Clinical trial NCT04391179
Conditions: COVID Corona Virus Infection Covid-19 SARS-CoV-2 Infection
Keywords: Oxygen
Sponsor: University of Michigan
Start date: 2020-05-31; Completion date: 2021-02-22
Enrollment: 99 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The most severe manifestations of COVID-19 include respiratory failure, coagulation problems, and death. Inflammation and blood clotting are believed to play an important role in these manifestations. Research in humans has shown that dipyridamole can reduce blood clotting. This research study is being conducted to learn whether 14 days of treatment with dipyridamole will reduce excessive blood clotting in COVID-19.

This study will enroll participants with confirmed coronavirus (SARS-CoV)-2 infection that are admitted. Eligible participants will be randomized to receive dipyridamole or placebo for 14 days in the hospital. In addition, data will be collected from the medical record, and there will also be blood draws during the hospitalization.

Detailed description:

Arms: arm 1: 100 milligrams (mg) by mouth (PO) four times a day (QID) arm 2: Placebo given by mouth four times a day
Interventions: intervention 1: Dipyridamole 100 Milligram(mg) intervention 2: Placebo oral tablet
Intervention descriptions: intervention 1: Drug will be given for 14 days while in the hospital. intervention 2: Placebo will be given for 14 days while in the hospital.

Protocol documents:
Prot_002.pdf: 
DICER (Dipyridamole to prevent Coronavirus Exacerbation of Respiratory Status) 
Clinical Research Protocol 6.0 
NCT04391179
July 12th, 2021


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CLINICAL RESEARCH PROTOCOL 
DICER (Dipyridamole to prevent Coronavirus Exacerbation of Respiratory Status) 
Protocol Number: 
HUM00179783 
Version and Version Date: 
Internal Ver 6.0; July 12th, 2021 
Investigational Product: 
Dipyridamole 
IND Number: 
149516 
Development Phase: 
Phase II Proof-of-concept and feasibility 
IND Holder 
Yogendra Kanthi, MD 
1150 West Medical Center Drive 
Ann Arbor, Michigan 48109 
Funding Organization: 
University of Michigan 
National and UM Site Principal 
Investigator  
Name: Jason S. Knight, MD, PhD 
Telephone: (734) 615-1880 
Fax: (734) 763-4151 
E-mail: jsknight@med.umich.edu
Medical Monitor: 
DSMB (central) 


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VERSION HISTORY 
 
Version 
Date 
Ver 1.0( Internal version 5.2) 
06May2020 
Ver 2.0 
16Jun2020 
Ver 2.1 
15Jul2020 
Ver 3.0 
19Jul2020 
Ver 4.0 
11Aug2020 
Ver 5.0 
23Nov2020 
Ver. 6.0 
12-July-2021 
 
 
 


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SUMMARY OF CHANGES 
 
Item/Section 
Change (s) 
 
Please see Summary of Changes 
 
 


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TABLE OF CONTENTS 
CLINICAL RESEARCH PROTOCOL ..........................................................................1 
VERSION HISTORY ........................................................................................................2 
SUMMARY OF CHANGES .............................................................................................3 
TABLE OF CONTENTS ..................................................................................................4 
LIST OF TABLES .............................................................................................................7 
LIST OF ABBREVIATIONS ...........................................................................................8 
PROTOCOL SYNOPSIS ..................................................................................................9 
1 
BACKGROUND - DIPYRIDAMOLE ...................................................................14 
1.1 
NON-CLINICAL STUDIES OVERVIEW........................................................17 
1.2 
CLINICAL STUDIES OVERVIEW ..................................................................17 
2 
STUDY RATIONALE..............................................................................................18 
3 
STUDY OUTCOMES ..............................................................................................19 
3.1 
PRIMARY OUTCOME ......................................................................................19 
3.2 
SECONDARY OUTCOMES ..............................................................................19 
3.3 
SAFETY OUTCOMES .......................................................................................20 
3.4 
EXPLORATORY OUTCOMES ........................................................................20 
4 
STUDY DESIGN ......................................................................................................22 
5 
CRITERIA FOR EVALUATION ...........................................................................23 
5.1 
SAFETY EVALUATIONS .................................................................................23 
5.2 
OTHER EVALUATIONS ...................................................................................24 
6 
PARTICIPANT SELECTION ................................................................................24 
6.1 
STUDY POPULATION ......................................................................................24 
6.2 
INCLUSION CRITERIA ....................................................................................24 
7 
CONCURRENT MEDICATIONS..........................................................................25 
7.1 
ALLOWED MEDICATIONS AND TREATMENTS ......................................25 
7.2 
PROHIBITED MEDICATIONS AND TREATMENTS .................................25 
8 
STUDY TREATMENTS ..........................................................................................25 
8.1 
METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS25 
8.2 
BLINDING ...........................................................................................................25 
8.3 
FORMULATION OF TEST AND CONTROL PRODUCTS .........................26 
8.3.1 
FORMULATION OF TEST PRODUCT ....................................................26 
8.3.2 
FORMULATION OF CONTROL (PLACEBO) PRODUCT ...................26 
8.3.3 
PACKAGING AND LABELING .................................................................26 
8.4 
SUPPLY OF STUDY DRUG AT THE SITE ....................................................26 
8.4.1 
GENERIC STUDY DRUGS WILL BE PURCHASED BY THE 
PHARMACY. DOSAGE/DOSAGE REGIMEN ........................................26 
8.4.2 
DISPENSING .................................................................................................26 
8.4.3 
ADMINISTRATION INSTRUCTIONS ......................................................26 
8.4.4 
SUPPLY OF STUDY DRUG AT THE SITE ..............................................27 
8.4.5 
STORAGE ......................................................................................................27 
8.5 
STUDY DRUG ACCOUNTABILITY ...............................................................27 
9 
STUDY PROCEDURES AND GUIDELINES ......................................................27 
9.1 
CLINICAL ASSESSMENTS ..............................................................................27 
9.1.1 
CONCOMITANT MEDICATIONS ............................................................27 
9.1.2 
DEMOGRAPHICS ........................................................................................28 


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9.1.3 
MEDICAL HISTORY ...................................................................................28 
9.1.4 
SOCIAL HISTORY .......................................................................................28 
9.1.5 
PHYSICAL EXAMINATION ......................................................................28 
9.1.6 
ELECTROCARDIOGRAM .........................................................................28 
9.1.7 
CHEST IMAGING ........................................................................................28 
9.1.8 
VITAL SIGNS ................................................................................................28 
9.1.9 
OXYGEN REQUIREMENTS AND MODIFIED WHO COVID-19 8-
POINT ORDINAL SCALE ASSESSMENT ...............................................28 
9.1.10 
ADVERSE EVENTS .....................................................................................29 
9.2 
CLINICAL LABORATORY MEASUREMENTS ...........................................29 
9.2.1 
D-DIMER, FERRITIN, LACTATE DEHYDROGENASE (LDH), C-
REACTIVE PROTEIN (CRP), COMPLETE BLOOD CELL COUNT 
WITH DIFFERENTIAL (CBC), FIBRINOGEN, PARTIAL 
THROMBOPLASTIN TIME (PTT), INTERNATIONAL 
NORMALIZED RATIO (INR) ARTERIAL BLOOD GASES (ABG), 
BASIC METABOLIC PANEL (BMP), HEPATIC FUNCTION PANEL 
(LFT) ...............................................................................................................29 
9.2.2 
PREGNANCY TEST .....................................................................................30 
9.3 
PHARMACOKINETIC MEASUREMENTS ...................................................30 
9.4 
RESEARCH LABORATORY MEASUREMENTS (SEE SCHEDULE OF 
EVENTS) ..............................................................................................................30 
9.4.1 
COAGULATION POTENTIAL ..................................................................30 
9.4.2 
BIOMARKERS OF BLOOD CELL ACTIVATION .................................30 
9.4.3 
LEUKOCYTES ..............................................................................................30 
10 EVALUATIONS BY DAY OF HOSPITALIZATION .........................................31 
10.1 
SCREENING ENROLLMENT VISIT (24 HOUR) .........................................31 
10.2 
DAY 1 TREATMENT .........................................................................................31 
10.3 
DAY 2 TREATMENT .........................................................................................31 
10.4 
DAY 3 TREATMENT .........................................................................................31 
10.5 
DAY 4 TREATMENT .........................................................................................32 
10.6 
DAY 5 TREATMENT .........................................................................................32 
10.7 
DAY 6 TREATMENT .........................................................................................32 
10.8 
DAY 7 TREATMENT .........................................................................................32 
10.9 
DAY 8 TREATMENT .........................................................................................33 
10.10 DAY 9 TREATMENT .........................................................................................33 
10.11 DAY 10 TREATMENT .......................................................................................33 
10.12 DAY 11 TREATMENT .......................................................................................33 
10.13 DAY 12 TREATMENT .......................................................................................34 
10.14 DAY 13 TREATMENT .......................................................................................34 
10.15 DAY 14 TREATMENT .......................................................................................34 
10.16 EARLY WITHDRAWAL INTERACTION .....................................................35 
10.17      30 Days after last dose of study drug (± 2 day)……………………………...34 
 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION .............35 
11.1 
ADVERSE EVENTS ...........................................................................................35 


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11.2 
AE SEVERITY.....................................................................................................36 
11.2.1 
AE RELATIONSHIP TO STUDY DRUG ..................................................36 
11.2.2 
SERIOUS ADVERSE EXPERIENCES (SAE) ...........................................37 
11.2.3 
SERIOUS ADVERSE EXPERIENCE REPORTING ...............................37 
11.3 
PROTOCOL DEFINED IMPORTANT MEDICAL FINDINGS 
REQUIRING REAL TIME REPORTING .......................................................37 
11.4 
MEDICAL MONITORING ................................................................................37 
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS ..............37 
12.1 
EARLY DISCONTINUATION OF STUDY DRUG ........................................37 
12.2 
WITHDRAWAL OF PARTICIPANTS FROM THE STUDY .......................38 
12.3 
REPLACEMENT OF PARTICIPANTS ...........................................................38 
13 PROTOCOL VIOLATIONS ...................................................................................38 
14 DATA SAFETY MONITORING ............................................................................38 
15 STATISTICAL METHODS AND CONSIDERATIONS .....................................39 
15.1 
DATA SETS ANALYZED ..................................................................................39 
15.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS .........................39 
15.3 
ANALYSIS OF PRIMARY ENDPOINT ..........................................................39 
15.4 
ANALYSIS OF SECONDARY ENDPOINTS ..................................................41 
15.5 
POWER ANALYSIS ...........................................................................................42 
15.6 
SAMPLE SIZE AND RANDOMIZATION ......................................................43 
16 DATA COLLECTION, RETENTION AND MONITORING .............................43 
16.1 
DATA COLLECTION INSTRUMENTS ..........................................................43 
16.2 
DATA MANAGEMENT PROCEDURES ........................................................44 
16.3 
DATA QUALITY CONTROL AND REPORTING ........................................44 
16.4 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS44 
16.5 
MONITORING ....................................................................................................44 
16.6 
PARTICIPANT CONFIDENTIALITY.............................................................44 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ........44 
17.1 
PROTOCOL AMENDMENTS ..........................................................................45 
17.2 
INSTITUTIONAL REVIEW BOARDS ............................................................45 
17.3 
INFORMED CONSENT FORM ........................................................................45 
17.4 
PUBLICATIONS .................................................................................................46 
PROTOCOL REFERENCES .........................................................................................47 
APPENDIX 1. SCHEDULE OF STUDY EVENTS ......................................................48 
APPENDIX 2. SUMMARY OF CHANGES .................................................................48 
 
 
 
 


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LIST OF TABLES 
 
Table 1:  
Adverse reactions reported in 2 heart valve replacement trials ..........18 
Table 2:  
AE Severity Grading................................................................................36 
Table 3:  
AE Relationship to Study Drug ..............................................................36 
 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
Adverse Event 
ARDS 
Acute respiratory distress syndrome 
CBC 
Complete blood cell count with differential 
COVID-19 
Coronavirus disease 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FiO2 
Fraction of inspired oxygen 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
Informed Consent Form 
IRB 
Institutional Review Board 
MICHR 
Michigan Institute for Clinical and Health Research 
PI 
Principal Investigator 
PMN 
Neutrophils 
SAE 
Serious Adverse Event 
SARS-
CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SpO2 
Peripheral pulse oximetry 


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PROTOCOL SYNOPSIS 
TITLE 
DICER (DIpyridamole to prevent Coronavirus Exacerbation of 
Respiratory status) 
IND Holder  
Yogendra Kanthi 
National and Site Principal 
Investigator 
Jason S. Knight, MD, PhD 
FUNDING ORGANIZATION 
University of Michigan, Taubman Medical Research Institute 
NUMBER OF SITES 
1 
RATIONALE 
 
Immune hyperactivation and thrombophilia appear to predict worse 
outcomes in individuals with COVID-19. Approximately one-quarter 
of patients admitted with COVID-19 will develop progressive 
respiratory dysfunction and require mechanical ventilation. The 
majority of hospitalized patients infected with COVID-19 develop 
coagulation dysfunction as indicated by elevated D-dimer, which 
predicts acute respiratory distress syndrome, venous thromboembolism, 
and mortality. The intent of this proof-of-concept study is to evaluate 
whether dipyridamole will reduce D-dimer elevation in participants 
with moderate COVID-19. Dipyridamole is an adenosinergic drug with 
a favorable safety profile, that reduces thrombosis, immune 
hyperactivation, and directly inhibits SARS-CoV-2 virus replication. A 
small clinical trial of dipyridamole in 31 patients with moderate- and 
severe-COVID-19 showed safety of dipyridamole and efficacy in 
reducing D-dimer levels, and a trend toward improved clinical 
outcomes. 
This is a proof-of-concept study to evaluate the effect of dipyridamole 
on participants with moderate coronavirus infection (COVID-19) with 
respect to increase in D-dimer, respiratory status, ventilation and 
mortality, and ICU admission. If this novel approach is effective in 
reducing the progression of D-dimer elevation, it will inform a larger, 
multi-center trial to determine efficacy in preventing progression of 
moderate to severe COVID-19 infection. The result may broadly 
improve care of patients with coronavirus infection.  
STUDY DESIGN 
This is a proof-of-concept multi-center, randomized, single-blinded, 
placebo-controlled phase II study. We will recruit female or male 
patients with moderate COVID-19 and randomize them to treatment 
with 14 days of dipyridamole, or placebo control. 
PRIMARY OBJECTIVE 
The first primary objective of this study is to evaluate the effect of 
dipyridamole on D-dimer changes in patients with moderate COVID-
19. 
The second primary objective, formerly a secondary objective, is to 
compare the effect of dipyridamole vs. placebo on a composite of 
clinical outcomes. 
PRIMARY OUTCOMES 
The first co-primary outcome is increase in plasma D-dimer levels 
compared to baseline. 


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The second co-primary endpoint is a clinical hierarchical composite of 
time to death, number of days on mechanical ventilation, decrease in 
daily average SpO2/FiO2 ratio, and cumulative sum of COVID ordinal 
score. 
SECONDARY OUTCOMES 
Days alive and free of organ support, where organ support is defined as 
receipt of invasive mechanical ventilation, vasopressor therapy, ECMO 
support, or dialysis. 
Individual components of composite endpoint. 
EXPLORATORY OUTCOMES 
Time to improvement in oxygenation status, initiation of mechanical 
ventilation or ICU care, proportion of patients requiring mechanical 
ventilation, change from baseline in hematology labs (C-reactive 
protein, LDH, ferritin, leukocyte count, platelet count) among patients 
with abnormal baseline values, time to hospital discharge, incidence of 
hospital readmission, proportion of surviving patients requiring 
supplemental oxygen at discharge, number of days on supplemental 
oxygen, arterial or venous thromboembolism (separately and pooled), 
gene expression / function / activation of peripheral blood leukocytes, 
and decrease in each of the following among patients with elevated 
baseline values: glomerular filtration rate, neutrophil activation, 
inflammatory / anti-inflammatory / other cytokines, and coagulant and 
anti-coagulant cytokines. 
NUMBER OF PARTICIPANTS 
The original protocol called for the enrollment of 80 participants in 
order to complete the study, randomized 1:1 to dipyridamole or 
placebo. However, the standard of care changed with the introduction 
of anti-inflammatory steroids which suggested an increase in sample 
size may be necessary, thus it was decided to double the number of 
participants to 160.  
 
During the January DSMB meeting it was decided to halt enrollment at 
100 participants due to futility. 
PARTICIPANT SELECTION 
CRITERIA 
Inclusion Criteria: 
1. Age ≥ 18 years  
2. Willing and able to provide informed consent prior to 
performing study procedures unless they have a legally 
authorized representative (LAR) 
3. Confirmed coronavirus (SARS-CoV-2) infection 
4. Currently hospitalized or anticipated hospitalization requiring 
supplemental oxygen  
 
Exclusion Criteria: 
1. In the opinion of at least two physicians, unlikely to survive for 
>48 hours from screening 
2. Concurrent enrollment in a clinical trial with a cytokine 
inhibitor (targeting IL-6, IL-6R, IL-1, or Janus kinase). Use of 
remdesivir is permitted. 


