Clinical trial NCT04424901
Conditions: COVID-19 Pneumonia Vascular Complications
Sponsor: UConn Health
Start date: 2020-05-03; Completion date: 2022-04-24
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Brief Summary:

The goal here is to evaluate dipyridamole in treating respiratory tract infection and circulatory dysfunction due to SARS-CoV-2 coronavirus in hospitalized CVID-19 patients.

Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). The infection is associated with a deleterious inflammatory response and a prothrombotic state in addition to tissue damage from direct viral entry and proliferation. Dipyridamole has anti-platelet and anti-inflammatory effects. The drug was recently demonstrated to have anti-SARS-Cov-2 effect primarily in vitro. The concentration causing anti-viral effect in vitro is within that in the blood of humans taking this drug. As an oral tablet, it has the advantage of easy administration.

Anti thrombotic, anti viral and anti inflammatory actions of this drug may be efficacious and safe in hospitalized subjects

Detailed description:
The original protocol stipulated an enrollment of 100 patients, randomized in a 1 to 1 distribution of treatment versus control \[placebo\] group. However, the study was terminated because of insufficient enrollment due to the dramatic reduction in the number of hospitalized COVID patients.

A total of 41 patients were randomized prior to study termination. Detailed reports and overall results were reviewed for all patients.

Adverse event occurrences were similar in groups. Given the severity of COVID, these numbers were not unexpected.

The DSMC concluded that all the AEs seen in study subjects are either unrelated or probably unrelated to the TOLD study intervention.

The DSMC reviewed the primary outcome results. No statistically significant change in either the platelet count or the D-dimer results.

Arms: arm 1: Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.

Day 3,6 \& 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.

Data collection ends on day 9. arm 2: For this arm, Dipyridamole 100 mg, tid is given for 7 days. Hospitalized patients meeting screen criteria receive standard Hospital care from which clinical event and lab data are collected.

Day 3,6 \& 9 research samples will be used for obtaining immunological profiles as well as metabolomic profiling and whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased susceptibility to infection and DIP treatment efficacy or safety. Other samples will be obtained for microbiome and viral analyses.

Data collection ends on day 9.
Interventions: intervention 1: Placebo intervention 2: Dipyridamole Tablets
Intervention descriptions: intervention 1: Daily dose while hospitalized up to 9 days intervention 2: Daily dose while hospitalized up to 9 days

