subcutis of animals given ≥5 
mg/kg). The mild necrosis in the subcutis noted in males administered 60 mg/kg and in females 
administered ≥5 mg/kg was considered adverse. 
 
2.2 RATIONALE 
 
The main hypothesis of this study is that a single subcutaneous administration of SP16 0.2 mg/kg is 
safe and well tolerated in patients with STEMI and associated with a reduction in the acute 
inflammatory response to STEMI, as measured as area-under-the-curve (AUC) for C reactive 
protein (CRP), the preferred inflammatory marker for cardiovascular risk prognostication. 
SP16 will be administered subcutaneously as this route has greater ease of administration than 
intravenous injection. A single dose administration has been selected based upon pre-clinical data 
and expected clinical use of SP16.  
 
The dose of SP16 was chosen based on the results of a Phase I trial (NCTNCT03651089, WIRB® 
Protocol #20181644) in which 3 cohorts of healthy volunteers received a single subcutaneous 
injection of SP16 or placebo: SP16 0.0125 mg/kg (n=6), 0.050 mg/kg (n=6), 0.200 mg/kg (n=6), or 
placebo (n=6). Safety assessments were performed throughout 12 hours of continuous monitoring 
followed by return visits at 24 hours, 3 days, and 7 days. None of the SP16 doses showed any 
significant effects on any of the safety parameters as measured by comprehensive metabolic panel, 
complete blood count, liver function tests, thromboelastography, coagulation testing, 
electrocardiogram, and cardiac biomarkers (high sensitivity troponin I, CK-MB). All doses were 
well-tolerated and no patient reported injection site pain greater than 1/10 at 30 minutes after the 
dose. 
 
In a Phase IIA trial of 10 patients with ST-segment elevation myocardial infarction treated with 
plasma derived AAT11 the treatment was administered at a dose of 60 mg/kg, which is equimolar to 
an SP16 dose of 2 mg/kg. The 60 mg/kg dose of plasma-derived AAT was well-tolerated.11 Thus, 
the SP16 dose of 0.2 mg/kg is less than the equivalent dose of plasma-derived AAT which was 
well tolerated in the 10 patient Phase 1 clinical trial. However, in experimental settings SP16 was 
>20-fold more powerful than plasma derived AAT at an equimolar dose and >500-fold more 
powerful per mg of drug.10 
 


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2.3 POTENTIAL RISKS AND BENEFITS 
 
2.3.1 
KNOWN POTENTIAL RISKS 
 
Allergic reaction to any drug, including SP16, is possible, and severe allergic reactions can be life 
threatening.  
 
The dose of SP16 was chosen based on the results of a Phase I trial in which 3 cohorts of healthy 
volunteers received a single subcutaneous injection of SP16 or placebo: SP16 0.0125 mg/kg 
(n=6), 0.050 mg/kg (n=6), 0.200 mg/kg (n=6), or placebo (n=6). Safety assessments were 
performed throughout 12 hours of continuous monitoring followed by return visits at 24 hours, 3 
days, and 7 days. None of the SP16 doses showed any significant effects on any of the safety 
parameters as measured by comprehensive metabolic panel, complete blood count, liver function 
tests, thromboelastography, coagulation testing, electrocardiogram, and cardiac biomarkers (high 
sensitivity troponin I, CK-MB). All doses were well-tolerated and no patient reported injection 
site pain greater than 1/10 at 30 minutes after the dose. 
 
In clinical trials, the most common adverse reactions to plasma derived AAT (to which SP16 is 
related) occurring in >1% subjects were headache (7%), musculoskeletal discomfort (myalgias) 
(7%) and sore throat (pharyngitis) (2%). Rash, hot flushing and pruritus (itching) may also occur 
(<1%). All these reactions were considered mild or moderate and not severe and were self-
limiting with the end of the infusion.12 An elevation in the aminotransferase levels (ALT or AST) 
may occur (10%) deriving from subtle alterations in the muscles and/or liver. Such elevations 
were minor (less than 5-times baseline), transient (resolve within 3 months) and did not result in 
symptoms or any long-term consequences. Similar to any drug or intervention, the possibility of 
an unanticipated adverse reaction cannot be excluded. 
 
There is a possibility that an assessment completed during the screening phase will reveal an 
unrecognized disease or condition (i.e. pregnancy). The results of the tests will be discussed with 
the subject, and if requested, forwarded to a chosen physician. 
 
Loss of confidentiality is a potential risk. The likelihood of this occurring, however, is very low. 
Except when required for clinical practice or by law, subjects will not be identified by name, 
social security number, address, telephone number or any other personal identifier. Study related 
tests may be reported but subjects will not be identified.  
 
There is minimal risk associated with the physical procedures of the study. Additional blood 
draws may be needed as part of the study. The blood draws may result in minor bleeding or 
discomfort (rare) and infection (extremely rare) at puncture site. When possible, blood will be 
drawn from an existing indwelling peripheral venous catheter. 
 
2.3.2 
KNOWN POTENTIAL BENEFITS 
 
There are no guaranteed medical benefits to the study participants. There is a possibility that 
SP16 will result in a reduction in the inflammatory response to myocardial injury and this may 
portend a more favorable prognosis. All participants will be compensated for their participation. 
 
 


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3 
OBJECTIVES AND PURPOSE 
 
The primary objective of this study is to assess the effects of a single subcutaneous dose of SP16 on 
the acute inflammatory response in patients with STEMI. 
 