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3. Currently on invasive mechanical ventilation 
4. Hypotension defined as systolic blood pressure < 90 mmHg on 
two sequential readings at least 4 hours apart 
5. Pregnant or breastfeeding 
6. Concurrent dual antithrombotic therapy (aspirin or P2Y12 
inhibitor plus anticoagulation to treat deep venous thrombosis 
or pulmonary embolism (single antiplatelet or anticoagulant 
agent at prophylaxis or therapeutic dose is permitted) 
7. Aspartate aminotransferase (AST) or alanine aminotransferase 
(ALT) greater than 5x upper limit of normal, hemoglobin <8 
g/dL, or platelets <50,000 per mm3 
8. History of recent major bleeding, defined in accordance with 
the criteria of the International Society on Thrombosis and 
Hemostasis (ISTH).  
9. Any physical examination findings and/or history of any illness 
that, in the opinion of the study investigator, might confound 
the results of the study or pose an additional risk to the patient 
by their participation in the study 
TEST PRODUCT, DOSE, AND 
ROUTE OF 
ADMINISTRATION 
Dipyridamole, 100 mg four times per day to be taken by mouth 
Dipyridamole will be administered orally every day for up to 14 days 
until hospital discharge. 
CONTROL PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
Placebo will be prepared by a local pharmacy by contract. 
DURATION OF SUBJECT 
PARTICIPATION AND 
DURATION OF STUDY 
 
Treatment phase: 14 days of dipyridamole or placebo  
Follow-up: 30 days after last dose of drug  
 
The total duration of the study is expected to be 6 months.  
The participant recruitment is expected to be 4.5 months. 
This timeframe is based upon current COVID-19 projections.  Pending 
actual COVID-19 occurrence and participant recruitment, this duration 
may be extended. 
CONCOMITANT 
MEDICATIONS 
Allowed: Any, except as noted above in Exclusion Criteria or as 
deemed by the PI to be unsafe or likely to confound analysis 
EFFICACY EVALUATIONS 
This study is statistically powered to be a proof-of-concept phase II 
clinical trial 
SAFETY EVALUATIONS 
Each participant will have a complete blood cell count with differential 
(CBC), hepatic function panel (LFT) and coagulation panel done. This 
clinical evaluation will measure hemoglobin, platelet count, partial 
thromboplastin time, international normalized ratio, AST and ALT. 
Wherever possible, tests will be performed on blood drawn for clinical 
care. 


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Participants will be excluded from participating if their hemoglobin is < 
8 g/deciliter, platelets are < 50,000 / mm3, AST or ALT > 5 times the 
upper limit of normal at the time of screening. Coagulation panel and 
CBC will be done every other day. LFT will be done at least every four 
days. 
Blood pressure will be measured in study participants at least twice 
each day per institution protocol for hospitalized patients. Participants 
will be excluded from participating in this clinical trial if their systolic 
blood pressure is < 90 mmHg at the time of screening. The medical 
team will notify the study team if systolic blood pressure is < 90 mmHg 
on two sequential measurements at least 4 hours apart, and the study 
drug will be held until systolic BP is ≥ 90 mmHg on two sequential 
measurements at least 4 hours apart. The study team will review the 
medical record to determine whether the patient’s participation in the 
study trial should be terminated for the safety of the patient. 
PLANNED INTERIM 
ANALYSES  
Interim data analyses will be performed and study conduct reviewed by 
the DSMB at the specified milestones when the following number of 
participants have completed the study: 
1. Safety and futility will be evaluated after approximately 25% and 
50% of participants have completed the study or 10 deaths have 
occurred (whichever occurs first),  
2. Study conduct will be evaluated after approximately 25% and 50% 
of participants have completed the study, or three months after 
initiation of enrollment (whichever comes first).  
3. Efficacy will be evaluated when 50% of participants have completed 
the study. 
4. A second efficacy analysis will occur for clinical outcomes pursuant 
to the December 2020 DSMB meeting. 
The first efficacy endpoint will be the proportion of patients by 
treatment group whose change in D-dimer levels is at least +5% as 
estimated by simple linear regression.  The efficacy analysis will use 
the O’Brien-Fleming method to correct for interim analyses.  For the 
futility endpoint, if the lower limit for the 95% confidence interval of 
the daily change in D-dimer is above 9% at the time of the 50% interim 
analysis, the trial will be stopped.  The second efficacy endpoint will be 
a hierarchical composite outcome of time to death, days on ventilation, 
change in SpO2/FiO2 ratio, and Ordinal scores.  It will be analyzed 
using nonparametric win ratio analysis (Pocock et al., 2012).  Decisions 
regarding the secondary endpoint will be based on conditional power, 
which does not require adjustments for Type I error (Lan and Trost, 
1999; Siu and Lan, 2001; Lachin, 2006). 
Serious adverse events will be monitored by the committee on an 
ongoing basis throughout the study. 


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STATISTICS 
Primary Analysis Plan 
For analysis of the first primary endpoint, we will estimate patient-level 
relative change in D-dimer by fitting a random coefficients regression 
model to log-scale D-dimer levels.  The model will include treatment 
effects, baseline D-dimer levels, and stratification factors (sex and age), 
including treatment interactions with stratification factors. 
 
The hierarchical composite endpoint will be analyzed using a win ratio 
algorithm stratified by age and sex.  In a win-ratio analysis, all 
treatment patients are compared pairwise to all control patients, and the 
patient with better outcomes ‘wins’ (as determined by the hierarchy of 
the composite endpoint).  The algorithm results in a ranking of patients 
that are analyzed nonparametrically by a Mann-Whitney U test. 
SAMPLE SIZE RATIONALE 
Decision thresholds and power are based on a preliminary analysis of 
147 D-dimer measurements taken on 41 COVID-19 patients in the 
University of Michigan hospital. We used a simulation approach 
matching the patient population characteristics learned from the 
analysis of preliminary data reported above.  
For power simulation, the intraclass correlation coefficient (ICC) was 
set to 0.7, somewhat lower than the observed ICC of 0.77, in order to 
provide a margin for uncertainty in the pilot results. Power is based on 
a 13% daily increase in D-dimer levels for untreated patients, as 
observed in preliminary analysis. We posited a 50% reduction in the 
growth rate for the 100 mg dose. Using 2 arms with 40 subjects per arm 
(80 subjects in all), power is 0.91 for comparing the pooled 
dipyridamole participants to the controls.  
At the December 2020 DSMB meeting, it was decided to promote the 
hierarchical composite endpoint to a primary endpoint.  Sample size for 
this analysis are calculated according to methods presented in Yosef et 
al. (2019). 
 


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1 BACKGROUND - DIPYRIDAMOLE 
 
SARS-CoV-2 infection (COVID-19) is associated with a thrombophilic state marked by 
microvascular and macrovascular thrombosis, neutrophilic infiltration in lungs, and development 
of acute respiratory distress syndrome (ARDS)1,2. These form a self-amplifying feedback loop 
that results in increased immune activation, coagulation, and refractory respiratory failure. 
Currently there are no therapies for COVID-19, and treatments under investigation are 
incomplete as they only target specific disease mechanisms (eg. viral replication, individual 
cytokines, etc.). Treatments that target multiple disease-exacerbating pathways would present 
unique opportunities to augment current clinically available tools for COVID-19.  
 
Dipyridamole is an FDA-approved drug indicated for use as an antithrombotic agent in 
combination with vitamin K antagonists following cardiac valve replacement, or with aspirin for 
prevention of recurrent transient ischemic attacks. Two recent studies conducted in China have 
shown that dipyridamole suppresses coronaviral replication in vitro, and may suppress D-dimer 
elevation in a small study of patients with COVID-19 3,4. Patients with COVID-19-associated 
pneumonia were treated with dipyridamole 50 mg three times daily for seven days, in addition to 
treatment with ribavirin. As compared with ribavirin alone-treated controls, the dipyridamole-
treated patients demonstrated a significant improvement in D-dimer levels and platelet counts, 
and a possible trend toward improved clinical outcomes. Dipyridamole increases extracellular 
adenosine signaling by (1) preventing its reuptake; and (2) stabilizing intracellular cyclic AMP 
(cAMP) signaling. Dipyridamole potently reduces replication of the novel coronavirus strain 
(SARS-CoV-2) in vitro with EC50 100 nM (Figure 1), at plasma drug concentrations 
significantly lower than typically achieved plasma concentrations in patients treated with 
dipyridamole (1-4 µM) at the FDA-approved dose3-5. Among the cytokine families, Type 1 
interferons are the primary drivers of human anti-viral immune responses6. Human and animal 
studies show that dipyridamole induces production of type 1 interferons that are essential in the 
physiologic antiviral response7,8. Induction of protective type 1 interferons may be an additional 
mechanism by which dipyridamole exerts anti-viral effects9. Importantly, in a phase I/II 
randomized clinical trial, dipyridamole decreased chronic inflammation in patients with HIV on 
antiretroviral therapy by suppressing T cell activation and cytokine production10.        
 
Figure 1:  
Suppressive effects of DIP on SARS-CoV-2 replication in Vero cells4 
 
Elevated levels of both D-dimer (indicating thrombophilia) and neutrophils now also appear to 
predict severe disease and worse outcomes in individuals with COVID-1911. D-dimer, a 


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byproduct of fibrin formation and degradation, is used clinically as a highly sensitive biomarker 
of venous thromboembolism (VTE), and other thrombotic and inflammatory conditions. A 
recent, small clinical trial of dipyridamole in 31 patients with severe COVID-19 suggested 
potential efficacy of dipyridamole in reducing D-dimer levels and improving platelet counts4. 
Our group previously discovered that dipyridamole reduces venous thrombosis in an animal 
model by activating the adenosine 2A receptor (A2AR) (Figure 2)12. This adds further support to 
the rationale of this study as VTE is present in up to 40% of patients with COVID-1913. 
Figure 2:  
Dipyridamole reduces venous thrombosis in mice treated with 
human immune-activating (APS) antibodies.12 
 
The acute, exudative phase of ARDS is characterized by an increased immune response with 
high production of pro-inflammatory cytokines and chemokines, increased neutrophil infiltration 
and accumulation in the alveoli, and disruption of the alveolar epithelial-capillary barrier, which 
leads to increased vascular permeability and edema14. Neutrophil mediators such as reactive 
oxygen species, proteinases, and neutrophil extracellular traps (NETs) are potentially toxic to 
host cells and can result in thrombosis and bystander tissue damage.  NETs are extracellular 
tangles of DNA, histones, microbicidal proteins, and oxidant enzymes that are released by 
neutrophils to corral infections, but which—when not properly regulated—can amplify 
inflammation and venous thrombosis. We have recently found that dipyridamole reduces human 
neutrophil activation and NET formation ex vivo12. 
 
Severe cases of COVID-19 appear to be defined by neutrophilia, lymphopenia, 
thrombocytopenia, and elevated levels of IL-1β, IL-6, TNF-alpha, and D-dimer16, the latter 
suggesting a coagulopathy.  All these abnormalities could be potentially explained in part by 
increased levels of netting neutrophils.  NETs license macrophages to produce IL-1β production 
in many cardiovascular conditions.  The same is true for IL-6, either directly15, or via IL-1β-
mediated signaling16. Examples of NETs as drivers of coagulopathy are myriad, as intravascular 
NETosis have been shown to drive thrombotic events in all vascular beds. Of particular 
relevance here, we have discovered that dipyridamole inhibits human NET formation12—a 
critical effector of thrombo-inflammation5 and ARDS1,2. We have recently identified markedly 


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elevated indicators of NETosis in COVID-19 patients (Figure 3A)17. Our data show that the 
degree of NETosis measured in serum correlated with severity of COVID-19 respiratory illness 
and mechanical ventilation (Figure 3B). We also determined that serum from COVID-19 
patients is capable of inducing NETosis in healthy human neutrophils (Figure 4) suggesting the 
presence of a potentially self-amplifying loop of inflammation and thrombosis. 
 
Figure 3:  
Levels of NETs in serum associate with (A) COVID-19 infection and 
(B) COVID-associated mechanical ventilation.17 
 
 
 
Figure 4:  
Serum from patients with COVID-19 infection triggers NETs (yellow 
arrowheads) in healthy neutrophils (green-neutrophil elastase, blue-
DNA).17 
 
 
 
 
Thus, dipyridamole may be beneficial in patients with COVID-19. Given that the majority of 
hospitalized patients with COVID-19 develop coagulation dysfunction as indicated by elevated 
D-dimer18, and many will also develop ARDS and VTE18, it is critical to better understand the 
appropriate management of patients with COVID-19. 
Participants in this study will be administered dipyridamole or placebo. 
A 
B 


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1.1 
Non-Clinical Studies Overview 
From FDA-approved USPI for dipyridamole19 
Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in 
vitro and in vivo; the inhibition occurs in a dose-dependent manner at therapeutic concentrations 
(0.5-1.9 μg/mL). This inhibition results in an increase in local concentrations of adenosine which 
acts on the platelet A -receptor thereby stimulating platelet adenylate cyclase and increasing 
platelet cyclic-3',5'- adenosine monophosphate (cAMP) levels. Via this mechanism, platelet 
aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), 
collagen and adenosine diphosphate (ADP). 
Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of 
cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'-guanosine 
monophosphate-PDE (cGMPPDE), thereby augmenting the increase in cGMP produced by 
EDRF (endothelium-derived relaxing factor, now identified as nitric oxide). 
Hemodynamics 
In dogs intraduodenal doses of dipyridamole of 0.5 to 4.0 mg/kg produced dose-related decreases 
in systemic and coronary vascular resistance leading to decreases in systemic blood pressure and 
increases in coronary blood flow. Onset of action was about 24 minutes and effects persisted for 
about 3 hours. 
Similar effects were observed following intravenous dipyridamole in doses ranging from 0.025 
to 2.0 mg/kg. 
In humans the same qualitative hemodynamic effects have been observed. However, acute 
intravenous administration of dipyridamole may worsen regional myocardial perfusion distal to 
partial occlusion of coronary arteries. 
Pharmacokinetics and Metabolism 
Following an oral dose of dipyridamole capsules, the average time to peak concentration is about 
75 minutes. The decline in plasma concentration following a dose of dipyridamole capsules fits a 
two-compartment model. The alpha half-life (the initial decline following peak concentration) is 
approximately 40 minutes. The beta half-life (the terminal decline in plasma concentration) is 
approximately 10 hours. Dipyridamole is highly bound to plasma proteins. It is metabolized in 
the liver where it is conjugated as a glucuronide and excreted with the bile. 
1.2 
Clinical Studies Overview 
From current FDA-approved USPI for dipyridamole19 
It is believed that platelet reactivity and interaction with prosthetic cardiac valve surfaces, 
resulting in abnormally shortened platelet survival time, is a significant factor in thromboembolic 
complications occurring in connection with prosthetic heart valve replacement. 


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Dipyridamole tablets have been found to lengthen abnormally shortened platelet survival time in 
a dose-dependent manner. 
In three randomized controlled clinical trials involving 854 patients who had undergone surgical 
placement of a prosthetic heart valve, dipyridamole tablets, in combination with warfarin, 
decreased the incidence of postoperative thromboembolic events by 62 to 91 % compared to 
warfarin treatment alone. The incidence of thromboembolic events in patients receiving the 
combination of dipyridamole tablets and warfarin ranged from 1.2 to 1.8%. In three additional 
studies involving 392 patients taking dipyridamole tablets and coumarin-like anticoagulants, the 
incidence of thromboembolic events ranged from 2.3 to 6.9%. 
In these trials, the coumarin anticoagulant was begun between 24 hours and 4 days 
postoperatively, and the dipyridamole tablets were begun between 24 hours and 10 days 
postoperatively. The length of follow-up in these trials varied from 1 to 2 years. 
Dipyridamole tablets do not influence prothrombin time or activity measurements when 
administered with warfarin. 
2 STUDY RATIONALE 
The purpose of this study is to evaluate the putative benefit of dipyridamole to prevent 
progressive D-dimer elevation in COVID-19 severity. By protecting against the COVID-19 
thrombo-inflammatory storm and reducing platelet activation and NETs, dipyridamole may also 
protect against respiratory failure. 
 
Adverse reactions at therapeutic doses are usually minimal and transient. On long-term use of 
dipyridamole tablets, initial side effects usually disappear. The following reactions in Table 1 
were reported in two heart valve replacement trials comparing dipyridamole tablets and warfarin 
therapy to either warfarin alone or warfarin and placebo. 
Table 1:  
Adverse reactions reported in 2 heart valve replacement trials 
 
  
For patients taking dipyridamole, there is a 2% risk for the development of transient hypotension 
with systolic blood pressure < 90 mmHg with IV administration20. This study will administer 
only the oral tablet formulation, for which hypotension has not been described as a side effect. In 
a small clinical trial, patients with endotoxemia who were randomized to receive dipyridamole 


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(total 400 mg daily) or placebo control had no difference in blood pressure21. Participants in this 
clinical trial will receive 400 mg total daily dose of dipyridamole. The blood pressure of each 
participant will be measured to determine eligibility before randomizing the participants at 
screening. Patients will be ineligible for this clinical trial if their systolic blood pressure is less 
than 90 mmHg on two consecutive measurements > 4 hours apart at the time of screening. In 
order to ensure safety of our participants, blood pressure will be monitored at least twice daily 
throughout the study for clinical care. If while reviewing blood pressure values, the study team 
finds that the blood pressure is less than 90 mmHg on two sequential measurements at least 4 
hours apart, the study team will review the medical record to determine whether the patient’s 
participation in the study trial should be terminated for the safety of the patient.  
 