Protocol documents:
Prot_SAP_000.pdf: 
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Clinical Research Protocol
Title:
A randomized, open-label study of the vascular and microbiologic 
efficacy of dipyridamole plus standard care vs. standard care in 
hospitalized COVID19 patients.
Study Phase:
Phase 2 Proof of concept
Drug Name:
Dipyridamole
Indication:
Upper and lower respiratory tract infection in patients hospitalized 
with SARS-CoV-2
Multiple Principal 
Investigators:
Single Center, Dr. Liang (PI), Co-PIs: Drs. Kevin Dieckhaus, Jeffrey
R. Aeschlimann, Mark Metersky, Eric Mortensen, Christopher Pickett
Sponsor:
UConn School of Medicine
Sponsor Contact:
Bruce T. Liang , M.D.
Medical Monitor:
Peter Schulman, M.D.
Office: 860-679-3343
Email: schulman@uchc.edu
Pharmacovigilance
Jeffrey R. Aeschlimann, PharmD.
Pharmacovigilance 
Contact
Office: 860-679-1488
Email: aeschlimann@uchc.edu
Protocol Version: 2
Date: May 26, 2021
Sponsor:
UConn School of Medicine
Name of Finished Product:
Dipyridamole
Study Title:
A randomized, open-label study of the vascular and microbiologic efficacy of dipyridamole plus standard 
care vs. standard care in hospitalized COVID19 patients.
Study Number: 100
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TABLE OF CONTENTS
1.
INTRODUCTION
1.1 Indication
1.2 Background and Rationale 
Rationale for Study
2.
Study Objectives
Primary Outcome Secondary 
Outcome Exploratory Outcome
3.
Study Design
Standard Care
4.
Study Population
Inclusion Criteria 
Exclusion Criteria
Women of child-bearing Potential
5. Study Treatments, Procedures and Laboratory Testing
6. Adverse Events and Reporting
7. Efficacy Assessments
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1.1
Indication
Oral dipyridamole is being evaluated to treat respiratory tract infection and circulatory dysfunction 
due to SARS-CoV-2 coronavirus.
1.2
Background and Rationale 
Rationale for Study
Infection with SARS-CoV-2 causes human COVID-19 (HCoV-19). In severe illness, COVID 19 
infection results in lymphopenia, elevated D-dimer levels, hypercoagulation, hypertension, acute 
respiratory distress syndrome (ARDS), and acute cardiac injury.1 Dipyridamole (DIP) is an FDA- 
approved drug which inhibits adenosine uptake that leads to increased extracellular adenosine which 
in turn stimulates adenosine receptors-mediated vasodilator, anti-platelet and anti-inflammatory 
effects. These effects are also augmented by DIP’s inhibition of phosphodiesterase (PDE).
Pan-PDE inhibition may prevent lung (fibrosis) as well as acute heart, liver, and kidney injury.2
In addition, by virtually screening an FDA approved drug library, Liu, et. al3  have recently shown 
that DIP appears to bind to the HCoV-19 3c-like protease enzyme (nsp5 or Mpro) and also suppresses 
HCoV-19 (SARS-CoV-2) proliferation in Vero E6 cells with an IC50 ≤100 nM. The inhibitory 
activities compared favorably to those of chloroquine (which served as a positive control. Plasma 
concentrations in humans from routine dosing regimens (regimen of 50 mg three times per day) 
should exceed this IC50 value for the duration of the 7 day treatment interval proposed in this 
investigation. In vivo anti-viral effect of dipyridamole has been demonstrated in vesicular stomatitis 
virus-induced pneumonia with prolongation of survival.
In 12 COVID-19 patients, treated with prophylactic anti-coagulation therapy, the addition of DIP led 
to increased platelet and lymphocyte counts and reduced D-dimer levels as compared to standard-of- 
care patients3.
Reference 3 Liu, X. et al.
Figure 3,Excerpt Panel A
1 Guan W, et.al, Clinical Characteristics of Coronavirus Disease 2019 in China. NEJM 2020 Feb 28, 2020.
2 Insel PA, Murray F, Yokoyama U, et al. cAMP and Epac in the regulation of tissue fibrosis. Br J Pharmacol 2012; 
444 166(2): 447-56.
3 Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction 
Xiaoyan Liu, Zhou, Hai-Bin Luo, et. al
doi: https://doi.org/10.1101/2020.02.27.20027557
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Additionally, 2 weeks after DIP treatment, 3 of the severe cases and all 4 of the mild-to-moderate 
cases were discharged from the hospital. One patient died while 3 remaining patients were in 
remission in the hospital. In the control group, 3 of the 3 mild-to-moderate cases and 1 of 4 
severe cases were discharged and only 1 was in remission in the severe group with 1 death.
However, the trial was not randomized and was small in size, hence there was no statistical 
analysis for clinical outcomes.
Nevertheless, the combination of laboratory data indicating direct anti-SARS-CoV-2 activity and 
encouraging patient laboratory and clinical outcome data do advocate for the scientific basis for 
evaluating DIP in COVID-19 patients in a larger, randomized trial.
Profile of Patient Cohort Outcomes, Reference 3-
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2.
Study Objectives
Primary Outcome:
Primary objective is to evaluate an effect of DIP on 2 biomarkers- D-dimer and platelet count in 
hospitalized Covid-19 patients treated with DIP plus standard care vs. those treated with 
standard care alone.
Secondary Outcome:
The secondary objective is to evaluate the detection of SARS-CoV-2 RNA by RT-PCR 
(ThermoFisher EUA Test) for DIP treatment vs no treatment (over 9 days, 3 time points) as 
determined by analyses of coded research nasal or nasopharyngeal swabs or other validated 
respiratory specimens by the Jackson Laboratory (JAX) CLIA Laboratory. We will determine 
whether the treatment will alter the stool microbiome. We will also associate the microbiome 
compositions in treatment and no treatment patients with clinical outcome
Mortality will also be a secondary endpoint. Mortality will be assessed at 30 and 60 days after 
enrollment.
The safety of DIP therapy vs standard of care will be evaluated using tabulation of standard 
adverse events by body region.
Exploratory Outcomes:
To evaluate clinical outcome improvement or resolution of clinical parameters such as: fever 
(>100.5° F), cough, sputum production, imaging evidence of pneumonia, and Sp02 ≤ 93% on 
room air until hospital discharge or day 9, whichever occurs last. Those discharged before day 
9 will have telephone follow- up call pending patient’s consent for the call except for the DOC 
enrollees due to preservation of their confidentiality. No calls are made to DOC Subjects, after 
their discharge for follow up. 
Other exploratory endpoints will be determined with datapoints as part of the standard clinical 
care lab work of our COVID-19 infected hospitalized patients. These will include C-reactive 
protein (CRP), lymphocyte count (LC), prothrombin time (PT), activated partial thromboplastin 
time (APTT), plasma fibrinogen (FIB), serum ferritin (FER), thromboembolic event, cardiac 