4 
STUDY DESIGN AND ENDPOINTS 
 
4.1 DESCRIPTION OF THE STUDY DESIGN 
 
We designed a single-center, single-arm, open-label study of a single subcutaneous administration 
of SP16 (0.2 mg/kg) in patients with STEMI. Patients will be eligible within if undergoing PCI 
within 12 hours of chest pain onset and if able enrolled and treated within 6 hours of PCI. 
Biomarkers will be obtained at admission, and up to 72 hours (or at discharge whichever comes 
first), and at 14±2 days. Patients will then return to clinic at 365 days to for transthoracic 
echocardiography. 
 
We will also follow the patients up to 12 months and assess the incidence of heart failure and 
related events. 
 
4.2 STUDY ENDPOINTS 
 
4.2.1  
PRIMARY ENDPOINT 
 
The primary endpoint of the study is the difference in AUC for CRP at 14 days comparing SP16-
treated patients with historical controls treated with placebo in the VCUART, VCUART2, and 
VCUART3 studies that used identical screening and enrollment criteria.12,13 
 
Patients presenting with STEMI have an enhanced IL-1 response as witnessed by elevation in 
serum markers such as CRP.4 We anticipate that patients with STEMI will have increased CRP 
levels and its levels will predict adverse cardiovascular outcomes. We therefore hypothesize that 
SP16 will blunt the CRP increase during STEMI.  The rationale for measuring AUC for CRP is 
that it integrates measurements across multiple time points to more accurately capture the acute 
inflammatory response and is also an established prognostic marker in STEMI. The AUC will be 
calculated based upon CRP values at baseline, 72 hours, and 14 days. 
 
4.2.2 
SECONDARY ENDPOINTS 
 
Infarct size will be based upon the time-concentration AUC of CK-MB.11,14 CK-MB will be 
determined by direct chemiluminescent technology at admission, immediately after PCI, and 
every 6 hours until 72 hours (when available). CK-MB peak value will be defined as the maximal 
CK-MB level measured during hospitalization. For patients with fewer than 6 recorded CK-MB 
measurements, CK-MBauc will be estimated by a validated log-normal model incorporating the 
admission CK-MB level, the CK-MB peak level, and the time-to-CK-MB peak to reconstruct the 
typical time course of CK-MB curve.14 The time-to-CK-MB peak, as a measure of duration of 
myocardial injury, will be considered as the time between the initial onset of symptoms (chest 
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A transthoracic echocardiogram will be performed at baseline and 365 days. The echocardiogram 
will measure left and right ventricular and atrial dimensions, left and right ventricular systolic 
function, transmitral flow Doppler spectra, mitral and tricuspidal valve annulus tissue Doppler 
spectra, ejection time and stroke volume, inferior vena cava, aorta and pulmonary artery 
diameters and Doppler spectra, according to the recommendations of the American Society of 
Echocardiography.15 Results from clinically indicated studies will be used for baseline 
measurements. 
 
4.2.3 
PHARMACOKINETIC ASSESSMENT 
 
A dedicated tube of blood will be collected to measure SP16 concentration at baseline, 30, 90 
minutes, and 180 minutes. Pharmacokinetic data will be analyzed using non-compartmental 
analysis. This approach will yield estimates of pharmacokinetic parameters such as total 
clearance (CLtot), cmax (maximum concentration), tmax (time to Cmax), mean resident time 
(MRTsys), volume of distribution of the central compartment (Vdcc), volume of distribution at 
pseudo-steady-state (Vdpss), volume of distribution at steady-state (Vdss), total area-under-the-
curve (AUC∞), half-life (t1/2), and terminal rate constant (λ) without having to specify a 
particular compartment model. 
 
5 
STUDY ENROLLMENT AND WITHDRAWAL 
 
5.1 PARTICIPANT INCLUSION CRITERIA 
 
In order to be eligible for this study, patients must meet ALL the 3 criteria:  
 
1) Presentation to the hospital with acute STEMI defined as chest pain (or equivalent) with an 
onset within 12 hours and ECG evidence of ST segment elevation (>1 mm) in 2 or more 
anatomically contiguous leads that is new or presumably new (for intermittent pain lasting 
more than 12 hours, the time from the when the pain became severe and constant); 
2) Coronary intervention planned and/or completed within 12 hours of symptom onset, and 
enrollment in the study within 6 hours of angiogram (max 18 hours from symptom onset) 
3) Age>21years (NIH standard) 
 
5.2 PARTICIPANT EXCLUSION CRITERIA 
 
In order to be eligible for this study, patients must meet NONE of the Exclusion criteria. 
 
- 
Inability to give informed consent 
- 
Hemodynamic instability as defined as need for inotropic or vasoactive agents, or need for 
mechanical support devices (including intra-aortic balloon pump) 
- 
Pregnancy or breastfeeding 
- 
Preexisting congestive heart failure (AHA/ACC class C-D, New York Heart Association III-
IV) 
- 
Preexisting severe left ventricular dysfunction (EF<20%) 
- 
Preexisting severe valvular heart disease 
- 
Known active infections (acute or chronic) including known COVID-19 infection or 
symptoms consistent of COVID-19 infection or close contact with a patient with COVID-19 