Participants taking dipyridamole may be at higher risk of bleeding complications secondary to its 
antithrombotic effect. In clinical studies, dipyridamole did not increase risk of bleeding when 
added to aspirin or vitamin K antagonists22,23. Importantly, no excess bleeding was reported in a 
clinical trial with endotoxemic patients randomized to a received randomized clinical trial of 
dipyridamole in endotoxemia using the maximum recommended daily dose recommended by the 
FDA 21. Medical records will be reviewed daily for ISTH-defined major bleeding.  
For participants taking dipyridamole, there is a risk of developing other reactions from 
uncontrolled studies including diarrhea, vomiting, flushing and pruritus. In addition, angina 
pectoris has been reported rarely and there have been rare reports of liver dysfunction. As per the 
USPI, on those uncommon occasions when adverse reactions have been persistent or intolerable, 
they have ceased on withdrawal of the medication. 
In post-marketing reporting experience, there have been rare reports of hypersensitivity reactions 
(such as rash, urticaria, severe bronchospasm, and angioedema), larynx edema, fatigue, malaise, 
myalgia, arthritis, nausea, dyspepsia, paresthesia, hepatitis, thrombocytopenia, alopecia, 
cholelithiasis, hypotension, palpitation, and tachycardia. 
3 STUDY OUTCOMES 
3.1 
Primary Outcome 
 
1. Title: D-dimer 
Description: Change in plasma D-dimer level compared with baseline at enrollment 
Time Frame: Data gathered through day 14 
2. Title: Hierarchical composite rank score  
Description: Hierarchical composite rank score of death, days on ventilation, decline in 
daily average SpO2/FiO2 of 50 or more compared to enrollment, cumulative COVID 
ordinal score 
Time Frame: Data gathered through 28 ± 1 day 
3.2 
Secondary Outcomes 
1. Title: Data 
Description: Days to mortality. 
Time Frame: Data gathered through 28 ± 1 day 


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2. Title: Mechanical ventilation days 
Description: Days spent on mechanical ventilation. 
Time Frame: Data gathered through 28 ± 1 day 
3. Title: Change  in SpO2/FiO2 
Description: Dichotomized outcome of decrease in daily average SpO2/FiO2 of 50 or 
greater compared to enrollment SpO2/FiO2. 
Time Frame: Data gathered through day 14 
4. Title: Cumulative sum of Ordinal scores 
Description: Sum of daily Ordinal scores during hospitalization.  This is a rough 
approximation of duration and severity. 
Time Frame: Data gathered through day 14 
5. Title: Days alive and free of organ support 
Description: Organ support is defined as receipt of invasive or non-invasive mechanical 
ventilation, high flow nasal oxygen, vasopressor therapy, ECMO support, or dialysis.   
Time Frame: Data gathered through day 14 
3.3 
Safety Outcomes 
1. Title: Incidence of serious adverse events 
Description: Incidence of serious adverse events as defined in the study protocol. 
Time Frame: Data gathered through 30 days after administration of last drug dose 
2. Title: Incidence of severe hypotension 
Description: Hypotension with systolic blood pressure < 90 mmHg requiring more than 
a 1-L IV fluid bolus  
Time Frame: Data gathered through day 14 ± 1 day  
3. Title: Incidence of major bleeding  
Description: Incidence of major bleeding defined in accordance with the criteria of the 
International Society on Thrombosis and Hemostasis (ISTH) as bleeding that is 
associated with a decrease in the hemoglobin level of 2 g per deciliter or more, leads to a 
transfusion of 2 or more units of blood, occurs in a critical site, or contributed to death 
Time Frame: Data gathered through day 28 ± 1 day 
3.4 
Exploratory Outcomes 
1. Title: C-reactive protein, LDH, ferritin, leukocyte count, platelet count in blood 
Description: Improvement for participants with abnormal levels at day 1 (>standard 
laboratory cutoff) 
Time Frame: Data gathered through 28 ± 1 day 
2. Title: Incidence of mechanical ventilation or ICU care 
Description: Incidence of mechanical ventilation initiation or ICU care 
Time Frame: Data gathered through 28 ± 1 day 
3. Title: Time to hospital discharge 
Description: Time to hospital discharge will account for death and lost to follow up as a 
competing risk and censoring event, respectively. 
Time Frame: Data gathered through 30 days after last study drug administration 


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4. Title: Proportion of participants requiring supplemental oxygen  
Description: Incidence of participants alive without requirement for ongoing oxygen 
supplementation. 
Time Frame: Data gathered through 28 ± 1 day 
5. Title: Number of days of supplemental oxygen use 
Description: Number of days of supplemental oxygen use 
Time Frame: Data gathered through 28 ± 1 day 
6. Title: Time to improvement in average daily oxygenation 
Description: Time to first improvement in average daily SpO2/FiO2 ratio of 50 or 
greater compared to the nadir SpO2/FiO2 ratio 
Time Frame: Data gathered through 28 ± 1 day 
7. Title: Neutrophil activation studies 
Description: Decrease for participants with elevated levels at day 1 (>2 SD above 
established healthy-controls) 
Time Frame: Data gathered through day 14 ± 1 day 
8. Title: Inflammatory, anti-inflammatory, and other cytokines and molecules in blood 
Description: Increase or decrease for participants (>2 SD above established healthy-
control mean) 
Time Frame: Data gathered through day 14 ± 1 day 
9. Title: Coagulant and anticoagulant cytokines and molecules in blood 
Description: Increase or decrease for participants (>2 SD above established healthy-
control mean) 
Time Frame: Data gathered through day 14 ± 1 day 
10. Title: Incidence of arterial or venous thromboembolism 
Description: Arterial or Venous thromboembolism diagnosed by imaging study  
Time Frame: Data gathered through 28 ± 1 day 
11. Title: Incidence of venous thromboembolism 
Description: Venous thrombosis diagnosed by imaging study  
Time Frame: Data gathered through 28 ± 1 day 
12. Title: Incidence of arterial thrombosis 
Description: Arterial thrombosis diagnosed by imaging study  
Time Frame: Data gathered through 28 ± 1 day 
13. Title: Estimated glomerular filtration rate 
Description: Decrease for participants from day 1 (>1 SD laboratory cutoff) 
Time Frame: Data gathered through 28 ± 1 day 
14. Title: Leukocyte transcriptomics 
Description: Gene expression, function, and activation of peripheral blood leukocytes 
following treatment with dipyridamole. 
Time Frame: Days 1 and 5 


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4 STUDY DESIGN 
This is a proof-of-concept, single-center, single-blinded, placebo-controlled, randomized, 14-day 
trial. Participants who meet all inclusion criteria and none of the exclusion criteria will be offered 
the opportunity to complete the study.  
We plan to enroll 160 participants. If an interested patient is eligible for this study, the 
participant will begin a 14-day treatment period when they will be administered a study drug or 
placebo control for 14 days.  
Participants will be assigned to receive the treatments in a stratified, random blocks based on sex 
and age (above/below 65).Stratified blocks were generated using the ‘blockrand’ package in R. 
Clinical evaluations will be made daily. If lab studies from any of these days are abnormal to a 
clinically significant extent, the study investigator will further evaluate whether the abnormality 
is attributed to the study drug. 
Total treatment of participant is planned for 14 days, but patients will be followed for 30 days 
after their last dose of study drug. Total duration of the study is expected to be 6 months. Study 
Schematic is in Figure 5. 


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Figure 5:  
Schematic Representation of Study Design 
 
5 CRITERIA FOR EVALUATION 
5.1 
Safety Evaluations 
Each participant will have a complete blood cell count with differential (CBC), and hepatic 
function panel done on the day of admission per institutional protocol for all patients admitted 
with confirmed COVID-19 infection. This clinical evaluation will measure hemoglobin, and 
platelet count, AST and ALT. Hemoglobin and platelets will be measured every 2 days. AST and 
ALT will be measured every 4 days. Whenever possible, clinical tests will be added to blood 
already drawn for clinical care. 
Patients will be excluded from entering the study if their hemoglobin is < 8 g/deciliter, platelets 
are < 50,000 / mm3, AST or ALT > 5 times the upper limit of normal. These will be checked at 
least every 5 days in hospitalized participants per institutional and study protocol and will be 
reviewed by the study team for changes. If, after randomization, a participant develops 
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of normal, the study drug will be withheld and restarted if repeat lab testing shows resolution of 
the abnormality within 24 hours. 
Blood pressure will be measured in study participants at least twice daily. Participants will be 
excluded from participating in this clinical trial if their systolic blood pressure is < 90 mmHg on 
two sequential measurements at least four hours apart at the time of screening. If, after 
randomization, a participant develops hypotension with systolic blood pressure < 90 mmHg on 
two sequential measurements at least four hours apart, the study drug will be held and restarted if 
repeat blood pressure measurements show systolic blood pressure ≥ 90 mmHg on two sequential 
measurements at least 4 hours apart.  
Participation in the trial will be terminated at the discretion of the medical team attending 
physician or the PI if deemed important for the safety of the participant. 
5.2 
Other Evaluations 
We plan to evaluate participants’ blood samples for circulating, cellular, transcriptional, and 
genetic biomarkers of coagulation and immune responses in COVID-19. 
6 PARTICIPANT SELECTION 
6.1 
Study Population 
Participants with a laboratory test-confirmed diagnosis of COVID-19 who meet the inclusion and 
have no exclusion criteria will be eligible for participation in this study. 
6.2 
Inclusion Criteria 
1. Age ≥ 18 years 
2. Willing and able to provide informed consent prior to performing study procedures unless 
they have a legally authorized representative (LAR) 
3. Confirmed coronavirus (SARS-CoV-2) infection 
4. Currently hospitalized or anticipated hospitalization requiring supplemental oxygen   
6.3 
Exclusion Criteria 
1. In the opinion of at least two physicians, unlikely to survive for >48 hours from screening 
2. Concurrent enrollment in a clinical trial of a cytokine inhibitor (targeting IL-6, IL-6R, IL-
1, or Janus kinase). Use of remdesivir is permitted. 
3. Currently on invasive mechanical ventilation 
4. Hypotension defined as systolic blood pressure < 90 mmHg on two readings at least 4 
hours apart 
5. Pregnant or breastfeeding 
6. Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor (eg. clopidogrel, 
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(single antiplatelet agent, or anticoagulant agent at prophylaxis or therapeutic dose is 
permitted). 
7. Presence of any of the following abnormal laboratory values: aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN), 
platelets <50,000 per mm3, hemoglobin <8 g per deciliter 
8. History of recent major bleeding, defined in accordance with the criteria of the 
International Society on Thrombosis and Hemostasis (ISTH) as overt bleeding that was 
associated with a decrease in the hemoglobin level of 2 g per deciliter or more, led to a 
transfusion of 2 or more units of blood, occurred in a critical site within 30 days.  
9. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to 
the patient by their participation in the study. 
7 CONCURRENT MEDICATIONS 
All participants’ non-study medications will be at the discretion of the treating medical provider.  
7.1 
Allowed Medications and Treatments 
Any medications and supplements are allowed except as noted in the exclusion criteria and in the 
prohibited medications or as deemed by the PI to be unsafe or likely to confound analysis. If a 
prohibited medication would benefit the participant, the medical attending physician and PI will 
decide together whether the participant’s involvement in the clinical trial should be terminated. 
7.2 
Prohibited Medications and Treatments 
The following medications are prohibited during the study and administration will be considered 
a protocol violation. 
1. Dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep 
venous thrombosis or pulmonary embolism (single antiplatelet agent, or anticoagulant 
agent at prophylaxis or therapeutic dose is permitted).  
8 STUDY TREATMENTS 
8.1 
Method of Assigning Participants to Treatment Groups 
Up to 160 eligible participants will be randomly assigned to dipyridamole or placebo control in a 
1:1 ratio using stratified, random blocks based on sex and age (above/below 65).  Stratified 
blocks will be generated using the ‘blockrand’ package in R.  
8.2 
Blinding 
The study will be conducted as a single-blinded trial. 


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8.3 
Formulation of Test and Control Products 
8.3.1 
Formulation of Test Product 
Active drug: FDA-approved generic dipyridamole tablets  
The generic dipyridamole tablets will be over-encapsulated to ensure it looks identical to the 
matching placebo. 
8.3.2 
Formulation of Control (Placebo) Product 
Placebo capsules will be prepared by pharmacy.  The placebo capsules will look identical to the 
dipyridamole capsules. 
8.3.3 
Packaging and Labeling 
Packaging: the study drug will be delivered to the medical ward per routine institutional 
protocols. The medical team will administer the study drug per routine institutional protocols. 
Labelling example: label contents are compliant with Federal laws and state pharmacy laws for 
prescription and investigational drug labeling. Label contains required language, for example: 
“Caution: New Drug Limited by Federal (or United States) law to investigational use” 
8.4 
Supply of Study Drug at the Site 
8.4.1 
Generic study drugs will be purchased by the pharmacy. 
Dosage/Dosage Regimen 
Pharmacy and medical teams will be instructed to administer the study medication four times 
daily. If a research participant for some reason misses a dose of their study medication, 
pharmacy and medical team are encouraged to administer the dose as soon as possible. However, 
if it is ≤ 2 hours from their next dose, they will be asked to skip the missed dose and go back to 
their regular dosing schedule. Pharmacy and medical providers will be informed to not double 
the doses.  
8.4.2 
Dispensing 
Roles delegated to pharmacy are documented on the study-specific Delegation of Authority Log, 
which is signed by the lead pharmacist for the study. The lead pharmacist determines who or 
what specific pharmacy areas will perform the delegated roles. Staff performing delegated 
activities will sign or initial documents and/or forms as indicated in the Dispensing Guidelines 
and on other study-specific documents. Both research pharmacist and pharmacy technician will 
be involved in dispensing of study drug. 
8.4.3 
Administration Instructions  
The pharmacy will dispense study drug after randomization has been completed. The medical 
team will administer the study drug four times per day in both study groups (dipyridamole 100 


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mg QID, placebo QID). If a participant is discharged during the 14-day treatment period, the 
study drug will be disposed of per local institute policy.  
8.4.4 
Supply of Study Drug at the Site 
Initial shipment of generic dipyridamole tablets has been purchased by the pharmacy. 
Subsequent study drug purchase will be made depending on the enrollment rate. 
8.4.5 
Storage 
Generic dipyridamole tablets will be stored at USP controlled room temperature according to the 
package insert. If the temperature of study drug storage in the pharmacy exceeds or falls below 
this range, study drugs will be physically quarantined, and a temperature excursion report will be 
submitted to PI or designee for evaluation.  
Medical team will be instructed to store the study drug at room temperature. 
8.5 
Study Drug Accountability 
An accurate and current accounting of the dispensing will be maintained. Due to COVID -19 
pandemic, return drug may not be counted by the research pharmacist or study staff. After 
treatment is complete, the remaining study medications will be counted by two clinical staff. If 
the count cannot be verified by another staff, the single staff member should count twice before 
final disposal per local institutional guidelines  
Administration records of study drug will be verified in the medical record at the end of the 
study. Compliance below 80% compliance will be documented. 
9 STUDY PROCEDURES AND GUIDELINES 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
Prior to conducting any study-related activities, written informed consent containing Health 
Insurance Portability and Accountability Act (HIPAA) authorization will be signed and dated by 
the participant.   
9.1 
Clinical Assessments 
9.1.1 
Concomitant medications 
All concomitant medications will be documented during the study, including early termination 
when applicable.  Dose, route, unit frequency of administration, indication for administration and 
dates of medication will be captured. 


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9.1.2 
Demographics  
Demographic information (race, ethnicity, sex, date of birth, height and weight) will be recorded 
at the time of enrollment. 
9.1.3 
Medical history  
Relevant medical history, including history of current disease and information regarding 
underlying diseases will be obtained from the patient and/or by chart review, and recorded at the 
time of enrollment. 
9.1.4 
Social history  
Relevant social history, including history of pregnancy, tobacco and alcohol use, will be obtained 
from the patient and/or by chart review, and recorded at the time of enrollment. 
9.1.5 
Physical examination 
A complete physical examination will be performed by the medical team during the 
hospitalization. Abnormal physical exam findings will be documented, and the principal 
investigator will incorporate this information into consideration of continued eligibility from a 
safety perspective. 
9.1.6 
Electrocardiogram 
Electrocardiogram (ECG) will be performed by the medical team if clinically appropriate and 
documented in the eCRF if obtained. 
9.1.7 
Chest imaging 
Chest imaging will be performed by the medical team if clinically appropriate and documented 
in the eCRF if obtained. Imaging findings will be coded in binary variables for infiltrates, 
pneumonia, pleural effusion, consolidation, pulmonary embolism, RV strain, and cardiomegaly.  
9.1.8 
Vital signs 
Temperature, blood pressure, heart rate, respiration rate, and weight will be performed per 
institutional protocol. Blood pressure readings and pulse oximetry will be measured at least twice 
daily. 
 