Troponin I (cTnI), lactate dehydrogenase (LDH).
In collaboration with University of Michigan, -DICER (NCT#NCT04391179- DIP Trial), other 
investigational biomarkers from blood such as chemokines and neutralizing antibodies and 
isolated PBMCs will be studied. In collaboration with UConn Engineering exploratory basic 
science BioPhotonic analyses of opto-biological blood cell signatures in COVID-19 will be 
conducted.
3.
Study Design
This study is a randomized, open-labeled Phase 2, proof-of-concept single-center trial of the 
vascular and microbiologic efficacy of dipyridamole plus standard care vs. standard care in 
hospitalized COVID-19 patients.
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Approximately 100 patients with symptoms of a respiratory tract infection who test positive 
for SARS-CoV-2 by polymerase chain reaction (PCR) will be enrolled to receive 
dipyridamole 100 mg three times per day for seven consecutive days plus standard care 
(N=50) or receive standard care (N=50).
The rationale for dosing DIP at 100 mg three times daily is that it is below the maximum daily 
dosage approved by the FDA as adjunct therapy for preventing cardiac valve-associated 
thromboembolism
but yet this regimen should still achieve concentrations that will be above the IC50 values 
described in the Background and Rationale section.
Based on UConn Health hospitalization impact ongoing with COVID-19, it is anticipated that 
the 100 participants can be met during the proposed enrollment period. Research blood (total 30 
cc over study), stool & nasal or nasopharyngeal swab PCR (JAX) are to be obtained in the 
course of clinical care of COVID-19 care.
.
Standard of Care:
Standard supportive care for COVID-19 pneumonia is provided at UConn Health to all study 
participants. Non-study therapy is allowed with the exception of concurrent usage of any other 
investigational trial/drug therapy for SARS-CoV-2 while on DIP. Convalescent plasma which 
is not a drug therapy or investigational treatment can be given concomitant with DIP 
administration and will not be an exclusion. Other anti-platelet agents such as aspirin or NSAID 
are permitted. All standard care data that we anticipate analyzing for this proposed study are 
recorded on subject’s EPIC medical record by care providers as part of routine clinical care.
A subject discharged early (before day 9) shall have Safety and SOC lab values/tests 
obtained for their research dataset completion.
Subject Selection and Screening:
Each new COVID-19 patient admitted at UConn Health to their isolation/ biocontainment care 
unit will be considered for enrollment with the exception of those pregnant. Department of 
Corrections- DOC patients at UCH for care and those from Nursing Home/Assisted living, 
shall be included.
Consent may be conducted with pre-qualified prospects as well as those with designated-legally 
authorized representatives- LARs.
The Principal and above named, Co-Investigators, who are attending these patients or study 
appointed designees, will review in EPIC their record for the inclusion/exclusion criteria below 
and introduce the study to the prospects via attending or Nursing caregiver. When asked, if 
subject has interest, they will be provided with a Consent Form to review. They shall be 
consented by designated study staff, in a private manner after sufficient time for review has 
been offered and all questions have been asked. They will be provided a copy of the Consent 
form which they retain because of biocontainment needs. Fax transmission of completed 
document images, per policy, from the care area is to be utilized for subject and staff to 
complete. Phone image scanning and transmittal of images is acceptable from care areas, as 
necessary with use of UCH issued phone to UCH email. For those unable to read, an audio file 
can be reviewed and the consent procedure can be securely recorded to the study phone for 
both their reference and secured study file documentation.
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For LAR consent process, the study team may share consent materials with the LAR by email. 
The LAR can print, sign and scan or send an image (fax or photo) of the signed signature pages 
to the study team. The LAR would also send back the original wet-ink signature pages by mail 
or bring them to the site later, to be retained in the research record, but the documentation is 
valid even if only the image is recorded.
The study coordinator receives copies of the study documents, as above and then verifies and 
files, the consent and an audio file if used and then assigns the subject’s study number and 
randomized status. Random #s list has been generated for REDCap and is applied to subjects- 
DIP+ (those receiving DIP- 100mg, po, tid as an addition to standard care) or DIP-, (standard of 
care, only).
The study coordinator will transmit consents to Pharmacy, of all enrolled subjects and 
activates the EPIC order set to order DIP (100mg, tid X 7 days) from research pharmacy.
4.
Study Population
A total of approximately 100 COVID-19 infected hospitalized patients are planned-50 will be 
randomized to receive dipyridamole and 50 will not.
Inclusion Criteria:
1. Adults ≥18 years of age.
2. COVID-19 positive by PCR and hospitalized for vascular dysfunction, conditions related or 
unrelated to COVID-19, or respiratory infection with a range of respiratory severity as 
follows:
Moderate
●Diagnosed with SARS-CoV-2 infection by standard RT-PCR assay or equivalent testing
●Symptoms of moderate illness with COVID-19, which could include:
o Fever, cough, sore throat, malaise, headache, muscle pain, gastrointestinal symptoms; shortness of 
breath with exertion
●Clinical signs suggestive of moderate illness with COVID-19, such as:
o RR ≥ 20, HR ≥ 90, SaO2 ≥93% on room air or requires ≤2L oxygen by nasal cannula (NC) in 
order maintain SaO2 ≥93%, fever >38.3 Celsius
Severe
●Diagnosed with SARS-CoV-2 infection by standard RT-PCR assay or equivalent testing
●Symptoms suggestive of severe systemic illness with COVID-19, which could include: 
o any symptom of Moderate Illness; shortness of breath at rest or respiratory distress
●Clinical signs indicative of severe systemic illness with COVID-19, such as
o RR ≥ 30, HR ≥ 125, requires > 2L oxygen by NC in order maintain SaO2 ≥93%, PaO2/FiO2 <300
Critical
●Diagnosed with SARS-CoV-2 infection by standard RT-PCR assay or equivalent testing
●Evidence of critical illness, defined by at least 1 of the following:
o Respiratory failure defined based on resource utilization requiring at least 1 of the following:
◙, Endotracheal intubation and mechanical ventilation. Oxygen delivered by high-flow nasal cannula 
(heated, humidified, oxygen delivered via reinforced nasal cannula at flow rates