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in the prior 3 weeks (PCR testing results from current admission can be used but are not 
required) 
- 
Recent (<14 days) or active use of immunosuppressive drugs (including but not limited to 
high-dose corticosteroids [>1 mg/kg of prednisone equivalent], TNF-α  blockers, 
cyclosporine) not including NSAIDs or corticosteroids used for IV dye allergy only) 
- 
Recent (<14 days) or active use of anti-inflammatory drugs (not including NSAIDs or 
corticosteroids used for IV dye allergy only) 
- 
Known chronic inflammatory disease (including but not limited to rheumatoid arthritis, 
systemic lupus erythematosus) 
- 
Known active malignancy of any type, or prior diagnosis in the past 10 years 
- 
Neutropenia (absolute neutrophil count<1,800/mm3 [or <1,000/mm3 in African American 
patients]) 
- 
Severe impairment in renal function (estimated glomerular filtration rate <30 ml/kg*min) 
- 
Anticipated need for cardiac or major surgery  
- 
Known Allergy to SP16 
 
5.3 STRATEGIES FOR RECRUITMENT AND RETENTION 
 
5.3.1 
SCREENING 
 
All patients with suspected STEMI at VCU Health are identified with an alert system sent out to 
the on-call staff and the research team, call “Alpha Alert”. We will obtain a partial waiver for 
screening to prospectively identify subjects that may meet the inclusion criteria and access the 
electronic health records, if required by the Institutional Review Board. Every possible effort will 
be made to protect the privacy and confidentiality of the subjects. The information of those 
subjects who screen out or who decide to not enroll will be immediately discarded. Those who 
are found to be eligible and express interest in the study will be approached for consent. 
 
5.3.2  
CONSENTING 
 
With the exception of screening under a waiver of consent, no other study procedures will be 
completed prior to the subject consenting. Those individuals unable to provide consent and in 
whom a legally authorized representative cannot be found to consent will be excluded from the 
study. Potential participants will be approached as soon as possible after screening (including 
before catheterization) to discuss participation and obtain informed consent. However, patients 
will not receive treatment with SP16 upon successful completion of catheterization and 
completion of all screening criteria. Only appropriately trained investigators will attempt to 
obtain informed consent to participate in the study. 
 
5.3.3 
STUDY DRUG ADMINISTRATION  
 
Following screening and enrollment, the local investigational pharmacy will prepare the study 
drug for administration (0.2 mg/kg, up to 12 mg maximum). The drug will be administered by 
subcutaneous injection by the hospital nursing staff. 
 
5.4 PARTICIPANT WITHDRAWAL OR TERMINATION 


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Participants may withdraw voluntarily from the study or the PI may terminate a participant from 
the study. 
 
5.4.1 
REASONS FOR WITHDRAWAL OR TERMINATION 
 
Participants are free to withdraw from participation in the study at any time. An 
investigator may terminate participation in the study if: 
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• 
The participant meets an exclusion criterion (either newly developed or not 
previously recognized) that precludes further study participation. 
 
Halting criteria for study conduct are described separately in Sections Error! 
Reference source not found. and Error! Reference source not found.. 
 
5.4.2 
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
 
Effort will be made to complete follow-up for all participants who received investigational 
medication to ascertain safety endpoints. Participants who withdraw from the study prior to 
receipt of investigational medication will be considered screen failures and this enrollment spot 
will be replaced by another subject. Participants who receive investigational medication but 
refuse all forms of follow-up will be encouraged to seek alternative medical follow-up. 
 
5.5 PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause. The Sponsor and Principal Investigators will jointly evaluate study progress and 
risks to subjects after the first 3 subjects have completed. Written notification, documenting the 
reason for study suspension or termination, will be provided by the suspending or terminating party 
to regulatory authorities. If the study is prematurely terminated or suspended, the PI will promptly 
inform the Institutional Review Board (IRB) and will provide the reason(s) for the termination or 
suspension. 
 
Circumstances that may warrant termination or suspension include, but are not limited to 
determination of unexpected, significant, or unacceptable risk to participants. 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed and satisfy the sponsor, IRB and/or FDA. Specific halting rules are described in 
Section Error! Reference source not found.. 
 
6 
STUDY AGENT 
 
6.1 STUDY AGENT(S) AND CONTROL DESCRIPTION 
 
6.1.1 
ACQUISITION 
 


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SP16 will be supplied by the Sponsor Serpin Pharma LLC to the Investigational Drug Services 
(IDS) Pharmacy of Virginia Commonwealth University.  
 
6.1.2 
FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Investigational SP16 will be prepared by Serpin Pharma LLC. The pharmacy at the clinical site 
(VCU) will transfer the drug (SP16) from the vial into a tube in preparation for the injection.   
 
6.1.3 
PRODUCT STORAGE AND STABILITY 
 
The drug is stored in 4.5 mL, brown vials in -20oC.  The drug is formulated in water, pH 5.8-6.2, 
at 3 mg/mL. Final volume in each vial is 2.5 mL.  The drug was manufactured for phase II 
clinical trial on August 25, 2017.  The API stability after 12 and 24 months since manufacturing 
was found to be essentially unchanged. The expiration date was set as 12/31/2021. 
 
 
 
 
6.1.4 
PREPARATION 
 
SP16 API will be re-suspended in double distilled water and pH was adjusted to pH 5.9 ± 0.02 by 
adding 0.1M hydrochloric acid and/or 0.1M sodium hydroxide solution slowly. For complete 
details of formulation and sterile-fill-finish, please see MTA 172-2 and BMR-991. 
 
6.1.5 
DOSING AND ADMINISTRATION 
 
The drug can be thawed up to 6 hours from the time of injection and can be stored afterwards at 
4oC until injection.  Unused drug should be discarded and not be used for additional patients. 
Each subject will receive a single, weight-based dose of SP16 administered by subcutaneous 
injection (0.2 mg/kg, up to a maximum of 12 mg).  
 