9.1.9 
Oxygen requirements 
Pulse oximetry (SpO2), oxygen requirements (mode of delivery), fraction of inspired oxygen 
(FiO2), oxygen flow rate, and mode of mechanical ventilation will be recorded at least daily 
alongside vital signs measurement. Pulse oximetry will be measured at least twice daily. 


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9.1.10 
Modified WHO COVID-19 8-point Ordinal scale assessment  
Ordinal scale assessments will be made daily and on Day 28 as below: 
Modified COVID 8-point Ordinal Scale 
 
PATIENT STATE 
DESCRIPTOR 
SCORE 
Dead 
Death 
8 
Hospitalized – severe 
disease 
Ventilation + additional organ support (pressors, renal 
replacement therapy, ECMO) 
7 
Intubation and mechanical ventilation 
6 
Non-invasive ventilation or high-flow oxygen 
5 
Hospitalized – mild 
disease 
Oxygen by mask or nasal prongs 
4 
Hospitalized, no oxygen therapy 
3 
Ambulatory 
Limitation of activities 
2 
No limitation of activities 
1 
 
 
 
 
9.1.11 
National Early Warning Scores (NEWS2) 
The NEWS2 score will be made daily and on Day 28. 
9.1.12 
Adverse events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to study drug will 
be recorded on the source document. 
9.2 
Clinical Laboratory Measurements  
9.2.1 
D-dimer, Ferritin, lactate dehydrogenase (LDH), C-reactive protein 
(CRP), complete blood cell count with differential (CBC), fibrinogen, partial 
thromboplastin time (PTT), international normalized ratio (INR) arterial blood 
gases (ABG), basic metabolic panel (BMP), hepatic function panel (LFT) 
We anticipate blood will be drawn for clinical care at least every other day, and anticipate that 
most research blood studies will be performed on blood already drawn for clinical care. We will 
also extract data for any studies done for clinical care purposes. Blood will be obtained and sent 
to the clinical laboratory to measure LDH, CBC, CRP, D-dimer for standard of care at the 


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discretion of the medical team. D-dimer, fibrinogen, PTT, INR, ferritin, CBC, LFT, LDH, CRP, 
BMP will be measured on day 1 on blood drawn for clinical care. Although daily measurement 
of D-dimer would be ideal for the primary endpoint of this research study, we will measure D-
dimer every other day given ongoing medical resource constraints. D-dimer, fibrinogen, PTT, 
INR and CBC will be measured on days 3, 5, 7, 9, 11, 13 and 14 during hospitalization. CRP, 
ferritin, LDH, BMP will be measured on day 1, 5, 9, and 13, during hospitalization for research 
study using blood drawn for clinical care wherever possible. LFT will be measured on day 1 for 
clinical care, and at least every 4 days until end of drug treatment phase in blood drawn for 
clinical care wherever possible during hospitalization. ABG will only be recorded if performed 
for clinical care purposes.  
9.2.2 
Pregnancy test 
A urine pregnancy test, if not already performed for clinical care, will be obtained from female 
patients who are of childbearing age by the medical team prior to obtaining informed consent. 
9.3 
Pharmacokinetic measurements 
Not applicable. 
9.4 
Research Laboratory Measurements (see Schedule of Events)  
9.4.1 
Coagulation potential  
Blood will be obtained to investigate potential mediators of COVID-19 and novel parameters of 
coagulation and platelet activity measured in the study team’s research laboratories. 
9.4.2 
Biomarkers of blood cell activation 
Blood will be collected in sodium citrate, heparin, EDTA or serum separator tubes. The blood 
sample will be labeled and processed at the local sites before shipping to the study team’s 
research laboratories at the University of Michigan to evaluate novel biomarkers of blood cell 
activation, coagulation, and cytokines. 
9.4.3 
Leukocytes 
Blood will be collected in EDTA, sodium citrate, or heparin tubes. The blood sample will be 
labeled and sent for processing to the clinical and research labs. 


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10 EVALUATIONS BY DAY OF HOSPITALIZATION 
10.1 Screening Enrollment Visit (24 hour)  
1. 
Chart review to determine eligibility 
2. 
Review the study with the participant and obtain electronic or written informed consent 
3. 
Obtain urine pregnancy test in females of child-bearing potential, if not already   
performed for clinical care. 
4. 
Assign the participant a unique study number. 
5. 
Randomize participant 
10.2 Day 1 Treatment   
(Screening Enrollment visit and Day 1 can be on same day) 
1. Record demographics data. 
2. Record social history. 
3. Record medical history 
4. Record concomitant medications. 
5. Record vital signs, physical examination and oxygen requirements obtained by the 
medical team. 
6. Record clinical laboratory tests performed for routine clinical care 
a. 1x citrate tube 
b. 1x SST tube 
c. 1x EDTA tube 
7. Record chest imaging and electrocardiogram if performed by the medical team for 
routine clinical care.  
8. Collect blood for research laboratory tests. This will be coordinated with a clinical draw 
whenever possible. 
a. 5x citrate tubes  
b. 1x SST tube 
c. 1x PAXgene RNA tube 
9. Start study drug according to randomization 
10. Review and record any Adverse Events. 
10.3 Day 2 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
10.4 Day 3 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 


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3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 1x citrate tube 
b. 1x EDTA tube 
7. Collect blood for research laboratory tests on Day 3 (± 1 day) 
a. 1x citrate tube 
b. 1x SST tube 
10.5 Day 4 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
10.6 Day 5 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 1x citrate tube 
b. 1x SST tube 
c. 1x EDTA tube 
7. Collect blood for research laboratory tests on Day 5 (± 1 day) 
a. 5x citrate tubes  
b. 1x SST tube 
c. 1x PAXgene RNA tube 
10.7 Day 6 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
10.8 Day 7 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 


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3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 1x citrate tube 
b. 1x EDTA tube 
7. Collect blood for research laboratory tests on Day 7 (± 1 day) 
a. 1x citrate tube 
b. 1x SST tube 
10.9 Day 8 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
10.10 Day 9 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 
1x citrate tube 
b. 
1x SST tube 
            c. 
1x EDTA tube 
7. Collect blood for research laboratory tests on Day 9 (± 1 day) 
a. 1x citrate tube 
b. 1x SST tube 
c. 1x EDTA tube 
10.11 Day 10 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
10.12 Day 11 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 


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3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 1x citrate tube 
b. 1x EDTA tube 
7. Collect blood for research laboratory tests on Day 11 (± 1 day) 
a. 1x citrate tube 
b. 1x SST tube 
10.13 Day 12 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants assigned to study drug arms. 
5. Review and record any Adverse Events. 
6. Administer study drugs to participants according to randomization 
7. Collect blood for clinical laboratory tests 
10.14 Day 13 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. Concomitant medications review 
3. Review medical records to record data for endpoints. 
4. Administer study drugs to participants according to randomization 
5. Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 1x citrate tube 
b. 1x SST tube 
c. 1x EDTA tube 
7. Collect blood for research laboratory tests on Day 13 (± 1 day) 
a. 1x citrate tube 
b. 1x SST tube 
10.15 Day 14 Treatment  
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. 
Concomitant medications review 
3. 
Review medical records to record data for endpoints. 
4. 
Administer study drugs to participants according to randomization 
5. 
Review and record any Adverse Events. 
6. Collect blood for clinical laboratory tests (can be used for clinical care) 
a. 
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b. 
1x EDTA tube 
10.16 Early Withdrawal Interaction 
1. Record vital signs, oxygen requirements, and physical examination findings. 
2. 
Review medical records to record data for endpoints 
3. 
Concomitant medications review. 
4. 
Review and record any Adverse Events. 
5. 
Collect blood for clinical laboratory tests as described in the informed consent 
document. 
a. 
1x citrate tubes 
b. 
1x SST tube 
c. 
1x EDTA tube 
6. 
Collect blood for research laboratory tests as described in the informed consent 
document. 
a. 
1x citrate tubes 
b. 
1x SST tube 
7. 
Follow up call to participant for adverse events, 30 days after last dose of study drug 
 
10.17      30 Days after last dose of study drug (± 2 day) 
 
Chart review and follow up call to participant for AEs assessment up to 30 days after last dose of 
study drug (maximum of 44 days from initiation of trial participation). 
11 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
11.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a 
participant administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE is therefore any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom or disease temporally associated with the 
administration of an investigational product, whether or not related to that investigational 
product.  An unexpected AE is one of a type not identified in nature, severity, or frequency in the 
current protocol or of greater severity or frequency than expected based on the information in the 
protocol. 
The Investigator or designee will probe, via medical record review, for the occurrence of AEs 
during each study day for the duration of study drug administration, and record the information 
in the source documents.  Adverse events will be described by duration (start and stop dates and 
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11.2 AE Severity 
The guidelines shown in below Table 2 should be used to grade severity.  It should be pointed 
out that the term “severe” is a measure of intensity and that a severe AE is not necessarily 
serious. 
Table 2:  
AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical intervention or 
therapy required. The participant may be aware of the sign or symptom but 
tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The participant is at risk of death due to the adverse experience as it occurred. 
This does not refer to an experience that hypothetically might have caused death if 
it were more severe. 
 
11.2.1 
AE Relationship to Study Drug 
The relationship of an AE to the study drug will be assessed using the following the guidelines. 
Table 3:  
AE Relationship to Study Drug 
Relationship 
to Drug 
Comment 
Definitely 
Previously known toxicity of agent; or an event that follows a reasonable temporal 
sequence from administration of the drug; that follows a known or expected response 
pattern to the suspected drug; that is confirmed by stopping or reducing the dosage of the 
drug; and that is not explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from administration of the drug; that 
follows a known or expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is unlikely to be explained by the 
known characteristics of the participant’s clinical state or by other interventions. 
Possibly 
An event that follows a reasonable temporal sequence from administration of the drug; that 
follows a known or expected response pattern to that suspected drug; but that could readily 
have been produced by a number of other factors. 
Unrelated 
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11.2.2 
Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: major bleeding as defined by ISTH, AST or ALT > 10 times the upper limit of 
normal.  
Other important medical events may also be considered a SAE when, based on appropriate 
medical judgement, they jeopardize the participant or require intervention to prevent one of the 
outcomes listed.  
11.2.3 
Serious Adverse Experience Reporting 
Study personnel will document all SAEs that occur (whether or not related to study drug).  The 
collection period for all SAEs will begin after informed consent is obtained and end 30 days after 
administration of the last dose of study drug. 
In accordance with the standard operating procedures and policies of the local IRB, the study 
team will report SAEs to the IRB.  
11.3 Protocol Defined Important Medical Findings Requiring Real Time 
Reporting 
Not applicable. 
11.4 Medical Monitoring 
A DSMB has been established and a DSMB charter formed. Details are noted in the Data Safety 
section below. 
12 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
12.1 Early Discontinuation of Study Drug  
A participant may be discontinued from study treatment at any time if the participant, medical 
team, or the Site-Investigator feels that it is not in the participant’s best interest to continue.  The 
following is a list of possible reasons for study treatment discontinuation:  
• Participant withdrawal of consent 
• Participant is discharged earlier than 14 days 
• Adverse event that in the opinion of the investigator would be in the best interest of the 
participant to discontinue study treatment 
• Protocol violation requiring discontinuation of study treatment 


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If a participant is withdrawn from treatment due to an adverse event, the participant will be 
followed and treated by the study team until the abnormal parameter or symptom has resolved or 
stabilized.   
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
The reason for the participant’s withdrawal from the study will be specified in the participant’s 
source documents. Refer to Section 10 for early termination procedures. 
12.2 Withdrawal of Participants from the Study 
A participant may be withdrawn from the study at any time if the participant, the medical team, 
or the Site-Investigator feels that it is not in the participant’s best interest to continue.   
All participants are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
The reason for the participant’s withdrawal from the study will be specified in the participant’s 
source documents.  Refer to Section 10 for early termination procedures.   
12.3 Replacement of Participants  
Participants who withdraw from the study treatment will not be replaced.   
Participants who withdraw from the study will not be replaced.   
13 PROTOCOL VIOLATIONS 
A protocol violation occurs when the participant, study coordinator or the investigator fails to 
adhere to significant protocol requirements affecting the inclusion, exclusion, participant safety 
and primary endpoint criteria.  Protocol violations for this study include, but are not limited to, 
the following: 
• 
Use of a prohibited concomitant medication 
 
• 
Non-compliance with study drug regimen 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The National Investigator in consultation with IND Sponsor will determine if a 
protocol violation will result in withdrawal of a participant. 
When a protocol deviation occurs, a protocol deviation form detailing the deviation will be 
completed. A copy of the form will be filed in the study’s regulatory binder.  
14 DATA SAFETY MONITORING  
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB) 
composed of individuals with the appropriate expertise, including clinical trials, thrombosis 


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expertise, clinical pharmacology, biostatistics. Members of the DSMB will be independent from 
the study conduct and free of conflict of interest, or measures will be in place to minimize 
perceived conflict of interest. The study’s DSMB will review data relating to safety and efficacy, 
to conduct and review an interim analysis, and to ensure the continued scientific validity and 
merit of the study. The DSMB has been formed and includes experts in clinical trials, statistics, 
thrombosis, and pharmacology. A Charter has been written to guide the DSMB’s activities. 
There will be at least two interim review(s) conducted by the DSMB for the purpose of 
monitoring study conduct and assessing participant safety. Study conduct will be evaluated by 
the DSMB when approximately 25% and 50% of participants have completed the study, or three 
months after initiation of enrollment (whichever comes first). When approximately 25% and 
50% of participants have completed the study or 10 deaths have occurred (whichever occurs 
first), an interim data analysis to evaluate safety and futility will be conducted by an independent 
data monitoring committee. The interim analyses for efficacy will be limited to the review after 
50% of participants have completed the study to limit the cost to power from multiple interim 
analyses.  
Further details regarding the timing and content of the interim reviews is included in the 
statistical section below. 
15 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications 
to the analysis plan described below.   
15.1 Data Sets Analyzed 
Analyses will follow a modified intent to treat (mITT) paradigm.  All eligible participants who 
are randomized into the study and receive at least one dose of the study drug will be included in 
the analysis. 
Based on interim analysis for futility, it was decided to halt recruitment beginning January 19th, 
2021.  The final data analysis will begin:  
• after all 30-day post drug follow-up has been completed for all randomized patients, 
• after chart review and data cleaning are complete, and 
• after approval of the SAP by the study team. 
 
15.2 Demographic and Baseline Characteristics 
The following demographic variables at enrollment will be recorded: race, ethnicity, sex, date of 
birth, height and weight.   
15.3 Analysis of Primary Endpoints 
 
Due to changes in standard of care, the initial D-dimer endpoint may no longer be clinically 
meaningful. Standard care of treatment for COVID-19 has changed to include anti-inflammatory 


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steroids which decrease D-dimer levels.  Looking for an impact of dipyridamole to further 
reduce already diminished D-dimer levels is of limited value.  In light of the changes to standard 
of care, it was decided to evaluate the effect of dipyridamole on clinical outcomes more directly 
by elevating the hierarchical composite outcome from a secondary endpoint to a primary 
endpoint. 
 
The first primary endpoint is the relative change in D-dimer level over time during up to 14 days 
of hospitalization. We will assess the trend across D-dimer measurements obtained every second 
day, but we anticipate that some patients will have fewer measures (e.g. due to discharge before 
day 14).  Linear mixed effects regression will be used to assess the longitudinal trend in log-
transformed D-dimer values.  The regression model will have a fixed intercept and fixed slope 
for each treatment arm, and a random intercept and random slope for each subject. The model 
will also include treatment interactions by stratification factor (sex and age).  The primary 
hypothesis is that the treatment arm will have a smaller fixed slope than the control arm, 
indicating that treated subjects’ D-dimer levels either increase more slowly or decrease relative 
to those of the control subjects.   
 
Mixed effects regression makes use of all available information for each subject -- even a subject 
with a single D-dimer measurement can be included.  This technique efficiently makes use of the 
partial or full data observed from each subject, implicitly weighting subjects more if they have 
more observed points.  We note that subjects who do well and are discharged relatively earlier 
will be somewhat down-weighted due to having fewer measurements, but this is appropriate 
since our primary aim is to assess moderation of D-dimer increase in-hospital.  Discharge and 
other outcomes are discussed below as secondary aims.  We also note that this approach 
quantifies the change in D-dimer as a linear trend on the log scale.  Our preliminary analysis of 
D-dimer levels in patients with COVID-19 supports this simple approach to quantifying D-dimer 
variation.  Although D-dimer can fluctuate from day-to-day, the longer-term trend is primarily 
linear, but we acknowledge that some patients may exhibit other patterns of change. 
 