>20L/min with fraction of delivered oxygen ≥0.5), noninvasive positive pressure ventilation, ECMO,
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or clinical diagnosis of respiratory failure (i.e., clinical need for one of the preceding therapies, but 
preceding therapies not able to be administered in setting of resource limitation)
o Shock (defined by SBP < 90 mm Hg, or Diastolic BP < 60 mm Hg or requiring vasopressors)
3. Able to provide documented written informed consent to participate in the study -
a.
To be conducted and witnessed over telephone, by patient (per UCH Policy),
b. By use of Legal Authorized Representative, as qualified and designated in EPIC.
Exclusion Criteria:
1.Inability to swallow or ingest oral medication in either tablet form or in suspension form including 
per NG tube.
2.Patient is known to be pregnant.
3.Patients with a history of allergy or hypersensitivity to dipyridamole.
4.Patient is unable to consent in their language or does not have a designated LAR (per UCH Policy).
5.Bleeding disorders (e.g. thrombocytopenia with platelet counts < 50,000; on Warfarin with 
INR>3).
6.
Existing severe medical illnesses unrelated to Covid-19 infection such as end stage heart, kidney, 
liver disorders or hepatic insufficiency defined as liver enzymes ≥5 times upper limit normal if 
baseline is normal or 5 times baseline if baseline is abnormal.
7. Metastatic cancer.
8. Those with severe coronary artery disease, unstable angina, STEMI, Type 1 NSTEMI, 
hypotension (systolic blood pressure <90mmHg), myocarditis or 2nd degree Mobitz Type II or 
3rd degree atrioventricular block without pacemaker.
9. Bradycardia with persistent resting heart rate less than 60 bpm not due to cardio depressant 
medications such beta blocker or calcium channel blocker.
10. Those with myasthenia gravis and those treated with cholinesterase inhibitors.
11. Patient is enrolled in a clinical trial for another investigational drug designed to test for efficacy 
for SARS-CoV-2. [consent or infusion for convalescent plasma is not an exclusion].
Women of child-bearing Potential:
If the patient is a woman of childbearing potential, a negative pregnancy test will need to be recorded 
from standard of care information, prior to enrollment.
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Consent by Use of Legally Authorized Representative:
Due to the current visitor restrictions with COVID-19, telephone consent will be obtained from the 
LAR (those intubated and without decision making capacity) with the following steps:
1. A provider overseeing the care of the patient calls the LAR and explains the patient's condition. 
The provider informs the LAR about a potential trial that might be suitable for the patient.
2. If the LAR is interested, the provider tells the LAR that a member of the study team will call 
shortly.
3. A study team member calls, has a preliminary discussion with the LAR, and then asks if the LAR 
can receive a blank copy of the ICF on a fax machine or computer.
4. The study team member transmits the ICF and allows the LAR time to read it and print a copy.
5. At an agreed time, the study team member calls the LAR to discuss the ICF material with 
Another UConn Health employee on the line as a witness
6. If the LAR agrees to consent on behalf of the patient, the study team member asks the LAR to 
sign, date and note the time on his or her copy, fax the signature page back (or scan by use of 
cell phone and/or email it to study UCH email), and mail the original complete signed document, 
keeping a copy for him or herself.
7. At the time of the call, the team member writes, “phone consent by [name and telephone 
number]” in the LAR signature area with the date and time on a copy of the ICF. The study team 
member also completes the section for the person obtaining consent. The witness signs and dates 
the document. The study team member also writes a standard informed consent progress note 
utilizing documentation worksheet.
8. The copy signed by the LAR, the copy signed by the team member and witness, and the 
signature page faxed by the LAR are all placed in the research record with the progress 
note.
Test Product, Dose, and Mode of Administration:
The Study Drug is dipyridamole for those randomized to receive it. Patients will receive-100 
mg dose (2 tablets of dipyridamole 50 mg each tablet) to be taken by mouth 3 times daily for 7 
days.
Suspension may be used if such is necessary after enrollment. Drug dose will not be given when 
SBP
< 90 mmHg. Based on availability of product to purchase, the total dose of 100mg may also 
be given by taking 1 tablet of dipyridamole 25mg and one tablet of dipyridamole 75mg.
5.
Study Treatments, Procedures and Laboratory Testing
This is a randomized, open-label trial in which patients will be assigned randomly to either 
DIP plus standard care or standard care only. A patient is eligible after meeting enrollment 
criteria and once all inclusion criteria are met while no exclusion criteria exist, this includes 
negative pregnancy test of standard care, for females of childbearing potential. Subjects 
identified to enrollment log, are assigned study group, based on the REDCap random number 
list following their consent- Standard care plus DIP for 7 days (DIP+) or Standard care (DIP-).
Formulation and Packaging:
The site Investigator/Research Pharmacy will provide patients randomized to the DIP therapy 
arm with the medication via standard drug distribution methods used in the hospital. The 
inpatient nursing staff will administer the drug but will hold for SPB<90mmHg. The total
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amount of dosing completed and the duration of treatment period will be documented in the 
EPIC medical record and used for Research data additionally throughout the study.
Other concomitant, non-study medications:
For UConn Health COVID-19 hospitalized subjects, all concomitant medication used at and 
from the time of Consent, will be recorded. Any study drug designed to test for efficacy for 
SARS-CoV-2 will not be permitted during the period of DIP use in this protocol.
Treatment Period:
Screening (day 0): All patients that have met enrollment criteria will be approached for informed 
consent. Standard care and all medical information will be documented in UConn Health’s electronic 
medical record (EPIC). A review of EPIC record for previous drug and non-drug treatments (within 
past 30 days) and current medications will be conducted. Adverse events going forward from review of 
EPIC record and by inquiry of Provider Investigator as warranted will be documented.
Day 1: DIP 100 mg TID plus standard care or standard care only
Day 2: DIP 100 mg TID plus standard care or standard care only
Day 3: DIP 100 mg TID plus standard care or standard care only plus blood (11.7 c.c.), stool 