6.1.6 
ROUTE OF ADMINISTRATION 
 
SP16 will be administered by subcutaneous injection.  
 
6.1.7 
DOSE  
 
SP16 will be administered at a dose of 0.2 mg/kg (up to a maximum of 12 mg). SP16 is 
formulated as a 2-mL syringe containing 6 mg of SP16 (3 mg/mL), such that all patients will 
require 2 separate subcutaneous injections to deliver the total dose. 


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6.1.8 
DURATION OF THERAPY 
 
All subjects will receive a single dose of SP16 (consisting of 2 injections given in the same 
session). Additional doses will not be administered. 
 
6.1.9 
TRACKING OF DOSE 
 
Investigational drug storage will be recorded and maintained by the VCU IDS Pharmacy. Dose 
administration will be recorded electronically by the nurse in the catheterization laboratory. 
 
6.2 STUDY AGENT ACCOUNTABILITY PROCEDURES 
 
The VCU Investigational Drug Services Pharmacy will prepare all doses of SP16. After 
preparation of each SP16 dose, dose administration will be tracked by the electronic Medication 
Administration Record at VCUHealth. Tracking of all incoming doses, dispensed doses, 
administered dose and wasted doses will be handled by the IDS Pharmacy according to local and 
national regulations. A single shipment of all investigational doses will be delivered by Serpin 
Pharma LLC to the IDS Pharmacy prior to the start of enrollment. Any unused syringes will be 
returned to Serpin Pharma LLC at the end of the study period. 
 
7 
STUDY PROCEDURES AND SCHEDULE  
 
7.1 STUDY PROCEDURES/EVALUATIONS 
 
7.1.1 
STUDY SPECIFIC PROCEDURES 
 
The following research procedures will be performed. 
 
• 
Medical history through patient interview, and if available, medical record review by a 
licensed study physician. 
• 
Medication history as reported by the patient, and if available, through pharmacy refill 
records by a licensed study physician. 
• 
A complete review of systems and physical examination will be performed by a 
licensed study physician. 
• 
A 12-lead electrocardiogram (ECG) will be reviewed by the investigators. 
• 
Blood sample collection for comprehensive metabolic panel, complete blood cell count, 
coagulation tests, cardiac injury markers and pharmacokinetics will be performed by a 
registered nurse. Blood samples will be drawn from an indwelling venous catheter when 
possible. 
 
7.1.2 
STANDARD OF CARE STUDY PROCEDURES 
 
Patients will receive the standard of care for STEMI, and these procedures will be charged to the 
patient or insurance, as applicable.  
 
This may include: 


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• 
Coronary angiogram and angioplasty. 
• 
Echocardiography and cardiac magnetic resonance. 
• 
Laboratory tests including CK-MB 
• 
Monitoring in the Intensive Care Unit. 
• 
Medications. 
 
7.2 LABORATORY PROCEDURES/EVALUATIONS 
 
A Schedule of Procedures is included in Section 7.3.6. 
 
7.2.1 
CLINICAL LABORATORY EVALUATIONS 
 
The following laboratory evaluations will be performed. 
 
• 
Hematology: hemoglobin, hematocrit, white blood cells (WBC) with differential count, 
platelet count. 
• 
Biochemistry: sodium, potassium, carbon dioxide, chloride, blood urea 
nitrogen, creatinine, total bilirubin, total protein, albumin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase. 
• 
High-sensitivity CRP 
• 
Pharmacokinetics: SP16 concentration 
• 
Pregnancy test (if indicated) 
 
7.2.2 
OTHER ASSAYS OR PROCEDURES 
 
None. 
 
7.2.3 
SPECIMEN PREPARATION, HANDLING, AND STORAGE 
 
Laboratory testing will be handled by the VCU Health Department of Pathology. 
 
Blood samples for pharmacokinetics will be drawn from a venous catheter and stored at -80 C 
prior to analysis. Each sample will be labeled with the subject’s unique study identifier. 
 
7.2.4 
SPECIMEN SHIPMENT 
 
The drug will be shipped on dry ice using GMP procedures (Global Courier) from the 
manufacturing site in the UK to the pharmacy at VCU.  The entire drug supply for phase I would 
arrive in one shipment. The boxes and vials are labelled (see label sample). 
 


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7.3 STUDY SCHEDULE 
 
7.3.1 
SCREENING  
 
• 
Review medications history to determine eligibility based on inclusion/exclusion criteria. 
• 
Perform medical examinations needed to determine eligibility based on 
inclusion/exclusion criteria. 
• 
Physical examination, including vital signs 
• 
ECG 
• 
Review of all study procedures and answer any participant questions 
• 
Obtain informed consent 
• 
Collect demographic information 
• 
Collect blood for baseline pharmacokinetics, comprehensive metabolic panel, CRP, 
complete blood cell count, and pregnancy test (if appropriate). 
 