The second primary endpoint is a hierarchical composite of: 
• Time of death from any cause during study duration 
• Number of days on mechanical ventilation during study hospitalization 
• Decrease in SpO2/FiO2 ratio of at least 50 units relative to baseline at any time during the 
observation period, and 
• The cumulative sum of COVID ordinal scores during study hospitalization. 
The composite endpoint will be nonparametrically assessed by comparing global composite rank 
score outcomes24 across pairs of patients and evaluating a ‘win ratio’ using the Mann-Whitney U 
statistic.  Each pair consisting of one treated and one untreated subject is ranked as defined 
below: 
 
1. If both subjects die, then the subject who lives longer wins. 
2. If exactly one subject dies, then the subject who does not die wins.   
3. If the subjects are tied after step 2 (neither subject dies), then the subject with fewer days on 
ventilator wins. 
4. If the subjects are tied after step 3, and only one of the subjects has a decrease in SpO2 of 50 or 
greater, then the subject who does not have the decrease in SpO2 wins. 


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5. If the subjects are tied after step 4, then the subject with lower Ordinal score wins. 
6. If the subjects are tied after step 5, then their final result is a tie 
The win proportion is the probability that a treatment patient experiences better outcomes when 
compared to a placebo patient, thus representing the effect size. The analysis is powered to a 
0.67 win proportion. For the efficacy endpoint using the O’Brien-Fleming method to correct for 
interim analyses, we will use a P value cutoff of 0.006 for the midway point analysis and 0.044 
for the final analysis, yielding an overall alpha (type I error rate) of 0.05.  
15.3.1 
Interim Analyses of Primary Endpoints 
When approximately 25% and 50% of participants have completed the study or 10 deaths have 
occurred (whichever occurs first), an interim analysis for safety and futility will be conducted by 
the DSMB. The interim analyses for efficacy will be limited to the review after 50% of 
participants have completed the study to limit the cost to power from multiple interim analyses. 
The interim analysis of benefit for the primary endpoint will be conducted on a binary version of 
patient-level D-dimer change rates.  Rates will be estimated separately for each patient by simple 
linear regression and dichotomized by whether the rates was above a 5% daily increase.  
Treatment groups will be compared by a Fisher’s exact test.  We will use the O’Brien-Fleming 
method and Lan-DeMets alpha spending functions to preserve an overall Type I error rate of 
0.05.  Thus, the interim analysis will use a significance threshold of 𝛼𝛼= 0.006 (based on 45 
patients), and the remaining 0.044 of alpha will be divided evenly between the final analyses of 
the two primary endpoints. 
For futility of the D-dimer endpoint, if the lower limit for the 95% confidence interval of the 
daily change in D-dimer is above 9% for the dipyridamole population at the time of the 50% 
interim analysis, the trial will be stopped.  
It was decided in the December 2020 DSMB meeting to conduct benefit and futility analyses of 
the composite hierarchical primary endpoint for all patients with study completion as of 
December 31, 2020.  We proceed with the win ratio analysis described above but base futility 
and benefit decisions on the conditional power approach described in Lan and Trost (1999) and 
advanced in Siu and Lan (2001) and Lachin (2006).  This approach calculates the condition 
power (CP), defined as the probability of finding a significant result at the end of the study given 
the interim results and a presumption that the data reflect the true effect size.  Decision 
thresholds are predetermined as: 
• CP ≥ 0.9 : Stop study for benefit 
• 0.8 ≤ CP < 0.9 : Continue study to planned N = 127 
• 0.3 ≤ CP < 0.8 : Continue study to with re-estimated sample size not to exceed 160 
• CP < 0.3 : Stop study for futility 
15.4 
Analysis of Secondary Endpoints 
We will conduct secondary analyses on each component of the hierarchical composite endpoint: 


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• 
Time to death 
o Analysis: Cox proportional hazards regression 
• 
Number of days on mechanical ventilation during study hospitalization  
o Analysis: Poisson regression with subject-level random effects 
• 
Dichotomized (yes/no) decrease in SpO2/FiO2 ratio of at least 50 units relative to baseline 
at any time during the observation period  
o Analysis: Logistic regression 
• 
Cumulative sum of COVID ordinal scores during study hospitalization  
o Analysis: Mann-Whitney U-test (nonparametric) 
We will analyze an additional secondary endpoint: 
• 
Days free of organ support, where organ support is defined as receipt of invasive or non-invasive 
mechanical ventilation, high flow nasal oxygen, vasopressor therapy, ECMO support, or COVID-
related dialysis, and 
• 
Death at any time is assigned a value of 0 days. 
o Analysis: Mann-Whitney U-Test (nonparametric) 
Each analysis will include interactions of the study drug by stratification factor.   
15.5 
Analysis of Exploratory Endpoints 
The DICER study contains four major kinds of exploratory endpoints (listed in Section 3.5): 
continuous, change over time (continuous), binary, and time to event.  All analyses will be based 
on the mITT population except where specified in the definition of the endpoint.   
We will analyze continuous endpoints by ANOVA with treatment and stratification factors (sex 
and age) as predictors. 
We will analyze continuous change over time endpoints by mixed linear effect models using the 
same methodology described in Section 10.1 for the D-dimer primary efficacy endpoint. 
We will analyze binary endpoints by logistic regression with treatment and stratification factors 
(sex and age) as predictors. 
We will analyze time-to-event by Cox proportional hazards regression with treatment and 
stratification factors (sex and age) as predictors. 
 
In all analyses, the only estimate of interest will be the difference between treatment arms.  We 
will include treatment interactions by stratification factor in all models, and we will fit separate 
models where age is continuous versus where age is represented by an indicator variable for age 
≥ 65 years. Hypothesis tests will be two-sided. 
15.6 
Power analysis 
Decision thresholds and power are based on a preliminary analysis of 147 D-dimer 
measurements taken on 41 COVID-19 patients admitted to Michigan Medicine.  Using variance 


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components regression on log-transformed D-dimer levels, we found that the intraclass 
correlation coefficient (ICC) for participants (between-participant variance to total variance) was 
0.77 in a model controlling for days since admission and ICU status (binary) as fixed effects. 
ICU status serves as a proxy for case severity. An increasing trend in D-dimer levels (~13% per 
day) was common to both groups. The moderately high ICC reflects the contributions of around 
90% within-participant variation (day-to-day) relative to around 300% between-participant 
variation. Thus, D-dimer levels largely behave as a stable participant-level trait that may indicate 
the underlying extent of disease. Defining the endpoint in terms of the least squares slope of D-
dimer level using up to 7 measurements reduces the impact of daily D-dimer fluctuations and 
thereby increases statistical power. 
To assess power for the proposed design, we used a simulation approach matching the patient 
population characteristics learned from the analysis of preliminary data reported above.  For 
power simulation, the ICC was set to 0.7, somewhat lower than the observed ICC of 0.77, in 
order to provide a margin for uncertainty in the pilot results. Power is based on a 13% daily 
increase in D-dimer levels for untreated participants, as observed in preliminary analysis. We 
posited a 50% reduction in the growth rate for the 100 mg dose. Using 2 arms with 40 
participants per arm (100 participants in all), power is 0.91 for comparing the dipyridamole-
treated participants to the controls. However, the standard of care treatment has changed with 
introduction of anti-inflammatory steroids which suggests an increase in sample size may be 
necessary to complete the study. 
15.7 Sample Size and Randomization 
We will enroll 100 participants to complete this study based on the power calculation. Patients 
will be recruited for this study and randomized in a 1:1 ratio using stratified random blocks. This 
study is a proof-of-concept multi center, single-blinded, randomized, controlled trial to evaluate 
the effectiveness of dipyridamole to reduce progressive coagulation dysfunction associated with 
coronavirus infection.  
16 DATA COLLECTION, RETENTION AND MONITORING 
16.1 Data Collection Instruments 
The Site-Investigator or trained delegates will prepare and maintain adequate and accurate source 
documents designed to record all observations and other pertinent data for each participant 
treated with the study drug.   
Study personnel will enter data from source documents corresponding to a participant’s visit into 
secured, central databases. Participants will not be identified by name in the study database or on 
any study documents to be collected by the designee but will be identified by a participant 
number and initials. 
If a correction is made on a paper source document, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change. 


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The site investigator is responsible for all information collected on participants enrolled in this 
study.  All data collected during the course of this study must be reviewed and verified for 
completeness and accuracy by the investigator.   
16.2 Data Management Procedures 
The data will be entered into a HIPAA compliant database.   
16.3 Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis.  
16.4 Availability and Retention of Investigational Records 
The Site Investigator will make study data accessible to the IRB and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each participant will be maintained that includes the 
signed Informed Consent with HIPAA Authorization and source documentation related to that 
participant.  The Site Investigator will ensure the reliability and availability of source documents. 
All study documents (participant files, signed informed consent forms, copies of source 
documents, etc.) will be kept secured for a period of 7 years following the completion of the 
study.   
16.5 Monitoring 
The PI will be primarily responsible for monitoring data integrity. Monitoring is intended to 
protect participants’ rights and safety, and to ensure the integrity and quality of the data 
collected. The PI will ensure that all relevant IRBMED and FDA policies, procedures, and 
stipulations are followed by the study team. This study will be monitored by MICHR monitor. 
Monitoring will be conducted prior to the initiation of study enrollment and throughout the life 
cycle of the study. 
16.6 Participant Confidentiality 
In order to maintain participant confidentiality, only a participant study ID number and 
participant initials will identify all study participants on source documents and other 
documentation submitted to the IRB.  Bio specimen samples that will be analyzed in a 
collaborator’s research laboratory will only contain the participant study ID number. 
17 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
To maintain confidentiality, all laboratory specimens, evaluation forms, reports and other records 
will be identified by a coded number and initials only.  All study records will be kept in a locked 
file cabinet and code sheets linking a participant’s name to a participant identification number 
will be stored separately in another locked file cabinet.  Clinical information will not be released 
without written permission of the participant, except as necessary for monitoring by the FDA.  


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The Site Investigator will also comply with all applicable privacy regulations (e.g., Health 
Insurance Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
17.1 Protocol Amendments 
Any amendment to the protocol will be written by the Sponsor, National-Investigator or 
designee.  Protocol amendments will not be implemented without prior written IRB approval 
except as necessary to eliminate immediate safety hazards to participants.  A protocol 
amendment intended to eliminate an apparent immediate hazard to participants may be 
implemented immediately, provided the IRBs are notified within five working days. 
17.2 Institutional Review Boards  
The protocol and consent form will be reviewed and approved by the Institutional Review 
Boards at each institute prior to study initiation.  Serious adverse experiences regardless of 
causality will be reported to the IRB in accordance with the standard operating procedures and 
policies of the IRB, and the Site-Investigator will keep the IRB informed as to the progress of the 
study.  
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, consent forms, information concerning patient recruitment, payment or 
compensation procedures, or other pertinent information) will be submitted to the IRB.  The IRB 
written unconditional approval of the study protocol and the informed consent form will be in the 
possession of the Site-Investigator before the study is initiated.   
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB approval except when necessary to eliminate immediate hazards to the participants 
or when the change(s) involves only logistical or administrative aspects of the study.  Such 
modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved will be obtained.   
The IRB will be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the participants of the conduct of the study; an annual update and/or 
request for re-approval; and when the study has been completed. 
17.3 Informed Consent Form  
The Investigator or designee will prepare the informed consent form containing HIPAA 
authorization and the investigator will provide the documents to the IRB.  The consent form 
generated by the Site-Investigator will be approved by the IRB.  The Site-Investigator will store 
an IRB-approved copy of the Informed Consent Form in the study regulatory binder. 
A properly executed informed consent will be obtained from each participant prior to entering 
the participant into the trial.  Information will be given in both oral and written form and 
participants will be given ample opportunity to inquire about details of the study.  A copy of the 


Protocol HUM 00179783 
Confidential 
 
 
Version #: 6.0 
Version Date: 12 July 2021 
Page 46 of 48 
 
signed consent form will be given to the participant and the original will be maintained with the 
participant’s records. 
17.4 Publications  
The publication or presentation of any study results shall comply with all applicable privacy 
laws, including, but not limited to, the Health Insurance Portability and Accountability Act of 
1996.  
 
 


Protocol HUM 00179783 
Confidential 
 
 
Version #: 6.0 
Version Date: 12 July 2021 
Page 47 of 48 
 
PROTOCOL REFERENCES 
 
1. 
Perlman, S. & Dandekar, A.A. Immunopathogenesis of coronavirus infections: 
implications for SARS. Nat Rev Immunol 5, 917-27 (2005). 
2. 
Blondonnet, R., Constantin, J.M., Sapin, V. & Jabaudon, M. A Pathophysiologic 
Approach to Biomarkers in Acute Respiratory Distress Syndrome. Dis Markers 2016, 
3501373 (2016). 
3. 
Li, Z. et al. FEP-based screening prompts drug repositioning against COVID-19. bioRxiv, 
2020.03.23.004580 (2020). 
4. 
Liu, X. et al. Potential therapeutic effects of dipyridamole in the severely ill patients with 
COVID-19. Acta Pharm Sin B (2020). 
5. 
Gregov, D. et al. Dipyridamole: pharmacokinetics and effects on aspects of platelet 
function in man. Br J Clin Pharmacol 24, 425-34 (1987). 
6. 
Perry, A.K., Chen, G., Zheng, D., Tang, H. & Cheng, G. The host type I interferon 
response to viral and bacterial infections. Cell Res 15, 407-22 (2005). 
7. 
Galabov, A.S. & Mastikova, M. Dipyridamole induces interferon in man. Biomed 
Pharmacother 38, 412-3 (1984). 
8. 
Galabov, A.S. & Mastikova, M. Interferon-inducing activity of dipyridamole in mice. 
Acta Virol 27, 356-8 (1983). 
9. 
Tonew, E., Indulen, M.K. & Dzeguze, D.R. Antiviral action of dipyridamole and its 
derivatives against influenza virus A. Acta Virol 26, 125-9 (1982). 
10. 
Macatangay, B.J.C. et al. A Randomized, Placebo-Controlled, Pilot Clinical Trial of 
Dipyridamole to Decrease Hiv-Associated Chronic Inflammation. J Infect Dis (2019). 
11. 
Mehta, P. et al. COVID-19: consider cytokine storm syndromes and immunosuppression. 
Lancet (2020). 
12. 
Ali, R.A. et al. Adenosine receptor agonism protects against NETosis and thrombosis in 
antiphospholipid syndrome. Nat Commun 10, 1916 (2019). 
13. 
Chen, J. et al. Findings of Acute Pulmonary Embolism in COVID-19 Patients. SSRN 
Electronic Journal (2020). 
14. 
Matthay, M.A. et al. Acute respiratory distress syndrome. Nat Rev Dis Primers 5, 18 
(2019). 
15. 
Merza, M. et al. Neutrophil Extracellular Traps Induce Trypsin Activation, Inflammation, 
and Tissue Damage in Mice With Severe Acute Pancreatitis. Gastroenterology 149, 
1920-1931 e8 (2015). 
16. 
Ridker, P.M. From C-Reactive Protein to Interleukin-6 to Interleukin-1: Moving 
Upstream To Identify Novel Targets for Atheroprotection. Circ Res 118, 145-56 (2016). 
17. 
Zuo, Y. et al. Neutrophil extracellular traps in COVID-19. JCI Insight (2020). 
18. 
Chen, J. et al. Retrospective Analysis of Clinical Features in 101 Death Cases with 
COVID-19. medRxiv, 2020.03.09.20033068 (2020). 
19. 
Persantine (dipyridamole) [package insert]. Ridgefield, CT: Boehringer Ingelheim 
Pharmaceuticals, Inc. (December 2019). 
20. 
Lette, J. et al. Safety of dipyridamole testing in 73,806 patients: the Multicenter 
Dipyridamole Safety Study. J Nucl Cardiol 2, 3-17 (1995). 
21. 
Ramakers, B.P. et al. Dipyridamole augments the antiinflammatory response during 
human endotoxemia. Crit Care 15, R289 (2011). 


Protocol HUM 00179783 
Confidential 
 
 
Version #: 6.0 
Version Date: 12 July 2021 
Page 48 of 48 
 
22. 
Group, E.S. et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia 
of arterial origin (ESPRIT): randomised controlled trial. Lancet 367, 1665-73 (2006). 
23. 
Mok, C.K. et al. Warfarin versus dipyridamole-aspirin and pentoxifylline-aspirin for the 
prevention of prosthetic heart valve thromboembolism: a prospective randomized clinical 
trial. Circulation 72, 1059-63 (1985). 
24. 
Ramchandani, R., Schoenfeld, D.A. & Finkelstein, D.M. Global rank tests for multiple, 
possibly censored, outcomes. Biometrics 72, 926-35 (2016). 
 