and nasal swab collected for research purposes.
Day 4: DIP 100 mg TID plus standard care or standard care only
Day 5: DIP 100 mg TID plus standard care or standard care only
Day 6: DIP 100 mg TID plus standard care or standard care only plus blood (11.7 c.c.), stool 
and nasal swab collected for research purposes.
Day 7: DIP 100 mg TID plus standard care or standard care only
Day 8: Standard care only
Day 9: Standard care only plus blood 11.7 cc, stool and nasal swab collected for research 
purposes. Days 10 through patient discharge from the hospital (or death): Standard care only
Day 30: Follow-up phone call/EPIC review-mortality rate data collection
Day 60: Follow-up phone call/EPIC review-mortality rate data collection
During drug treatment period, that is day 1 through day 7, all medical record information will be 
recorded in EPIC. Research Specimens (blood, stool and nasal swabs) for viral presence by PCR will 
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be collected on Day 3, Day 6 and Day 9. Clinical responses as defined in the exploratory endpoints 
will be recorded throughout. Day 1 EKG is done, this includes within 2 hours of DIP administration. 
DIP, as above, is orally administered, including when necessary as suspension when standard care for 
subject includes gastric tube for medications (eg. intubation). During the study, any infection whether 
viral or non-viral will be captured. The site of infection and source of culture such as tracheal 
aspirate, sputum, blood or urine will also be recorded.
Patient Withdrawal of Consent:
Patients may withdraw from the study or study drug at any time at their discretion or patients may be 
withdrawn by the investigator or the sponsor for safety, behavioral or administrative reasons. If 
patient withdraws, the site investigator and study coordinator should attempt to document the reason 
and follow up for any adverse events. If patient also withdraws consent for disclosure of future 
information, no further study evaluation should be performed and no additional data will be collected. 
Follow up is to be for 2 days after withdrawal when permitted by patient. For those discharged prior 
to day 9, follow-up is by telephone to solicit information on fever, cough, sputum (exploratory 
objectives). DOC participants who may be discharged prior to completing the study and will not be 
contacted for information due to their privacy/confidentiality concerns.
Laboratory Research Studies:
We will collect whole blood (11.7 cc) for research data as well as stool samples and nasal or 
nasopharyngeal (NP) swabs for detection of SARS-CoV-2 RNA and viral susceptibility studies on Day 
3, 6 & 9 (+ or – 1 day).
If study subject is to be discharged, an end of study research sample set- (blood, nasal swab, stool) will 
be obtained on the discharge day (if not discharged on study Day 3, Day 6 or Day 9 ) in order to 
maximize trial & safety data collection and review. Per attached Table of Procedures (pg.25) study team 
will initiate EPIC order if SOC tests are not ordered/ done with discharge.
Whole blood (PBMCs, serum & plasma (EDTA and Citrate preserved)) will be used for exploring 
immunological profiles as well as metabolomic profiling including nanoscale bio-photonic data and 
whole genome sequencing for discovery of new biomarkers/ genomic regions that confer increased 
severity or susceptibility to infection and DIP treatment efficacy.
There will be basic science collaboration with UConn Health/UConn faculty, Jackson Laboratory and 
the University of Michigan “DICER” researchers who have DIP expertise. Samples for collaborative 
studies to aid understanding of SARS-CoV-2 infection, blood cell and immune response as well as 
possible DIP effect will be shared. Samples shared with Michigan and received from Michigan will 
include coded subject specific data from each trial for markers such as d-dimer, ferritin, etc. but no PHI 
or other identifiable information.
In addition, blood samples will be banked for future determination of serum levels of DIP in Liang 
Lab to ascertain exposure and pharmacokinetics of DIP in Covid-19 patients.
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Stool samples will be used to obtain microbiome analyses. These studies will be conducted in 
collaboration with Jackson Laboratory for Genomic Medicine. Research Nasal/NP swabs analyzed by
Jackson Laboratory CLIA lab are fully utilized as results are reported to the Research staff. Subjects 
wishing to receive results will be advised by designated study staff. Linda Choquette will be the IRB 
point person representing JAX-GM.
Confidentiality
Paper research records will be locked in a secure location in the Clinical Research Center, apart from 
the medical record. The records will include a research code such as “753-XXX” along with the 
subjects name and medical record number. All electronic files (e.g., database, spreadsheet) containing 
identifiable information will be password protected and encrypted. Any computer hosting such files 
will also have password protection. Only research staff will have access to the electronic files. A 
master list that links the code on the paper records to the subjects name will be kept in our electronic 
format. The research samples will be labelled with the research code only.
Appointed Study staff shall use access to EPIC to record all subject data to coded Case Report forms. 
These data are electronically maintained in a secure research REDCap database.
Prior to final study closure, any links between personal identifiers and each subject’s unique study ID 
will be deleted to generate a de-identified dataset.
Careful efforts to maintain confidentiality have been effective in our previous research and will be 
continued.
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Safety Assessments:
Safety will be assessed by means of collection of adverse events during the hospitalization.
6.
Adverse Events and Reporting:
Study Schedule of Assessments and Procedures for Adverse Events Monitoring
At Day 1, for Safety purpose, EKG is obtained on all subjects including those to be given DIP within 2 
hours after first dose.
All adverse events (AEs) will be reported. AEs should be considered to be unrelated only if definitively 
identified by an alternative explanation. They are defined as any untoward medical occurrence during 
administration of DIP and 2 days after administration of last dose.
Adverse events need not be causally related to DIP. Any of the protocol-defined primary, secondary or 
exploratory endpoints, other than mortality, would not be considered an AE.
AEs include hypersensitivity to DIP, drug interactions, overdose or withdrawal. Details of possible 
adverse effects and drug interactions are provided from extensive literature review in Appendix A- 