7.3.2 
DOSING (after PCI) 
 
• 
Re-verify that subject meets inclusion/exclusion criteria upon completion of reperfusion. 
• 
Review coronary angiogram  
• 
Administer dose of SP16 (0.200 mg/kg, up to 12 mg) within 6 hours of reperfusion 
• 
Blood samples for pharmacokinetics will be collected at 30 +/- 15 min, 90 +/- 15 min, 180 
+/- 15 min and after SP16 administration  
 
7.3.3 
DISCHARGE (or 72 hours, whichever comes first) 
 
• 
Blood samples for hsCRP, safety labs (CBC, CBMP) and pharmacokinetics will be 
collected at 72 hours (or at discharge, whichever comes first). 
• 
Assess patient for adverse events 
• Record adverse events as reported by participant 
 
7.3.4 
VISIT 4: FOLLOW-UP VISIT (Day 14+/- 2) 
 
• 
History and physical exam 
• 
Blood sample for safety laboratory tests (CBC, CMP) 
• 
Blood sample for hsCRP  
• 
Assess patient for adverse events 
• 
Record adverse events as reported by participant. 
 


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7.3.4 
VISIT 5: FOLLOW-UP VISIT 2 (Day 90+/-14) 
 
• 
History and physical exam 
• 
Blood sample for safety laboratory tests (CBC, CMP) 
• 
Assess patient for adverse events 
• 
Record adverse events as reported by participant. 
 
7.3.5 
VISIT 6: FOLLOW-UP VISIT 3 (Day 365 +/- 30) 
 
• 
History and physical exam 
• 
Assess patient for adverse events 
• 
Transthoracic echocardiography 
• 
Record adverse events as reported by participant. 
 
7.3.6  
SARS-CoV2 SCREENING AND TESTING 
 
Screening and testing for SARS-CoV2 infection will performed as indicated by current VCU 
Health guidelines. These guidelines are frequently updated and are available to the PI and study 
physicians via the VCU Health intranet. Screening procedures include questions targeted at 
assessing symptoms and exposure risk. Testing may be performed by means of nasopharyngeal 
or oropharyngeal swab and polymerase chain reaction assay. As of August 21, 2020, every 
patient admitted to the hospital will be screened by specific questions and tested by a 
nasopharyngeal swab at time of admission. Patients being seen in the outpatient clinics will be 
screened by history only. 
 
7.3.7 
SCHEDULE OF EVENTS TABLE 
 
 
 
 
Procedures 
Screening 
Dosing 
Initial Inpatient 
(6 hours) 
Discharge 
(or 72 hours) 
Follow-up 
(14 days) 
Follow-up 2 
(90 days) 
Follow-up 3 
(365 days) 
Informed consent 
X 
X 
 
 
 
 
 
Verify subject meets inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Screening (and testing) for SARS-CoV2 virus* 
X 
 
 
 
X 
X 
X 
Medical history and physical examination 
X 
 
 
X 
X 
X 
X 
CBC w/diff, pltsa 
X 
 
 
X 
X 
X 
 
Comprehensive metabolic panela 
X 
 
 
X 
X 
X 
 
Serum Pregnancy testb 
X 
 
 
 
 
 
 
ECGa 
X 
 
 
 
 
 
 
Administer SP16 or matching placebo 
 
X 
 
 
 
 
 
hsCRP 
X 
 
 
X 
X 
 
 
Pharmacokinetic analysis 
X 
 
Xc 
 
 
 
 
Echocardiography 
 
 
Xa 
 
 
 
X 
Subject interview for adverse events 
 
 
 
X 
X 
X 
X 
Record adverse events if and as reported by 
participant 
 
 
X 
X 
X 
X 
X 
*per VCU Health standard of care  
aIf not already performed for routine care  
bIf applicable 
cDrawn at 0, 30 min, 90 min and 180 mins 
post-dose 
 
 
 
 
 
 
 


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7.4 CONCOMITANT MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
The patients will receive standard of care for STEMI. There will be no restrictions. 
 
7.5 JUSTIFICATION FOR USE OF PLACEBO 
 
Not applicable. 
 
7.5.1 
PRECAUTIONARY MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
None. 
 
7.6 PROHIBITED MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
There will be no restriction to medications, treatments, or procedures. 
 
7.7 PROPHYLACTIC MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Prophylactic medications, treatments or procedures will not be administered. 
 
7.8 RESCUE MEDICATIONS, TREATMENTS, AND PROCEDURES 
 
Rescue medications, treatments and procedures, such as anti-histamines, topical or systemic 
corticosteroids may be administered at the discretion of a licensed study physician in order to treat 
problems that emerge during the conduct of the study such as rash or allergic/anaphylactic 
reactions. There will be no restrictions with respect to the type or nature of rescue medications, 
treatments and procedures, which will be chosen at the discretion of a licensed study physician. 
 
7.9 PARTICIPANT ACCESS TO STUDY AGENT AT STUDY CLOSURE 
 
The investigational drug will not be available outside the study. 
 
8 
ASSESSMENTS OF SAFETY 
 
8.1 SPECIFICATION OF SAFETY PARAMETERS 
 
All adverse events (AEs) that occur during the study will be recorded. At each study visit, subjects 
will be interviewed to identify any AEs that have occurred. In addition, physical examinations, 
laboratory tests and other pre-specified assessments will be evaluated to identify AEs. 
 
Risks to subjects will be minimized by restricting study procedures to appropriately trained 
personnel. 
 
8.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention 
in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 


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Note: Laboratory/ECG/vital signs abnormalities are not an AE in themselves unless clinically 
relevant or meet the definition of an AE. 
 
8.1.2 
DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
Serious adverse event or serious suspected adverse reaction. An AE or suspected adverse reaction 
is considered "serious" if, in the view of either the investigator or sponsor, it results in any of the 
following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
8.1.3 
DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The office of human research protection (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the IRB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
 
This study will use the OHRP definition of UP. 
 