 
APPENDIX 1. Schedule of Study Events 
See attached SOE document 
APPENDIX 2. Summary of Changes 
 
 
 

SAP_003.pdf: 
Dipyridamole to Prevent Coronavirus Exacerbation of Respiratory Status (DICER) 
in COVID-19 
Statistical Analysis Plan
NCT04391179
February 3rd, 2022


Statistical Analysis Plan 
 
TRIAL FULL TITLE 
DICER (Dipyridamole to prevent Coronavirus Exacerbation of 
Respiratory Status) 
SAP VERSION 
1.0 
SAP VERSION DATE 
February 3, 2022 
TRIAL STATISTICIAN 
Adam Martin-Schwarze, PhD 
SABER, School of Public Health 
University of Michigan 
Protocol Version (SAP 
associated with) 
6.0 
TRIAL PRINCIPAL 
INVESTIGATOR 
Jason S. Knight, MD, PhD 
1150 West Medical Center Drive 
Ann Arbor, Michigan 48109 
TRIAL CHAIR 
Yogendra Kanthi, MD 
1150 West Medical Center Drive 
Ann Arbor, Michigan 48109 
SAP AUTHOR(s) 
Adam Martin-Schwarze, PhD 
Elizabeth Freiheit, PhD 
 
1 SAP Signatures 
I give my approval for the attached SAP: 
Statistician (Author) 
Name:   
Adam Martin-Schwarze 
Signature: 
 
 
Date: 
 
February 3, 2022 
Principal Investigator 
Name:   
Jason S. Knight, MD. PhD 
Signature: 
 
Date: 
 
February 10, 2022 
  
Trial Chair 
Name:    
Yogendra Kanthi, MD 
Signature: 
Date:   
February 10, 2022 
 
 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 2 of 25 
 
2 Table of Contents 
1 
SAP Signatures 
1 
2 
Table of Contents 
2 
3 
Abbreviations and Definitions 
5 
4 
Introduction 
6 
4.1 
Preface 
6 
4.2 
Scope of the Analyses 
6 
5 
Study Objectives and Endpoints 
6 
5.1 
Study Objectives 
6 
5.2 
Endpoints 
6 
5.2.1 
Primary Endpoint 
7 
5.2.2 
Secondary endpoints 
7 
5.2.3 
Safety Endpoints 
7 
5.2.4 
Exploratory Endpoints 
7 
6 
Study Methods 
8 
6.1 
General Study Design and Plan 
8 
6.2 
Inclusion-Exclusion Criteria and General Study Population 
9 
6.2.1 
Inclusion Criteria 
9 
6.2.2 
Exclusion Criteria 
9 
6.3 
Study Assessments 
11 
6.4 
Clinical Assessments 
12 
6.4.1 
Concomitant medications 
12 
6.4.2 
Demographics 
12 
6.4.3 
Medical history 
12 
6.4.4 
Social history 
12 
6.4.5 
Physical examination 
12 
6.4.6 
Electrocardiogram 
12 
6.4.7 
Chest imaging 
12 
6.4.8 
Vital signs 
12 
6.4.9 
Oxygen requirements 
12 
6.4.10 
Modified WHO COVID-19 8-point Ordinal scale assessment 
12 
6.4.11 
National Early Warning Scores (NEWS2) 
13 
6.4.12 
Adverse events 
13 
6.5 
Clinical Laboratory Measurements 
13 
6.5.1 
D-dimer, Ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), complete 
blood cell count with differential (CBC), fibrinogen, partial thromboplastin time (PTT), 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 3 of 25 
 
international normalized ratio (INR), arterial blood gases (ABG), basic metabolic panel (BMP), 
hepatic function panel (LFT) 
13 
6.5.2 
Pregnancy test 
13 
6.5.3 
Pharmacokinetic measurements 
13 
6.6 
Research Laboratory Measurements (see Schedule of Events) 
14 
6.6.1 
Coagulation potential 
14 
6.6.2 
Biomarkers of blood cell activation 
14 
6.6.3 
Leukocytes 
14 
7 
Sample Size 
14 
7.1 
D-dimer Calculations 
14 
7.2 
Win Ratio Calculations 
14 
8 
General Analysis Considerations 
15 
8.1 
Timing of Analyses 
15 
8.2 
Analysis Populations 
15 
8.2.1 
Modified Intent to Treat Population (mITT) and Safety Population 
15 
8.3 
Covariates and Subgroups 
15 
8.4 
Missing Data 
15 
8.5 
Extra Data 
16 
8.6 
Interim Analyses and Data Monitoring 
16 
8.6.1 
Safety Review 
16 
8.6.2 
Efficacy Review 
16 
8.6.2.1 
Primary D-dimer Endpoint 
16 
8.6.2.2 
Primary Hierarchical Composite Endpoint 
16 
8.7 
Multiple Testing 
17 
9 
Summary of Study Data 
17 
9.1 
Subject Disposition 
17 
9.2 
Derived variables 
18 
9.2.1 
Hierarchical Composite Endpoint Used in Win Ratio Analysis 
18 
9.3 
Protocol Violations 
19 
9.4 
Demographic and Baseline Variables 
20 
9.5 
Concurrent Illnesses and Medical Conditions 
20 
9.6 
Treatment Compliance 
20 
10 Efficacy Analyses 
20 
10.1 
Primary Efficacy Analysis: D-dimer 
21 
10.2 
Primary Efficacy Analysis: Hierarchical Composite Endpoint 
21 
10.3 
Secondary Efficacy Analyses 
21 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 4 of 25 
 
10.4 
Exploratory Efficacy Analyses 
22 
11 Safety Analyses 
22 
11.1 
Extent of Exposure 
22 
11.2 
Adverse Events 
23 
11.2.1 
AE Severity 
23 
11.2.2 
AE Relationship to Study Drug 
23 
11.3 
Deaths, Serious Adverse Events and other Significant Adverse Events 
23 
11.4 
Clinical Laboratory Evaluations 
24 
11.5 
Prior and Concurrent Medications 
24 
12 Other Analyses 
24 
13 Reporting Conventions 
24 
14 Summary of Changes to the Protocol and/or SAP 
24 
15 References 
24 
 
 
 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 5 of 25 
 
 
3 Abbreviations and Definitions 
ABG 
Arterial blood gases 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARDS 
Acute respiratory distress syndrome 
AST 
Aspartate aminotransferase 
BMP 
Basic metabolic panel 
CBC 
Complete blood cell count with differential 
COVID-19 
Coronavirus disease 2019 
CP 
Conditional Power 
CRF 
Case report form 
CRP 
C-reactive protein 
DICER 
Name of the Study: Dipyridamole to prevent Coronavirus Exacerbation of 
Respiratory Status 
ECMO 
Extracorporeal membrane oxygenation 
FiO2 
Fraction of inspired oxygen 
GFR 
Glomerular filtration rate 
INR 
International normalized ratio 
ISTH 
International Society on Thrombosis and Hemostasis 
LDH 
Lactate dehydrogenase 
LFT 
Hepatic function panel 
NEWS2 
National Early Warning Score 
PTT 
partial thromboplastin time 
SABER 
Statistical Analysis of Biomedical and Educational Research unit in the University of 
Michigan School of Public Health 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SpO2 
Peripheral pulse oximetry 
ULN 
Upper limit of normal 
 
 
 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 6 of 25 
 
4 Introduction 
4.1 Preface 
This Statistical Analysis Plan (SAP) describes statistical methods and analyses for the DICER study. 
This document should be read in tandem with the DICER Study Protocol version 5.0, dated 
November 23, 2020. 
Immune hyperactivation and thrombophilia appear to predict worse outcomes in individuals with 
COVID-19. The majority of hospitalized patients infected with COVID-19 develop coagulation 
dysfunction as indicated by elevated levels of D-dimer protein, which predicts acute respiratory 
distress syndrome (ARDS), venous thromboembolism, and mortality. Dipyridamole is an 
adenosinergic drug with a favorable safety profile that reduces thrombosis, reduces immune 
hyperactivation, and directly inhibits SARS-CoV-2 virus replication. A small clinical trial of 
dipyridamole in 31 patients with moderate- and severe-COVID-19 showed safety of dipyridamole and 
efficacy in reducing D-dimer levels, and a trend toward improved clinical outcomes (Liu et al, 2020). 
The intent of this proof-of-concept study is to evaluate whether the drug dipyridamole will reduce D-
dimer elevation in participants with moderate COVID-19 as measured by: increase in D-dimer, 
respiratory status, ventilation and mortality, and ICU admission. If this novel approach is effective in 
reducing the progression of D-dimer elevation, it will inform a larger, multi-center trial to determine 
efficacy in preventing progression of moderate to severe COVID-19 infection. The result may broadly 
improve care of patients with coronavirus infection. 
4.2 Scope of the Analyses 
The purpose of this document is to describe primary and secondary statistical analyses to be 
conducted with regard to the efficacy and safety of dipyridamole versus placebo in the DICER clinical 
trial. 
5 Study Objectives and Endpoints 
5.1 Study Objectives 
Due to changes in standard of care for COVID-19 patients, this study has two co-primary objectives, 
with the original secondary endpoint being elevated to a co-primary endpoint. The first and original 
primary objective of this study is to compare the effect of dipyridamole vs. placebo on plasma D-
dimer changes in patients with moderate COVID-19.  The second primary objective, formerly a 
secondary objective, is to compare the effect of dipyridamole vs. placebo on a composite of clinical 
outcomes including death, survival time, days on mechanical ventilation, decrease in SpO2/FiO2 ratio, 
and cumulative COVID ordinal scores. 
5.2 Endpoints 
For convenience, we give names to the following times and time windows: 
• 
Baseline or Day 1: Date of the first study drug administration 
• 
Study Hospitalization: Day 1 through either Day 14 or hospital discharge, whichever is first 
• 
Observation Period: The 28-day period following first study drug administration 
• 
Study Duration: The period from baseline until 30 days after last study drug administration 
 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 7 of 25 
 
If an endpoint is to be evaluated at all three of the above time points, we use the phrase ‘at any time 
point’. 
 
Endpoints are presented in a numbered list to facilitate references to endpoints when conducting the 
final analysis. 
5.2.1 
Primary Endpoint 
The first co-primary endpoint is increase in plasma D-dimer levels compared to baseline. 
The second co-primary endpoint is a clinical hierarchical composite of: 
• 
Time to death from any cause during study duration 
• 
Number of days on mechanical ventilation during study hospitalization 
• 
A dichotomized (yes/no) decrease in daily average SpO2/FiO2 ratio of at least 50 units relative 
to Day 1 at any time during the observation period 
• 
Cumulative sum of COVID ordinal scores during study hospitalization 
5.2.2 
Secondary endpoints 
1. Days alive and free of organ support, where: 
o Organ support is defined as receipt of invasive mechanical ventilation, vasopressor 
therapy, ECMO support, or dialysis 
2. Individual components of composite endpoint 
5.2.3 
Safety Endpoints 
3. During the observation period, incidence of bleeding associated with: (i) a decrease in the 
hemoglobin level of at least 2 g per deciliter, (ii) transfusion of at least 2 units of blood, (iii) 
occurrence in a critical site, or (iv) contributing to death 
4. Incidence of serious adverse events (SAEs) during study duration 
5. Incidence of hypotension with systolic blood pressure below 90 mmHg and requiring a 1-liter 
IV fluid bolus during study hospitalization 
5.2.4 
Exploratory Endpoints  
Based on consultation with the DICER researchers, SABER will only analyse a subset of the 
exploratory endpoints specified in the original protocol.  Numbers in the following list (e.g. 
#17) refer to Section 3.4 Exploratory Outcomes in the protocol, version 5.0. 
6. Blood Oxygenation 
o Time to increase in daily average SpO2/FiO2 ratio of at least 50 units relative to Day 1 
during the observation period (#17) 
7. Ventilation 
o Initiation of mechanical ventilation or ICU care during observation period (yes/no) 
(#6) 
o Initiation of mechanical ventilation during observation period (yes/no) (#11) 
o Initiation of ICU care during observation period (yes/no) 
8. Change from baseline at Day 5 for: C-reactive protein, LDH, ferritin, total leukocyte count, 
neutrophils, lymphocytes, and platelet count in the blood (#4) 
o Daily changes from Day 1 in neutrophils and lymphocytes 
9. Hospitalization 
o Time to hospital discharge (#7) 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 8 of 25 
 
o Incidence of hospital readmission during study duration (#30) 
10. Supplemental Oxygen 
o Proportion of surviving patients still requiring supplemental oxygen at the end of the 
observation period (#8) 
o Number of days on supplemental oxygen during observation period (#9) 
11. Imaging: Proportion of study population with each of the following: 
o Arterial or venous thromboembolism diagnosed by imaging study during study 
duration (#25) 
o Venous thrombosis diagnosed by imaging study during study duration (#26) 
o Arterial thrombosis diagnosed by imaging study during study duration (#27) 
12. Change from Day 1 in daily average glomerular filtration rate (GFR) during observation 
period, assessed daily through Day 5 (#28) 
13. An alternative version of the second co-primary endpoint decision-rule: 
o Time to death from any cause during study duration 
o Number of days on mechanical ventilation during study hospitalization 
o A dichotomized (yes/no) decrease in daily average SpO2/FiO2 ratio of at least 50 units 
relative to enrollment date at any time during the observation period 
o A dichotomized (yes/no) increase in Ordinal Score at any time relative to enrollment 
 
Analyze dichotomized (yes/no) increase in Ordinal Score at any time relative 
to enrollment as a standalone endpoint 
Additional analyses done separately from SABER (to be done at a future date): 
14. A dichotomized (yes/no) decrease for patients with elevated Day 1 neutrophil activation 
during study hospitalization, where elevated is defined as > 2 SD above established healthy 
controls (#22) 
15. A dichotomized (yes/no) decrease for patients with elevated Day 1 inflammatory, anti-
inflammatory, and other cytokines in during study hospitalization, where elevated is defined 
as blood defined as > 2 SD above established healthy controls (#23) 
16. A dichotomized (yes/no) decrease for patients with elevated Day 1 coagulant and 
anticoagulant cytokines in blood during study hospitalization, where elevated is defined as 
blood defined as > 2 SD above established healthy controls (#24) 
17. Gene expression, function, and activation of peripheral blood leukocytes following treatment 
on Days 1 or 5 (#29) 
6 Study Methods 
6.1 General Study Design and Plan 
Our primary hypotheses are that patients on dipyridamole will evidence a smaller increase in D-dimer 
levels and better clinical outcomes on the COVID ordinal score than patients on placebo.   
 
This is a proof-of-concept, placebo-controlled, single-blinded, randomized, 14-day trial of 160 
patients.  
 
Participants were assigned treatments to dipyridamole or placebo in 1:1 fashion using stratified, 
random blocks based on sex and age (above/below 65).  Stratified blocks were generated using the 
‘blockrand’ package in R. 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 9 of 25 
 
 
After randomization, treatment was administered four times daily up until hospital discharge or 14 
days, with clinical evaluations made daily.  Clinically significant abnormal lab studies were evaluated 
for relationship to the study drug.  Clinical data capture and survival follow-up occurred on Day 28 ± 
1.  Patient follow-up occurred again 30 days after last dose of study drug.  The study schematic is 
presented in Figure 1. 
 
Figure 1 Schematic Representation of Study Design 
 
6.2 Inclusion-Exclusion Criteria and General Study Population 
6.2.1 
Inclusion Criteria 
1. Age ≥ 18 years 
2. Willing and able to provide informed consent prior to performing study procedures unless 
they have a legally authorized representative (LAR) 
3. Confirmed coronavirus (SARS-CoV-2) infection 
4. Currently hospitalized or anticipated hospitalization requiring supplemental oxygen 
6.2.2 
Exclusion Criteria 
1. In the opinion of at least two physicians, unlikely to survive for >48 hours from screening 
2. Concurrent enrollment in a clinical trial of a cytokine inhibitor (targeting IL-6, IL-6R, IL-1, or 
Janus kinase). Use of remdesivir is permitted.  