Additional Data on Dipyridamole.
SAEs include but are not limited to death, or life threatening condition leading to pending risk of death 
or occurrence of disability/incapacity.
Side effects inconsistent with Consent Form will also be recorded as AEs.
Adverse reactions at therapeutic doses of dipyridamole, are usually minimal and transient. With long term 
use of Dipyridamole tablets, initial side effects usually disappear. With the use of therapeutic warfarin, 
the following reactions were reported in two heart valve replacement trials, comparing Dipyridamole 
tablets with ongoing warfarin therapy to either warfarin alone or warfarin with placebo:
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Dizziness (13.6% vs. 8.2%)
Abdominal distress (6.1% vs. 3.5%)
Headache (2.3% vs. 0.0%)
Rash (2.3% vs. 1.1%)
Other reported adverse reactions from uncontrolled studies include diarrhea, vomiting, flushing and 
pruritus. In addition, angina pectoris has been reported rarely and there have been rare
reports of liver dysfunction
We will use National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE 
v.5) to grade the severity of adverse events.
The PI or Co-Investigators will timely obtain all information to ascertain the outcomes and determine both 
severity as well as causality.
The PI, Co-Investigators and designated CRC nursing study staff are responsible for surveillance and 
grading of toxicities, AE, and SAE during administration of dipyridamole and 2 days after administration of 
the last dose. Study staff will document AEs using the EPIC Adverse Events Activity. All initial entries by 
CRC staff will be documented as current grade 0 if not straight forward. The PI or Co-Investigator are 
responsible for determining the relationship of the AE/SAE and whether its association with the study drug is 
unrelated, unlikely, possible, probable or definite. The PI or Co-Investigator reviews and manages AEs in 
EPIC and assesses each AE for causality and required course of action in accordance with the protocol.
Study staff will report any such toxicities promptly to the PI or Co-investigator so that action may be taken 
to remove additional harm to the study participants. The PI assures that protocol specifics for toxicity 
management and reporting are followed and reported to the regulatory authorities.
Sponsor Investigator with assistance of Co-Investigators will follow up AE’s via EPIC Research Event 
Activity until resolution or stabilization of the AEs.
Per UCH Policy, 2009-001.0 events constituting unanticipated problems involving risk to subjects (or others) 
must be reported to the IRB as soon as possible but no later than 5 business days from discovery of the event 
via a Problem Report Form within iRIS .
All AEs will be documented in EPIC Research Adverse Event Activity.
For unexpected fatal or life-threatening suspected adverse reactions the Sponsor Investigator will also report to 
the FDA as soon as possible but no later than 7 calendar days following discovery of the event via a Med 
Watch form FDA3500
DSMB will also monitor and receive reports of all AEs and SAEs.
Data and Safety Monitoring Committee (DSMB) and Stopping Rules:
A DSMB will be established prior to enrollment to monitor and be kept informed of AEs and SAEs during the 
trial. The committee is to review data regarding enrollment, safety and adverse events. The committee will meet 
after the first 10 subjects are enrolled and again with 25, 50, 75 and 100 enrolled.
The DSMB will also monitor efficacy for the primary endpoints. For example, if during enrollment, a 
statistically significant difference is reached before the target 100 patient goal is met, the study could be 
stopped early for evidence of efficacy. Alternately it could be stopped for unacceptable AE profile as deemed 
by DSMB.
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Study suspension / stopping.
A decision to discontinue the study will be based on established study stopping rules defined in the Charter 
for DSMB.
If supplies of clinical trial such as the drug dipyridamole, supplies to collect research samples or personal 
protective equipment become unavailable or limited, the study will be suspended.
We do not project that the trial on hospitalized COVID19 patients will interfere with the current public health 
measures by federal or state. However, any new federal or state public health measurethat would make it not 
feasible to carry out the study or that continuing study under new public health measures would pose safety to 
the participating patients. In such a case, the study would be suspended.
Overall, PI/study team will update the IRB per Appendix B (study team meeting after each 10 completed 
subjects) at Continuation and Sponsor Investigator shall inform the FDA of all situations as needed and 
then determine continuation of the trial as appropriate.
Subject-specific stopping criteria.
Patients may withdraw from the study or study drug use at any time, at their discretion. Patients 
may be withdrawn by the Sponsor Investigator for safety, tolerability of the drug, behavioral, or 
administrative reasons.
If patient withdraws, the site investigator and study coordinator should attempt to document the reason and 
follow up for any adverse events if permitted for 48 hours by telephone.
If patient also withdraws consent for disclosure of future information, no further study evaluation should be 
performed and no additional data will be collected.
Any subject treated with DIP who exhibits NCI CTCAE (v.5) grade 3 or higher adverse event or laboratory 
values will be stopped from further dosing with DIP. EPIC has embedded this grading reference for use by 
appointed study team to review, assign and collate ongoing AEs for systematic and timely review by Sponsor 
Investigator and for use by DSMB.
In addition to stopping further DIP treatment, the adverse events will be treated or intervened upon, as per 
UCH Standard of Care.For example, hypotension will be treated with fluid or pressor if
the latter is needed. Hypertension will be treated with anti-hypertensive medications or higher dosage of such 
existing medication. Particular attention will be given to cardiovascular (hypotension
(SBP ≤90mmHg), hypertension, bradycardia, acute kidney injury), hepatobiliary toxicity, and allergic or 
anaphylaxis reaction.
Please see attached Appendix B for the severity grade by NCI CTCAE v.5.
Trial-specific stopping criteria
In monitoring the adverse events, we will conduct an assessment of the frequency or the proportion of DIP vs. 
untreated patients with a serious adverse event, and in this case, with particular attention to cardiovascular, 
hepatic and hypersensitivity adverse events. We propose to define a reasonable threshold proportion above 