8.2 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.2.1 
SEVERITY OF EVENT 
 
For AEs not included in the protocol defined grading system, the following guidelines will be 
used to describe severity. 
 
• Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 


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functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. 
 
8.2.2 
RELATIONSHIP TO STUDY AGENT 
 
For all collected AEs, the clinician who examines and evaluates the participant will determine the 
AE’s causality based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. 
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition. 
• Possibly Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later 
be upgraded to “probably related” or “definitely related,” as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to drug administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of 
the trial medication) and in which other drugs or chemicals or underlying disease 
provides plausible explanations (e.g., the participant’s clinical condition, other 
concomitant treatments). 
• Not Related – The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.2.3 
EXPECTEDNESS 
 
The PIs will be responsible for determining whether an AE is expected or unexpected. An AE 
will be considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study agent. 
 
8.3 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 


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The occurrence of an AE or serious adverse event (SAE) may come to the attention of study 
personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form. Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with 
the training and authority to make a diagnosis), and time of resolution/stabilization of the event.  
 
All AEs occurring while on study must be documented appropriately regardless of relationship. All 
AEs will be followed to adequate resolution. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The PI will record all reportable events with start dates occurring any time after informed consent 
is obtained until 7 days after the administration of investigational medication. At each study visit, 
the investigator will inquire about the occurrence of AE/SAEs since the last visit. Events will be 
followed for outcome information until resolution or stabilization. 
 
8.4 REPORTING PROCEDURES 
 
8.4.1 
ADVERSE EVENT REPORTING 
 
Adverse (non-serious) events will be reported to the IRB on an annual basis and to the Sponsor at 
designated Safety Review milestones. 
 
8.4.2 
SERIOUS ADVERSE EVENT REPORTING 
 
The investigators will report all adverse events to the Sponsor and local IRB. Serious, unexpected 
adverse events will be reported to the local IRB and to the Sponsor within 5 business days. All 
other AEs (unexpected but not serious or expected) will be reported to the Sponsor as a summary 
during follow up and at the completion of the study. All other AEs will be reported to the IRB at 
the time of regular (i.e. yearly) continuing review submissions. 
 
The Sponsor will report all serious, unexpected adverse events as an IND safety report to the 
FDA no later than 15 calendar days after the sponsor’s initial receipt of this information. Fatal or 
life-threatening unexpected experiences for which there is a possibility that the experience may 
have been caused by the drug will be reported by the Sponsor to the FDA by telephone or 
facsimile transmission no later than 7 calendar days after receipt of this information. An annual 
report which includes summaries of all IND safety reports will be submitted to the FDA each 
year in the annual report by the Sponsor. 
 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the 
event to be chronic. Other supporting documentation of the event may be requested by the study 
sponsor and should be provided as soon as possible. 
 


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The study Sponsor will be responsible for notifying FDA of any unexpected fatal or life-
threatening suspected adverse reaction as soon as possible but in no case later than 7 calendar 
days after the Sponsor's initial receipt of the information. 
 
8.4.3 
UNANTICIPATED PROBLEM REPORTING 
 
Incidents or events that meet the OHRP criteria for UPs require the creation and completion of an 
UP report form. It is the Site Investigator’s responsibility to report UPs to their IRB and to the 
Study Sponsor.  
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline: 
• UPs will be reported to the IRB and to the study Sponsor within 5 business days of the 
Investigator becoming aware of the problem. 
 
8.4.4 
EVENTS OF SPECIAL INTEREST 
 
Not applicable. 
 
8.4.5 
REPORTING OF PREGNANCY 
 
In the event that a subject becomes pregnant after screening and before enrollment, that subject 
will be excluded from participation. Pregnancy that occurs after receipt of investigational 
medicine will prompt reporting to the patient’s primary physician for appropriate monitoring and 
follow-up. 
 
8.5 STUDY HALTING RULES 
 
Administration of study agent will be halted under the circumstances described below. The 
Principal Investigators will halt enrollment immediately and notify the Sponsor within 24 hours. 
The Study Sponsor will inform the Data Safety Monitoring Board (DSMB) members within 24 
hours of becoming aware and will provide the DSMB with AE listing reports. The DSMB will 
convene an ad hoc meeting by teleconference or in writing as soon as possible. The DSMB will 
provide recommendations for proceeding with the study to the Study Sponsor and Principal 
Investigators. The Study Sponsor will inform the FDA of the temporary halt and the disposition of 
the study. 
 
Enrollment in the study will be terminated if the any of following occur: 
• 
Serious adverse event, if determined to be probably or definitely related to the 
investigational medication in a patient who have received SP16 or is unexpected in nature. 
 
Enrollment in the study will be halted until joint review by the PIs and Sponsor if any of the 
following occur: 
• Two identical unexpected serious adverse events in two separate subjects. 
 
In addition, the Principal Investigators may choose to halt enrollment, if in their opinion, continued 
enrollment would pose an unacceptable risk to subjects. Additional description of halting and 
stopping is provided in Premature Suspension or Stopping of the Study Section 5.5. 


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8.6 SAFETY OVERSIGHT 
 
Safety oversight will be under the direction of the Principal Investigators and Sponsor. The 
Principal Investigators and Sponsor will review safety data on an ongoing basis. The occurrence of 
any adverse events specified in Section 8.5. will prompt a safety review of the Principal 
Investigators and Sponsor in consideration to Halting Rules. 
 