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 10 of 25 
 
3. Currently on invasive mechanical ventilation 
4. Hypotension defined as systolic blood pressure < 90 mmHg on two readings at least 4 hours 
apart 
5. Pregnant or breastfeeding 
6. Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor (eg. clopidogrel, 
ticagrelor) plus anticoagulation to treat deep venous thrombosis or pulmonary embolism 
(single antiplatelet agent, or anticoagulant agent at prophylaxis or therapeutic dose is 
permitted). 
7. Presence of any of the following abnormal laboratory values: aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) greater than 5 x upper limit of normal (ULN), 
platelets <50,000 per mm3, hemoglobin <8 g per deciliter 
8. History of recent major bleeding, defined in accordance with the criteria of the International 
Society on Thrombosis and Hemostasis (ISTH) as overt bleeding that was associated with a 
decrease in the hemoglobin level of 2 g per deciliter or more, led to a transfusion of 2 or more 
units of blood, occurred in a critical site within 30 days. 
9. Any physical examination findings and/or history of any illness that, in the opinion of the 
study investigator, might confound the results of the study or pose an additional risk to the 
patient by their participation in the study. 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 11 of 25 
 
6.3 Study Assessments  
 
 
 
Table 1. Schedule of Events 
Study Day 
Screening 
Enrollment 
Day 
1 
Days 3, 
7, 11 
Days 5, 
9, 13 
Even 
Days 2-12 
Day 
14 
Day 
28 
Early 
Withdrawal 
30 Days 
After Drug  
Screening via chart review 
X 
 
 
 
 
 
 
 
 
Screening for eligibility 
X 
 
 
 
 
 
 
 
 
Informed consent  
X 
 
 
 
 
 
 
 
 
Pregnancy test a 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
Social history b 
 
X 
 
 
 
 
 
 
 
Physical exam SOC review c 
 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
Study drug administration 
 
X 
X 
X 
X 
X 
 
 
 
Vitals/Oximetry SOC review c 
 
X 
X 
X 
X 
X 
Xj 
X 
 
Respiratory status SOC reviewc 
 
X 
X 
X 
X 
X 
 
X 
 
Clinical progress review 
 
X 
X 
X 
X 
X 
 
X 
 
Clinical care lab result review 
 
X 
X 
X 
X 
X 
 
X 
 
ECG clinical care data review d 
 
X 
X 
X 
X 
X 
 
X 
 
Chest imaging review d 
 
X 
X 
X 
X 
X 
 
X 
 
BMP e 
 
X 
X 
X 
 
 
 
X 
 
D-dimer e  
 
X 
X 
X 
 
X 
 
X 
 
Ferritin e 
 
X 
 
X 
 
 
 
X 
 
LDH e  
 
X 
 
X 
 
 
 
X 
 
CRP e 
 
X 
 
X 
 
 
 
X 
 
CBC w/ diff  e 
 
X 
X 
X 
 
X 
 
X 
 
FBN e  
 
X 
X 
X 
 
X 
 
X 
 
PTT/INR e  
 
X 
X 
X 
 
X 
 
X 
 
ABG d 
 
X 
 
 
 
 
 
 
 
LFT e 
 
X 
 
X 
 
 
 
X 
 
Research blood draw i 
 
Xf 
Xf 
Xf 
 
 
 
X 
 
Concomitant meds/therapies 
 
X 
X 
X 
X 
X 
Xg 
X 
 
AE assessment 
 
X 
X 
X 
X 
X 
Xg 
X 
Xh 
a Performed in subjects of child-bearing potential, if not already performed for clinical care reasons 
b Social history including pregnancy history, tobacco and alcohol use 
c Medical chart review for extraction of standard-of-care data. 
d Only if performed while patient is inpatient/hospitalized for clinical care reasons. Data will be recorded. 
e Lab results will be extracted from blood drawn for clinical care, whenever possible.. 
f Blood collection will be coordinated with blood draw for clinical care lab studies, whenever possible.  
g Medical chart review for secondary endpoints will continue until Day 28.  
h Chart review and phone call for AEs assessment until 30 days after last dose of study drug, maximum of 44 days from 
initial participation date. 
i: Research lab draws on study days 3,5,9,11,13 will have +/- 1 day window. 
 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 12 of 25 
 
Prior to conducting any study-related activities, written informed consent containing Health Insurance 
Portability and Accountability Act (HIPAA) authorization will be signed and dated by the participant. 
6.4 Clinical Assessments 
6.4.1 
Concomitant medications 
All concomitant medications will be documented during the study, including early termination when 
applicable. Dose, route, unit frequency of administration, indication for administration and dates of 
medication will be captured. 
6.4.2 
Demographics 
Demographic information (race, ethnicity, sex, date of birth, and height and weight) will be recorded 
at the time of enrollment. 
6.4.3 
Medical history 
Relevant medical history, including history of current disease and information regarding underlying 
diseases will be obtained from the patient and/or by chart review, and recorded at the time of 
enrollment. 
6.4.4 
Social history 
Relevant social history, including history of pregnancy, tobacco and alcohol use, will be obtained 
from the patient and/or by chart review, and recorded at the time of enrollment. 
6.4.5 
Physical examination 
A complete physical examination will be performed by the medical team during the hospitalization. 
Abnormal physical exam findings will be documented, and the principal investigator will incorporate 
this information into consideration of continued eligibility from a safety perspective. 
6.4.6 
Electrocardiogram 
Electrocardiogram (ECG) will be performed by the medical team if clinically appropriate and 
documented in the eCRF if obtained. 
6.4.7 
Chest imaging 
Chest imaging will be performed by the medical team if clinically appropriate and documented in the 
eCRF if obtained.  Imaging findings will be coded in binary variables for infiltrates, pneumonia, 
pleural effusion, consolidation, pulmonary embolism, RV strain, and cardiomegaly. 
6.4.8 
Vital signs 
Temperature, blood pressure, heart rate, respiration rate, height, weight will be performed per 
institutional protocol. Blood pressure will be measured at least twice daily. 
6.4.9 
Oxygen requirements 
Pulse oximetry (SpO2), oxygen requirements (mode of delivery), fraction of inspired oxygen (FiO2), 
oxygen flow rate, and mode of mechanical ventilation will be recorded at least daily alongside vital 
signs measurement. Pulse oximetry will be measured at least twice daily. 
6.4.10 Modified WHO COVID-19 8-point Ordinal scale assessment  
Ordinal scale assessments will be made daily and on Day 28 as below: 


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Table 2. Modified COVID 8-Point Ordinal Scale 
Patient State 
Descriptor 
COVID  
Ordinal Score 
Dead 
Death 
8 
Hospitalized – 
severe disease 
Ventilation + additional organ support (pressors, renal replacement 
therapy, ECMO) 
7 
Intubation and mechanical ventilation 
6 
Non-invasive ventilation or high-flow oxygen 
5 
Hospitalized – 
mild disease 
Oxygen by mask or nasal prongs 
4 
Hospitalized, no oxygen therapy 
3 
Ambulatory 
Limitation of activities 
2 
No limitation of activities 
1 
 
6.4.11 National Early Warning Scores (NEWS2) 
The NEWS2 score will be made daily and on Day 28.  We omit details of NEWS2, because it will not 
be analyzed in this SAP. 
6.4.12 Adverse events 
Information regarding occurrence of adverse events will be captured throughout the study. Duration 
(start and stop dates), severity/grade, outcome, treatment and relation to study drug will be recorded 
on the source document. 
6.5 Clinical Laboratory Measurements 
6.5.1 
D-dimer, Ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), complete 
blood cell count with differential (CBC), fibrinogen, partial thromboplastin time (PTT), 
international normalized ratio (INR), arterial blood gases (ABG), basic metabolic panel 
(BMP), hepatic function panel (LFT) 
We anticipate blood will be drawn for clinical care at least every other day, and anticipate that most 
research blood studies will be performed on blood already drawn for clinical care. We will also 
extract data for any studies done for clinical care purposes. Blood will be obtained and sent to the 
clinical laboratory to measure LDH, CBC, CRP, D-dimer for standard of care at the discretion of the 
medical team. D-dimer, fibrinogen, PTT, INR, ferritin, CBC, LFT, LDH, CRP, BMP will be 
measured on day 1 on blood drawn for clinical care. Although daily measurement of D-dimer would 
be ideal for the primary endpoint of this research study, we will measure D-dimer every other day 
given ongoing medical resource constraints. D-dimer, fibrinogen, PTT, INR and CBC will be 
measured on days 3, 5, 7, 9, 11, 13 and 14 during hospitalization. CRP, ferritin, LDH, BMP will be 
measured on day 1, 5, 9, and 13, during hospitalization for research study using blood drawn for 
clinical care wherever possible. LFT will be measured on day 1 for clinical care, and at least every 4 
days until end of drug treatment phase in blood drawn for clinical care wherever possible during 
hospitalization. ABG will only be recorded if performed for clinical care purposes. 
6.5.2 
Pregnancy test 
A urine pregnancy test, if not already performed for clinical care, will be obtained from female 
patients who are of childbearing age by the medical team prior to obtaining informed consent. 
6.5.3 
Pharmacokinetic measurements 
Not applicable. 


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6.6 Research Laboratory Measurements (see Schedule of Events) 
6.6.1 
Coagulation potential 
Blood will be obtained to investigate potential mediators of COVID-19 and novel parameters of 
coagulation and platelet activity measured in the study team’s research laboratories. 
6.6.2 
Biomarkers of blood cell activation 
Blood will be collected in sodium citrate, heparin, EDTA or serum separator tubes. The blood sample 
will be labelled and processed at the local sites before shipping to the study team’s research 
laboratories at the University of Michigan to evaluate novel biomarkers of blood cell activation, 
coagulation, and cytokines. 
6.6.3 
Leukocytes 
Blood will be collected in EDTA, sodium citrate, or heparin tubes. The blood sample will be labelled 
and sent for processing to the clinical and research labs. 
7 Sample Size  
7.1 D-dimer Calculations 
Decision thresholds and power calculations are based on a preliminary analysis of 147 D-dimer 
measurements taken on 41 COVID-19 patients in the University of Michigan hospital in Spring 2020.  
Quantities were estimated through simulation based on the preliminary data. 
The presumed analysis is a variance components regression on log-transformed D-dimer values with 
fixed effects for ICU status (a binary proxy for case severity) and days since admission.  The model 
assumes random effects for linear subject-level log-D-dimer trends over time.  We set an intraclass 
correlation coefficient (ICC) of 0.7, which reflects large between-subject variation relative to within-
subject variation and is conservatively lower than the observed ICC of 0.77.  
Power is based on a mean 13% daily increase in D-dimer levels for untreated patients, as observed in 
preliminary analysis. We posited a 50% reduction in the growth rate (i.e. 6.5% daily increase) for the 
100 mg dose of study drug. Based on 2 arms with 40 subjects per arm (80 subjects in all), power is 
0.91 for comparing the pooled dipyridamole participants to the controls.  
7.2 Win Ratio Calculations 
The standard of care treatment for COVID-19 changed with the introduction of anti-inflammatory 
steroids, which appear to influence D-dimer concentrations.  It was therefore determined to elevate 
the secondary endpoint to become a co-primary endpoint.  This endpoint is a composite of clinical 
outcomes including death, survival time, mechanical ventilation days, decrease in SpO2/FiO2 ratio, 
and cumulative COVID-19 ordinal scores.   
This endpoint will be assessed nonparametrically by comparing outcomes across all possible pairs of 
treatment-placebo patients and evaluating a ‘win ratio’ using the Mann-Whitney U-statistic (Pocock et 
al., 2012).  See Section 8.6.2.2 for details.  The win proportion is interpreted as the probability that a 
study drug patient experiences a better outcome than a placebo patient, and in this sense, it represents 
the effect size for the analysis.  We powered our analysis on a presumed 0.67 win proportion (i.e. a 
patient on study drug is twice as likely to have a better outcome as a patient on placebo).  We 
calculated sample size requirements using the formulas provided in Yosef et al. (2019). 


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Because we set a 0.006 Type I error significance (alpha) for the interim analysis for benefit of D-
dimer, we could only use 0.044 of the original 0.05 for the primary endpoints.  We divided the 0.044 
between the two co-primary endpoints, leaving a 0.022 two-sided Type I error.  Accounting for a 10% 
dropout, we require 127 patients to have 80% power to significantly detect a win ratio of 0.67. 
8 General Analysis Considerations 
8.1 Timing of Analyses 
Based on interim analyses for futility, it was decided to halt recruitment beginning January 19, 2021.  
The final data analyses will begin: 
• 
after all 30-day post drug follow-up has been completed for all randomized patients, 
• 
after chart review and data cleaning according to the data management plan are complete, and 
• 
after approval of this SAP document by the study team. 
8.2 Analysis Populations 
8.2.1 
Modified Intent to Treat Population (mITT) and Safety Population 
All randomized patients who received at least one dose of dipyridamole or placebo will be included in 
the mITT population.  The safety population will be the same as the mITT population.  The mITT 
population will serve as the basis for comparisons of dipyridamole versus placebo and for assessment 
of safety. 
8.3 Covariates and Subgroups 
Models to compare dipyridamole versus placebo will include both stratification factors as predictors: 
sex and age.  The analysis will include interactions between study drug and stratification factors.  Age 
will be modelled both as a continuous covariate and as a grouping factor (in separate models).  For 
longitudinal responses, models will also include days since first drug administration.  Where 
appropriate, models will include baseline values of the response variable. 
The win ratio analysis for the clinical hierarchical composite endpoint will be stratified according to 
age and sex (Dong et al., 2018). 
8.4 Missing Data 
We anticipate three sources of missing response data in this study: missing data entries, loss to follow-
up, and early hospital discharge.  We will summarize missingness for primary study endpoints.  In 
preliminary results, a large majority of patients have early hospital discharge. 
For the primary response and other longitudinal analyses, we address missing response data through 
random coefficients regression, which incorporates missingness through the standard errors of 
subject-level trend estimates.  This strategy assumes missing entries are missing at random and that 
missing entries from early termination or discharge would not differ from the trend in the observed 
data.  For time-to-event responses, we address early termination and discharge by right-censoring. 
The DICER team will review data to minimize missingness in sex, age, and baseline values.  
Following Schafer et al. (1997), if these variables are missing for more than 5% of patients, we will 
impute them using SAS PROC MI and PROC MIANALYZE if necessary.  Otherwise, we will 
exclude missing records from the analyses. 


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8.5 Extra Data 
The protocol calls for certain procedures only on specified days (e.g. coagulation panels including D-
dimer on Days 1, 3, 5, 7, 9, 11, 13, and 14) but allows for collection on other days when ordered by 
the clinician.  We choose to include these ad hoc data in all analyses, because the frequency of 
sampling the time scale of change in response variables is anticipated to be long compared to 
sampling, and clinician-ordered sampling should not introduce sizeable bias. 
8.6 Interim Analyses and Data Monitoring 
8.6.1 
Safety Review 
The analysis plan includes interim review by the DSMB for the purpose of monitoring study conduct 
and assessing participant safety after 50% of patients have completed the study or 10 deaths have 
occurred (whichever happens first).  This review includes the number, proportion, and listing of 
participants with SAEs (including segregation of those involving deaths), treatment-emergent AEs, 
and discontinuation of study medication due to AEs. These presentations are descriptive, with no 
formal inferential methods used. No specific rules for halting study enrollment or study interventions 
for safety are specified; however, the DSMB may request formal inferential testing to assess the risk-
benefit profile of these study medications in this study population. 
8.6.2 
Efficacy Review 
8.6.2.1 
Primary D-dimer Endpoint 
We conduct two interim analyses of efficacy with respect to the D-dimer primary endpoint after 50% 
of patients have completed the study: a test for benefit and a test for futility.  The analyses use the 
mITT population at the time of reporting. 
To analyze for benefit, we separately estimate the change in D-dimer (on the log scale) for each 
patient and then convert those estimates into a binary outcome indicating whether the patient’s change 
was at least a 5% daily increase.  We apply Fisher’s exact test to assess whether one treatment arm is 
clearly superior.  We use the O’Brien-Fleming method to correct for interim analyses and the Lan-
DeMets spending function to preserve an overall Type I error rate of 0.05.  This projects to α = 0.003 
after 40 patients.  We test sensitivity to: (i) the inclusion/exclusion of subjects lacking baseline D-
dimer measures, and (ii) the inclusion/exclusion of measures after Day 7, by which time most patients 
have been discharged. 
To analyze for futility, we examine the estimated daily percent change in D-dimer measures within 
only the dipyridamole treatment arm.  This is calculated as in the benefit analysis, except it is 
dichotomized with respect to a 5% daily increase.  The termination for futility criterion is whether the 
lower 95% confidence bound for mean daily increase is above 9% as determined by a one-sample t-
test. 
8.6.2.2 
Primary Hierarchical Composite Endpoint 
We conduct an interim analysis of the efficacy with respect to the hierarchical composite endpoint 
using data as December 31, 2020.  This analysis was added to the protocol at the December 15, 2020 
DSMB meeting to assess whether there may be evidence of treatment differences in clinical 
outcomes. 
The analysis uses the win ratio, a modification of the Mann-Whitney U-statistic (Pocock et al., 2012; 
Finkelstein and Schoenfeld, 2018).  A description of the win ratio algorithm is provided in Section 
9.2.1 and Table 3.  We calculate U-statistics by comparing all possible pairs of treatment-vs-placebo 


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patients according to the win ratio algorithm.  This generates a summary U-statistic for each patient 
and estimates the win ratio — the proportion of comparisons ‘won’ by dipyridamole patients.  We 
obtain confidence intervals for the win ratio by bootstrapping the data in-hand and spending only the 
α for Type I error that remains from the D-dimer analysis according to the Lan-DeMets spending 
function. 
To decide futility or benefit, we apply conditional power (Lan and Trost, 1999; Siu and Lan, 2001; 
Lachin, 2006).  This approach is advantageous, because it does not require an adjustment for the Type 
I error nor an adjustment on the final critical value to claim significance.  Our calculations of 
conditional power (CP) are based on the estimated effect at the time of analysis for a total sample size 
of N = 127 (based on win ratio sample size calculations in Yosef et al., 2019): 
CP = Pr(𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟𝑟 𝐻𝐻0 𝑎𝑎𝑎𝑎 𝑡𝑡ℎ𝑒𝑒 𝑒𝑒𝑒𝑒𝑒𝑒 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 | interim data, estimated effect size is unbiased). 
The decision to proceed with the trial depends on the value of CP as follows: 
1. CP < 0.3 : Stop for futility 
2. If 0.3 ≤ CP < 0.8: Continue the trial but re-estimate sample size up to N = 160 
3. If 0.8 ≤ CP < 0.9: Continue the trial with N = 127 
4. CP ≥ 0.9 : Stop for benefit  
8.7 Multiple Testing 
In the primary analyses, we use the O’Brien-Fleming method to correct for interim analyses and the 
Lan-DeMets spending function to preserve an overall Type I error rate of 0.05.  We will use a 
Bonferroni adjustment to maintain familywise error for the five secondary analyses.  We will not 
apply a multiple testing adjustment to exploratory endpoints; any findings associated with exploratory 
endpoints will require confirmation before reporting.   
9 Summary of Study Data 
Descriptive summary statistics will be tabulated for baseline patient demographics and clinical 
characteristics separately by intervention group and overall.  All tables will be annotated with the total 
population size relevant to that table (usually the mITT), including missing observations.  For 
continuous variables, the estimated mean, standard deviation, median, minimum, and maximum will 
be reported. For categorical variables, number and percentages will be reported (excluding missing 
values).  
9.1 Subject Disposition 
Patient consent, screening, randomization, degree of study completion (completion of in-hospital 
follow-up, 28-day follow-up, and 30-day post-drug follow-up), and reasons for dropout will be 
summarized in a table and a CONSORT diagram.  Numbers will be provided by treatment group and 
overall where appropriate. 