which DIP treatment will cease. Most of the data were obtained from patients receiving DIP by intravenous 
administration. Few data exist on those receiving oral DIP. When such oral route data are available, we use 
them to define the threshold proportion. In addition, the reported frequency of adverse effect was obtained in 
non-COVID 19 patients who have a higher incidence of cardiovascular complications. We first report the 
known or expected incidence of cardiovascular, hepatic and hypersensitivity adverse effects. Then, we propose 
the stopping consideration by the DSMB by the proportion of such effects in treated vs. untreated subjects in a 
table.
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Cardiovascular:
1.
Chest pain-19.7% in a study of adjunct IV administration for thallium myocardial perfusion 
imaging reported chest pain (5). Angina was rare (6).
2.
Bradyarrhythmia-0.2% via IV route was reported during myocardial imaging (5).
3.
Abnormal ECG such as ST-T segment changes (7.5%) or extrasystoles (5.2%) occurred not 
uncommonly from the IV experience (5).
4.
Hypotension had an incidence of 4.6% by IV route (5).
5.
Myocardial infarction frequency was 0.1% (5).
6.
Tachycardia had a frequency of 3.2% (5) although in a postmarketing surveillance study, it 
was rarely found (6). In this proposed protocol, the frequency may not be high given that we 
will have excluded those with conduction abnormalities or severe coronary artery disease.
Hepatic effects:
Increased liver enzymes have been rarely reported in those taking DIP in postmarking 
surveillance (6). However, it has been reported that frequency of liver enzyme abnormalities 
was similar with DIP as with placebo (LiverTox: Clinical and Research Information on 
Drug-induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and 
Digestive and Kidney Diseases, 2012-Last Update January 4, 2018).
 Hypersensitivity reaction:
Rare reports of allergic reaction such as urticarial, pruritus and rash was rarely reported with 
IV use (5, 7-9). In postmarketing surveillance, hypersensitivity was also rare as was 
angioedema (6).
Additionally, Based on a review of (1) the dipyridamole product insert, (2) the primary 
medical literature, (3) FDA Medwatch, and (4) the FDA Adverse Event Reporting System 
(FAERS) for (a) potentially serious/life-threatening adverse events as described in the DIP 
product labeling & in the FDA database, and (b) plausible relationships of DIP pharmacologic 
effects to possible serious/life threatening adverse effects, the DSMB will evaluate the 
following possible types of adverse effects for consideration of possible early termination of 
the study at the pre-defined interim analysis milepoints:
Adverse Event
Increase in total prevalence (%) in DIP-Treated patients versus Standard—Care 
Patients at Pre-Specified study analysis milepoints (n=total # of patients enrolled) 
for consideration of premature discontinuation of TOLD study
n=10
n=25
n=50
n=75
Severe and/or life- 
threatening bleeding 
event1
> 40%4
> 25%5
> 9%6
> 8%7
Severe liver toxicity2
> 40%
> 25%
> 9%
> 8%
Severe and/or life-
> 40%
> 25%
> 9%
> 8%
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threatening 
cardiovascular event3
Severe thrombocytopenia 
(Platelet counts
<10/mm3)
> 40%
> 25%
> 9%
> 8%
1 – Gastrointestinal hemorrhage requiring transfusion, intracerebral hemorrhage,
2 – Asymptomatic elevation of AST, ALT, alkaline phosphatase or Bilirubin to more than 5x upper 
limit of normal, that is ≥ grade 3 by the NCI CTCAE v.5 criteria.
3 – Acute myocardial infarction, worsening angina symptoms, or ≥ NCI CTCAE v.5 grade 3 
hypertension
or hypotension or bradycardia
4 – A prevalence of this event in 2/5 DIP patients versus 0/5 Standard Care patients results in a 
P=0.22 (One-tailed Fisher Exact test)
5 - A prevalence of this event in 3/12 DIP patients versus 0/13 Standard Care patients results in a 
P=0.096 (One-tailed Fisher Exact test)
6 - A prevalence of this event in 3/25 DIP patients versus 0/25 Standard Care patients results in a 
P=0.117 (One-tailed Fisher Exact test)
7 - A prevalence of this event in 3/37 DIP patients versus 0/38 Standard Care patients results in a 
P=0.115 (One-tailed Fisher Exact test)
Other side effects from oral ingestion include dizziness (13.6%), headache (2.3%), abdominal 
discomfort (6%). The frequencies in DIP-treated vs. untreated COVID-19 patients are not known but 
will be monitored. The Study will be subject to auditing by UConn Health Human Subject Protection 
program, prior to enrollment and at any subsequent time.
7.
Efficacy Assessments
The assessment of vascular responses will be made based on biomarker (platelet count & D-Dimer) 
determinations as defined in the primary endpoint at days 3, 6, 9 or at discharge day-premature 
discontinuation such as patient’s withdrawal or occurrence of SAE. The assessment of microbiologic 
response will be made based on PCR performed on specimens collected on Day 3, 6 & 9 or 
discharge day,-premature discontinuation such as patient’s withdrawal or occurrence of SAE.
Clinical responses of each enrolled subject as defined in the exploratory endpoints will be evaluated at 
Day 3, Day 6, Day 9 (± 1 day) or at discharge day- premature discontinuation such as patient’s 
withdrawal or an occurrence of SAE that disallows continued participation in the trial. Those who are 
discharged before day 9 and grant permission for follow-up telephone contact will provide 
information (48 hrs) on fever, cough and/or sputum. This will not apply to DOC enrollees due to 
confidentiality concerns.
Statistical Methods and Sample Size Calculation:
The primary outcome measure for efficacy evaluation will be an increase in the platelet counts or a 
decrease in D-dimer level on day 3, 6 or day 9. For the primary efficacy evaluation, these 
determinations will be based on a modified intent to treat population (MITT).
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The MITT population will be comprised of all randomized patients who received less than one full 
day or less than 3 doses over 24 hours of the study drug, that is, the study will include patients who 
received only a single dose of DIP. In Liu et. all, as cited above (pg. 3, ref 3), D-dimer level rose by 9 
± 8 fold (mean and SE) by 6-9 days in hospitalized COVID19 patients who did not receive DIP (1).
In order to detect a 6.5 fold reduction in the extent of D-dimer increase in DIP-treated patients, we 
will need to enroll 25 subjects in each group to have 80% power at a two-sided significance level of
0.05. In order to detect a 6.3 fold reduction in the extent of D-dimer increase in DIP-treated patients, 
we will need to enroll 35 subjects in each group to have 90% power at a two-sided significance level 
of 0.05.
Platelet counts rose by 1.35 ± 0.25 fold by 6-9 days in in hospitalized COVID19 patients who did not 