8.7   ADJUDICATION OF CLINICAL EVENTS 
 
8.7.1 
Event-adjudicating committee 
 
The event-adjudicating committee is composed of a general cardiologist, a cardiologist with 
training in heart failure, and a general internal medicine specialist. The committee will meet at 
the end of the study and adjudicate all the events. The committee will be blinded to treatment 
allocation. In order to favor allocation concealment, the committee will also be blinded to C-
reactive protein levels, which may be affected by treatment.  
 
8.7.2 
Definition of the events 
 
The events adjudicated will include:  
- 
Death;  
- 
Cardiac death (in which a direct cause attributable to cardiac disease is present); 
- 
Sudden cardiac death (in which cardiac death occurred out of the hospital and suddenly; 
or in the hospital due to ventricular arrhythmias unrelated to other concomitant cardiac 
conditions); 
- 
Non-cardiac death (in which the event of death is considered not to be a direct 
consequence of cardiac disease); 
- 
Incidence of heart failure during the index hospitalization (defined as dyspnea 
beginning or persisting >24 hours after admission and meeting both of the following 
criteria: 
o physical signs of heart failure - including 2 or more of the following: edema, 
crackles/rales, jugular vein distention, hepatojugular reflex, tachypnea, rapid 
weight gain, S3 gallop, abdominal distension/ascites, radiologic evidence of 
worsening edema, pulmonary artery occlusive pressure (wedge) >18 mmHg or 
cardiac output <2.2 l/min-m2; 
o need for additional/increased heart failure therapy - including one of the 
following:   initiation or significant increase of oral diuretics, requirement of 
intravenous diuretics, inotropes or vasodilators, need for ultrafiltration due to 
decompensated heart failure; 
- 
Re-hospitalization for any cause; 
- 
Re-hospitalization for heart failure (meeting all criteria listed above for heart failure 
during index hospitalization) 
- 
Incidence of heart failure (not hospitalized) defined as new or worsening dyspnea and 
meeting one of the two of the following criteria: 
o physical signs of heart failure - including 2 or more of the following: edema, 
crackles/rales, jugular vein distention, hepatojugular reflex, tachypnea, rapid 
weight gain, S3 gallop, abdominal distension/ascites, radiologic evidence of 


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worsening edema, pulmonary artery occlusive pressure (wedge) >18 mmHg or 
cardiac output <2.2 l/min-m2; 
o need for additional/increased heart failure therapy - including one of the 
following:   initiation or significant increase of oral diuretics, requirement of 
intravenous diuretics, inotropes or vasodilators, need for ultrafiltration due to 
decompensated heart failure; 
- 
Acute myocardial infarction, as defined by the WHO consensus statement 
- 
Unstable angina, or need for coronary revascularization 
- 
Cardiac tachy- or brady-arrhythmias leading to a new hospitalization or to prolongation 
of hospital stay; 
- 
Acute renal failure (defined as in increase in plasma creatinine levels of 50% or 0.5 
mg/L); 
- 
Acute respiratory failure (not due to heart failure); 
- 
Sepsis or other serious infection requiring antibiotic therapy; 
- 
Acute stroke. 
 
The analysis will consider time to first event and time to each event. It will also consider event 
rates at 3 and 12 months, in order to favor comparisons with other studies. The number of days 
free of hospitalization during the first 1, 3, 6 and 12 months will also be measured and compared 
between groups. 
 
8.7.3 
Implications of the findings of the event-adjudicating committee 
 
The events will be adjudicated only after the completion of the study, and therefore the findings 
by the committee will have no implications on the conduct of the study. 
 
9 
CLINICAL MONITORING 
 
Monitoring for this study will be performed by the Principal Investigators to ensure that the rights 
and well-being of human subjects are protected, that the reported trial data are accurate, complete, 
and verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with GCP, and with applicable regulatory requirement(s). Complete review 
of Case Report Forms will be performed by the Principal Investigators during Safety Milestones as 
described in Section Error! Reference source not found.. 
 
10  
STATISTICAL CONSIDERATIONS 
 
10.1 ANALYSIS DATASETS 
 
• 
All analyses will be conducted on the Safety Analysis Dataset (e.g., participants 
who received the investigational product). 
 
10.2 DESCRIPTION OF STATISTICAL METHODS 
 
10.2.1 
GENERAL APPROACH 
 
Baseline measurements and demographic characteristics will be summarized with median and 


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interquartile range. Descriptive summaries of categorical measurements will consist of 
frequencies and proportions. The summaries for each measurement will be provided separately 
for the treatment group and in comparison with placebo-treated patients of VCUART, 
VCUART2 and VCUART3 clinical trials. Between group comparisons between the two 
treatment groups will be conducted with the chi-square test for categorical variables and the 
Mann-Whitney test for continuous variables. An assessment of sample size or power analyses is 
not performed for this pilot Phase IB/IIA study. A two-sided p-value < 0.05 will be considered 
statistically significant. 
 
11 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA/DOCUMENTS 
 
Virginia Commonwealth University will maintain appropriate medical and research records for this 
trial, in compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of participants.  
 
12 
QUALITY ASSURANCE AND QUALITY CONTROL 
 
The PIs will oversee all data collection and recording on Case Report Forms. They will periodically 
review Case Report Forms. 
 
13 
ETHICS/PROTECTION OF HUMAN SUBJECTS 
 
13.1 ETHICAL STANDARD 
 
Principal Investigators will ensure that this study is conducted in full conformity with Regulations 
for the Protection of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 
CFR Part 56, and/or the ICH E6. 
 