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Figure 2.  CONSORT Diagram 
  
9.2 Derived variables 
9.2.1 
Hierarchical Composite Endpoint Used in Win Ratio Analysis 
The win ratio analysis of the hierarchical composite outcome requires a direct comparison of 
outcomes between each dipyridamole patient and placebo patient.  The patient with the superior 
outcome is adjudicated the ‘winner’ and receives a +1 score, while the ‘loser’ scores -1.  The criteria 
for comparison are below and are summarized in Table 3: 
1. 
If one participant dies and one lives, the participant who does not die wins (Scenario 1) 
2. 
If both participants die, then the participant who lives longer wins (Scenario 2) 
Consented
n = ##
Eligible
n = ##
Randomized
n = ##
Dipyridamole
n = ##
Completed In-
Hospital on Drug
n = ##
Terminations 
Reported
Completed 28-day 
Follow-up, n = ##
Terminations 
Reported
Completed 30-day 
Follow-up, n = ##
Overall
n = ##
Completed In-
Hospital on Drug
n = ##
Terminations 
Reported
Completed 28-day 
Follow-up, n = ##
Terminations 
Reported
Completed 30-day 
Follow-up, n = ##
Placebo
n = ##
Completed In-
Hospital on Drug
n = ##
Terminations 
Reported
Completed 28-day 
Follow-up, n = ##
Terminations 
Reported
Completed 30-day 
Follow-up, n = ##


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3. 
If both participants die and live the same number of days, then there is a tie (Scenario 3). 
4. 
If neither participant dies, then the participant with fewer days on ventilator wins 
(Scenario 4). 
5. 
If the participants are tied after step 4, and only one of the participants has a decrease in 
daily average SpO2/FiO2 of 50 or greater, then the participant who does not have the 
decrease in SpO2/FiO2 wins (Scenario 5). 
6. 
If the participants are tied after step 5, then the participant with lower cumulative COVID 
ordinal score wins (Scenario 6), 
7. 
If the participants are tied after step 6, then their final result is a tie (Scenario 7). 
Table 3. Description of Hierarchical Composite Endpoint Win Scenarios 
Scenario 
Death [1] 
Survival [1] 
Number of days 
on mechanical 
ventilation [2] 
Decrease from 
baseline in 
SpO2/FiO2 > 50 
[3] 
Sum of COVID 
ordinal scores 
[4] 
Score 
1 
Dead 
 
 
 
 
-1 
Alive 
 
 
 
 
+1 
2 
Dead 
Shorter 
 
 
 
-1 
Dead 
Longer 
 
 
 
+1 
3 
Dead 
Tied 
 
 
 
0 
Dead 
Tied 
 
 
 
0 
4 
Alive 
N/A 
Longer 
 
 
-1 
Alive 
N/A 
Shorter or None 
 
 
+1 
5 
Alive 
N/A 
Tied 
Yes 
 
-1 
Alive 
N/A 
Tied 
No 
 
+1 
6 
Alive 
N/A 
Tied 
Tied 
Higher 
-1 
Alive 
N/A 
Tied 
Tied 
Lower 
+1 
7 
Alive 
N/A 
Tied 
Tied 
Tied 
0 
Alive 
N/A 
Tied 
Tied 
Tied 
0 
[1] Death and survival are assessed from the time of study medication to 30 days after the last dose of study drug (a maximum 
of 44 days from consent).  Participants are censored at the time of drop-out or the data cutoff date (if no event has occurred). 
[2] Number of days on mechanical ventilation are counted from the time of study medication until hospital discharge.  If a 
participant is re-hospitalized and receives ventilation, these data are not counted. 
[3] Oxygenation measurements are collected from EHR records.  Baseline is defined as the average of measurements taken 
between 8 hours prior to start of study medication and the start of study medication administration.  A 50-point drop is defined 
as a participant who experiences two consecutive measures of at least 50 points below baseline.  Post-baseline measurements 
are assessed up to and including day 44 (from consent). 
[4] COVID ordinal scores are defined in Table 2. 
 
The cumulative sum of COVID ordinal scores used in Step 6 is calculated as the time-weighted sum 
of daily ordinal scores, with units of ordinal score days.  For example, if a subject started medication 
at 9:00 pm on Day 1 with a score of 4, and that score decreased to 3 at 6:00 am the next day, and that 
patient was discharged at noon on the third day, then the cumulative sum of ordinal scores would be: 
{3 ℎ𝑟𝑟𝑟𝑟× 4 + (6 ℎ𝑟𝑟𝑟𝑟× 4 + 18 ℎ𝑟𝑟𝑟𝑟× 3) + 12 ℎ𝑟𝑟𝑟𝑟× 3}
24 ℎ𝑟𝑟𝑟𝑟/𝑑𝑑𝑑𝑑𝑑𝑑
= 12 + (24 +  54) + 36
24
= 5.25 
The use of the cumulative ordinal score in Step 6 of the above algorithm is meant as a combined 
measure of the severity and duration of a patient’s illness, since longer hospitalizations and larger 
daily ordinal scores will both increase the cumulative total. 
9.3 Protocol Violations 
A protocol violation occurs when the participant, study coordinator or the investigator fails to adhere 


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to significant protocol requirements affecting the inclusion, exclusion, participant safety and primary 
endpoint criteria. Protocol violations for this study include, but are not limited to, the following: 
1. Use of a prohibited concomitant medication 
2. Non-compliance with study drug regimen 
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a protocol 
violation. The principal investigator in consultation with IND Sponsor will determine if a protocol 
violation will result in withdrawal of a participant.  A listing of protocol deviations by intervention 
group and overall will be provided. 
9.4 Demographic and Baseline Variables 
Demographic variables for participants will be: 
1. Age in years at consent 
2. Dichotomized age (≤ 65 or > 65) 
3. Sex 
4. Race (American Indian / Alaska Native, Asian, Black / African American, Native Hawaiian / 
Other Pacific Islander, White, Unknown) 
5. Ethnicity (Hispanic, non-Hispanic) 
6. Height 
7. Weight 
Baseline variables for participants will be: 
8. D-dimer 
9. SpO2 and SpO2/FiO2 
10. COVID ordinal scale score 
11. Hematology labs: C-reactive protein, LDH, ferritin, leukocyte count, and platelet count in the 
blood 
12. Temperature 
13. Glomerular filtration rate (GFR) 
9.5 Concurrent Illnesses and Medical Conditions 
All participants’ non-study medications will be administered at the discretion of the treating medical 
provider.  Any medications and supplements are allowed except: 
• 
Dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep 
venous thrombosis or pulmonary embolism).  Single antiplatelet agent, or anticoagulant agent 
at prophylaxis or therapeutic dose is permitted. 
• 
Any medication deemed by the PI to be unsafe or likely to confound analysis. 
9.6 Treatment Compliance 
We will summarize participant medication exposure, including missed doses, using descriptive 
statistics including n, mean, median, standard deviation, minimum, and maximum.  The summary will 
include the total number of patients on drug from Day 1 through Day 14 separately by treatment. 
10 Efficacy Analyses 
Continuous variables will be summarized using descriptive statistics including n, mean, median, 


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standard deviation, minimum, and maximum. Qualitative variables will be summarized using counts 
and percentages. Summaries will be provided by treatment groups and overall. Two-sided hypotheses 
will be tested for efficacy endpoints at the 5% level.  
Unless otherwise stated, analyses will be performed on the mITT population and will be programmed 
in SAS software (SAS Institute, Inc., Cary, NC), while graphics will be generated using R (R Core 
Team, 2020). 
10.1 Primary Efficacy Analysis: D-dimer 
The first co-primary endpoint is mean daily change in D-dimer during up to 14 days of 
hospitalization. We will assess longitudinal trends in the mITT analysis set via linear mixed effects 
regression of log-transformed D-dimer values:  
log(D-dimerit) = Intercepti + Slopei × t  
where i indexes the patient, and t is time since first drug administration.  The intercept will consist of 
an overall intercept term plus terms for treatment, both stratification factors (sex and an indicator for 
age ≥ 65 years), baseline log(D-dimer), and a random patient effect.  We will model treatment 
interactions by stratification factor. 
The hypothesis is that patients in the treatment arm will have a smaller mean slope than those in the 
placebo arm.  Because we are conducting an interim analysis for efficacy (Section 8.6.2.1), we adopt 
the O’Brien-Fleming method to partition the overall Type I error rate: α = 0.006 for the interim 
analysis, and 0.022 for each primary efficacy analysis based on an interim population of n = 45.  
10.2 Primary Efficacy Analysis: Hierarchical Composite Endpoint 
The second co-primary endpoint is a hierarchical composite endpoint of death, survival, mechanical 
ventilation, SpO2/FiO2, and cumulative COVID ordinal scores.  With one exception, the analysis of 
the mITT population will be identical to the interim analysis described in Section 8.6.2.2 based off the 
win ratio algorithm described in Section 9.2.1.  The interim analysis was pooled across stratification 
factors (age and sex).  The primary efficacy analysis will stratify win-ratio calculations by age and sex 
and estimate an overall win ratio across strata (Dong et al., 2018). 
The hypothesis is that patients in the treatment arm will experience better outcomes than patients in 
the placebo arm, leading to a win proportion significantly higher than 0.5.  Because we are conducting 
an interim analysis for efficacy (Section 8.6.2.1), we adopt the O’Brien-Fleming method to partition 
the overall Type I error rate: α = 0.006 for the interim analysis, and 0.022 for each primary efficacy 
analysis based on an interim population of n = 40. 
10.3 Secondary Efficacy Analyses 
We will conduct secondary analyses on each component of the hierarchical composite endpoint: 
• 
Time to death 
o Analysis: Cox proportional hazards regression 
• 
Number of days on mechanical ventilation during study hospitalization  
o Analysis: Negative binomial regression 
• 
Dichotomized (yes/no) decrease in SpO2/FiO2 ratio of at least 50 units relative to baseline at 
any time during the observation period  
o Analysis: Logistic regression 


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• 
Cumulative sum of COVID ordinal scores during study hospitalization  
o Analysis: Mann-Whitney U-test (nonparametric) 
We will analyze an additional secondary endpoint: 
• 
Days alive and free of organ support, where organ support is defined as receipt of invasive 
mechanical ventilation, vasopressor therapy, ECMO support, or incident dialysis 
o Analysis: Mann-Whitney U-Test (nonparametric) 
Each analysis will include interactions of the study drug by stratification factor. 
10.4  Exploratory Efficacy Analyses 
The DICER study contains four major kinds of exploratory endpoints (listed in Section 5.2.4): 
continuous, change over time (continuous), binary, and time to event.  All analyses will be based on 
the mITT population except where specified in the definition of the endpoint.   
We will analyze continuous endpoints by ANOVA with treatment and stratification factors (sex and 
age) as predictors. 
We will analyze continuous change over time endpoints by mixed linear effect models using the same 
methodology described in Section 10.1 for the D-dimer primary efficacy endpoint. 
We will analyze binary endpoints by logistic regression with treatment and stratification factors (sex 
and age) as predictors. 
We will analyze time-to-event by Cox proportional hazards regression with treatment and 
stratification factors (sex and age) as predictors. 
In all analyses, the only estimate of interest will be the difference between treatment arms.  We will 
include treatment interactions by stratification factor in all models, and we will fit separate models 
where age is continuous versus where age is represented by an indicator variable for age ≥ 65 years. 
Hypothesis tests will be two-sided. 
11 Safety Analyses 
Safety analyses will be performed on the mITT analysis set. Summaries of safety data and will 
include frequency, proportion, and listing of participants experiencing events.  All summaries will be 
by treatment group and overall.  Safety endpoints are: 
• 
Incidence of serious adverse events (SAEs) during study duration, 
• 
Proportion of participants with hypotension (systolic blood pressure below 90 mmHg and 
requiring a 1-liter IV fluid bolus) during study hospitalization, 
• 
Proportion of participants during the observation period, with major bleeding as defined by 
the ISTH: (i) a decrease in the hemoglobin level of at least 2 g per deciliter, (ii) transfusion of 
at least 2 units of blood, (iii) occurrence in a critical site, or (iv) contributing to death. 
11.1 Extent of Exposure 
We will summarize participant medication exposure, including missed doses, using descriptive 
statistics including n, mean, median, standard deviation, minimum, and maximum.  The summary will 
include the total number of patients on drug from Day 1 through Day 14 separately by treatment. 


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11.2  Adverse Events 
11.2.1 AE Severity 
The guidelines shown in Table 4. AE Severity Grading will be used to grade severity. We point out 
that a grading of “severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 4. AE Severity Grading 
Severity (Toxicity Grade)  
Description  
Mild (1)  
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The participant may be aware of the sign 
or symptom but tolerates it reasonably well.  
Moderate (2)  
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required.  
Severe (3)  
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible.  
Life-threatening (4)  
The participant is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically might 
have caused death if it were more severe.  
 
11.2.2 AE Relationship to Study Drug 
The relationship of an AE to the study drug will be assessed using the guidelines in . 
Table 5. AE Relationship to Study Drug 
Relationship to Drug  
Comment  
Definitely  
Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or 
expected response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that is not explained by 
any other reasonable hypothesis.  
Probably  
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to the 
suspected drug; that is confirmed by stopping or reducing the dosage of the 
drug; and that is unlikely to be explained by the known characteristics of 
the participant’s clinical state or by other interventions.  
Possibly  
An event that follows a reasonable temporal sequence from administration 
of the drug; that follows a known or expected response pattern to that 
suspected drug; but that could readily have been produced by a number of 
other factors.  
Unrelated  
An event that can be determined with certainty to have no relationship to 
the study drug.  
 
11.3 Deaths, Serious Adverse Events and other Significant Adverse Events 
An SAE is defined as any AE that results in any of the following outcomes:  
• 
Major bleeding as defined by the ISTH 
• 
AST or ALT > 10 times the upper limit of normal 
Other important medical events may also be considered a SAE when, based on appropriate medical 


Statistical Analysis Plan 
 DICER Study 
March 8, 2021 
 
 
Page 24 of 25 
 
judgement, they jeopardize the participant or require intervention to prevent one of the outcomes 
listed. 
Study personnel will document all SAEs that occur (whether or not related to study drug). The 
collection period for all SAEs will begin after informed consent is obtained and end 30 days after 
administration of the last dose of study drug.  SAEs will be graded for severity and relationship to 
study drug.  In accordance with the standard operating procedures and policies of the local IRB, the 
study team will report SAEs to the IRB. 
11.4 Clinical Laboratory Evaluations 
As detailed in Section 6.5.1, blood will be drawn for clinical care at least every other day, and we 
anticipate that most research blood studies will be performed on blood already drawn for clinical care. 
Clinical laboratory evaluations will be summarized using number, mean, standard deviation, median, 
minimum and maximum. Relative changes from baseline to end of study hospitalization will be 
similarly summarized. These summaries will be done by treatment group and overall. In addition, we 
will produce box plots overlaid with dot plots of lab values at each time point (overall and by 
treatment group). 
Spaghetti plots will be provided to evaluate lab value patterns for patients who have out of range 
values (either high or low). 
11.5 Prior and Concurrent Medications 
The total number and proportion of patients taking concurrent medications will be summarized 
descriptively by treatment group and overall. 
12 Other Analyses 
None at this time. 
13  Reporting Conventions 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported as 
“<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will be reported 
to one decimal place greater than the original data. Quantiles, such as median, or minimum and 
maximum will use the same number of decimal places as the original data. Estimated parameters, not 
on the same scale as raw observations (e.g., regression coefficients) will be reported to 3 significant 
figures. 
14 Summary of Changes to the Protocol and/or SAP 
 
No changes to the protocol and/or SAP have affected the analysis plan as of January 19, 2022.  
15 References 
Dong, G, Qiu, J, Wang, D, and Vandemeulebroecke, M. (2018). The stratified win ratio. Journal of 
biopharmaceutical statistics, 28(4), 778-796.  


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 DICER Study 
March 8, 2021 
 
 
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