13.2 INSTITUTIONAL REVIEW BOARD 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to 
the consent form will be IRB approved; a determination will be made regarding whether previously 
consented participants need to be re-consented. Western Institutional Review Board (Puyallap, 
WA) will serve as the IRB of record for this study. 
 
13.3 INFORMATED CONSENT PROCESS 
 
13.3.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS 
PROVIDED TO PARTICIPANTS 
 
All study procedures will be completed after to the subject consenting with the exception of 
screening under a waiver of consent. Those individuals unable to provide consent and in whom a 
legally authorized representative cannot be found to consent will be automatically excluded from 
the study. Only appropriately trained investigators will attempt to obtain informed consent to 
participate in the study. Considering, the emergency nature of the condition, we will request the 


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Institutional Review Board to approve a short consent form to be followed by a full-length 
consent form.  
 
13.3.2 
CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is an ongoing process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. Extensive 
discussion of risks and possible benefits of participation will be provided to the participants and 
their families. Consent forms will be IRB-approved and the participant will be asked to read and 
review the document. The investigator will explain the research study to the participant and 
answer any questions that may arise. All participants will receive a verbal explanation in terms 
suited to their comprehension of the purposes, procedures, and potential risks of the study and of 
their rights as research participants. When a potential candidate is identified, he or she will be 
provided with a consent form that explains the purposes of the study, the study procedures, the 
potential risks of participation, and all other requisite information as required by law. The consent 
form will also explain that continuation in the study is “voluntary” and that the patient has “the 
right to withdraw from the study at any time”. A copy of the informed consent document will be 
given to the participants for their records. 
 
13.4 PARTICIPANT AND DATA CONFIDENTIALITY 
 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and 
the sponsor(s) and their agents. This confidentiality is extended to cover testing of biological 
samples in addition to the clinical information relating to participants. Therefore, the study 
protocol, documentation, data, and all other information generated will be held in strict confidence. 
• 
Coded identifiers will be attached to data or samples. 
• 
The key to coded identifiers will be stored in a password-protected database compliant 
with local standards and will be accessible only to the research team. Case Report Forms 
and written informed consent forms will be stored in a locked cabinet within a locked 
office with access restricted to the study team. 
• 
Coded data and samples, but not the key, will be shared with the Sponsor. 
 
The study participant’s contact information will be securely stored at the clinical site for internal 
use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and Institutional regulations. 
 
13.4.1 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS OR DATA 
 
• 
Intended Use: Samples and data collected under this protocol may be used to 
accomplish the objective of this study.  No genetic testing will be performed. 
• 
Storage: Access to stored samples will be limited using physical restrictions to locked 
storage areas and coded identifiers. Samples and data will be stored using codes 
assigned by the investigators. Data will be kept in password- protected computers.  
Only investigators will have access to the samples and data. 
 
13.5 FUTURE USE OF STORED SPECIMENS 
 


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Not applicable. 
 
14 
DATA HANDLING AND RECORD KEEPING 
 
14.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data. Black ink is required to ensure clarity of reproduced copies. When making 
changes or corrections, cross out the original entry with a single line, and initial and date the 
change. Clinical data (including AEs, concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered onto Case Report Forms. 
 
14.2 STUDY RECORDS RETENTION 
 
Study documents should be retained for a minimum of 5 years beyond completion of this study or 
2 years after the last approval of a marketing application in an ICH region and until there are no 
pending or contemplated marketing applications in an ICH region or until at least 2 years have 
elapsed since the formal discontinuation of clinical development of the investigational product, 
whichever is later. No records will be destroyed without the written consent of the Sponsor, if 
applicable. It is the responsibility of the Sponsor to inform the investigator when these documents 
no longer need to be retained. 
 
14.3 PROTOCOL DEVIATIONS 
 
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP 
requirements. The noncompliance may be either on the part of the participant, the investigator, or 
the study site staff. As a result of deviations, corrective actions are to be developed by the site and 
implemented promptly. 
 
These practices are consistent with ICH S7A, B:16,17 
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3 
• 
5.1 Quality Assurance and Quality Control, section 5.1.1 
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
 
It is the responsibility of the site to use continuous vigilance to identify and report deviations 
within 3 working days of identification of the protocol deviation. All deviations must be addressed 
in study source documents, reported to the local IRB per their guidelines. The site PI/study staff is 
responsible for knowing and adhering to their IRB requirements.  
 
14.4 PUBLICATION AND DATA SHARING POLICY 
 
This study will be registered on clinicaltrials.gov. The results of this study will be presented at 
conferences and published in a peer-reviewed medical journals in a way that no identifiers are 
included.  


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15 
STUDY ADMINISTRATION 
 
15.1 STUDY LEADERSHIP 
 
The PIs and Sponsor will serve as study leadership.  
 
16 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Therefore, any actual conflict of interest of persons who have a 
role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 
such conflicts managed in a way that is appropriate to their participation in the trial.   
 
 
17 
APPENDIX 
 
Version 
Date 
Significant Revisions 
v.1 
12/13/2019 
Initial version 
v.2 
03/27/2020 
Suspension of enrollment and modification of follow up 
procedures in response to COVID-19 pandemic 
 
 
 


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18 
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14 Abouzaki NA, Christopher S, Trankle C, Van Tassell BW, Carbone S, Mauro AG, Buckley L, 
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16 ICHS7A-  
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7A/Step4/S7A_G
uideline.pdf 
7 ICHS7b- 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Safety/S7B/Step4/S7B_G
uideline.pdf