receive DIP (1). In order to detect a 0.2 fold further increase in the extent of platelet increase in DIP- 
treated patients, we will need to enroll 25 subjects in each group to have 80% power at a two-sided 
significance level of 0.05. In order to detect the same 0.2 fold further increase in platelet with 90% 
power at two-sided level of 0.05, we will need to enroll 35 subjects in each group.
Additionally, the changes in biomarker levels and the number of abnormal biomarkers from baseline 
to day 6 or day 9, plus the temporal trends will be compared between arms using linear mixed effects 
models.
The number and percentage of study participants who show clinical improvement will be determined.
The secondary endpoint will be the absence of SARS-CoV-2 in the specimen taken on Day 3, 6 or 9 
as assessed by polymerase chain reaction. The number and percentage of those showing 
disappearance of the virus will be tabulated by treatment assignment.
The secondary endpoint is the non-detection of the SARS-CoV-2 based on PCR of specimens at Day 
3, 6 or 9 (± 1 day) in the MITT population.
Based on the efficacy of hydroxychloroquine-azithromycin in eliminating SARS-COv-2 in 20 patients 
4and a potent anti-viral efficacy of DIP in vitro3, we expect that we will be powered to detect 
elimination of this virus by DIP should DIP be efficacious in patients. Assuming an attrition of 30%, 
we plan to enroll 50 subjects in each group. If attrition is less, then fewer than 50 patients will need be 
enrolled. Nevertheless, the study sample sizes described above will provide power (80% power at an 
alpha level of 0.05) to detect an absolute reduction of 30-40% in the proportion of patients in the two 
study groups with positive nasopharyngeal PCR for detection of SARS-CoV-2 virus at the 3 defined 
evaluation timepoints.
The number and percentage of those showing disappearance of the virus will be tabulated by 
treatment assignment and compared between arms at day 5 and day 9 using a logistic mixed effects
4 Gautret, P. et. al Hydroxychloroquine and azithromycin as a treatment of COVID-19:results of an open-label non- 
randomized clinical trial. International Journal of Antimicrobial Agents (2020) 
https://doi.org/10.1016/j.ijantimicag.2020.105949
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regression model.
Exploratory clinical endpoints will also be assessed for improvement. The overall combined primary, 
secondary and exploratory endpoints at each time point in terms of percentage of subjects who show 
improvement will be calculated. Trend analyses will be conducted.
The exploratory outcome measure of success is defined as improvement or resolution of clinical 
parameters such as fever <100.5° F, decrease in cough as reported by patient, improvement in chest 
imaging evidence of pneumonia, Sp02 ≥ 93% on room air until hospital discharge or day 9 
whichever occurs last.
Other exploratory endpoints include C-reactive protein (CRP), lymphocyte count, prothrombin time 
(PT), activated partial thromboplastin time (APTT), plasma fibrinogen (FIB), and serum ferritin, cTnI, 
LDH.
Exploratory clinical endpoints will also be assessed for improvement and compared between arms 
using logistic regression models. We also will assess for the percentages of patients in each study 
group who: progress to requiring ICU care, needing intravenous vasopressor therapy and/or 
mechanical ventilation, as well as progression to organ failure such as kidney or liver failure or 
ARDS. All the statistical analyses will be performed in R version 3.6.1. A p-value smaller than 5% 
will be considered statistically significant.
General Statistical Considerations:
Each baseline variable will be summarized overall and for the two arms separately, using mean and 
standard deviation for continuous variables and frequencies and percentages for categorical variables. 
Baseline variables will be compared between arms by two-sample t-test for continuous variables and 
by Fisher’s exact test for categorical variables. The unbalanced variables in the two arms will be 
adjusted in the models for outcome comparisons to reduce the confounding effects.
Statistical test comparisons between randomized groups will be made for oral dipyridamole plus 
standard of care versus standard of care. Analyses of primary and secondary endpoints will be 
conducted by the modified intention-to-treat approach. If the primary outcome reaches significance, a 
hierarchical, sequentially rejective process will be followed for the secondary and exploratory 
endpoints. It is expected that randomization will make the baseline characteristics similar. If not, an 
analysis of covariance will be conducted for control for baseline differences. There are two primary 
outcomes (D-Dimer and Platelet count) in this study to evaluate an effect of DIP. In order to control 
the Type I error, we considered the Bonferroni correction method in the interim analyses of 25 
patients to date.  In this analysis, the Bonferroni corrected significance level would be 0.025 instead 
of 0.05 in each hypothesis test. It will be applied to interpret the hypothesis results in primary 
outcomes in the interim analyses after 50 and 75 patients enrolled
A comprehensive Statistical Analysis Plan (SAP) will be finalized prior to the interim analysis.
                Missing data: If a test result from primary or secondary endpoints is not available or that the test is not done, 
               the subject will be included in the MITT population in the statistical analysis. The multiple imputation 
               method will be applied to impute variables in multivariate analyses where the imputed data will be 
               analyzed for sensitivity analyses, compared to the results using available data. Day 3 will be the primary 
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               time endpoint. The two primary endpoints will be analyzed separately as stated. Mortality is considered 
               one of serious adverse events. It will be summarized by frequencies and percentages and will be compared 
               between arms by Fisher’s exact test.
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Appendix-A
ADDITIONAL DATA ON DIPYRIDAMOLE:
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 were reported in 
two heart valve replacement trials, comparing Dipyridamole tablets and warfarin therapy to either 
warfarin alone or warfarin with placebo:
Dizziness (13.6% vs. 8.2%)
Abdominal distress (6.1% vs. 3.5%)
Headache (2.3% vs. 0.0%)
Rash (2.3% vs. 1.1%)
Other reactions from uncontrolled studies include diarrhea, vomiting, flushing and pruritus. In 
addition, angina pectoris has been reported rarely and there have been rare reports of liver dysfunction
Contraindications

Hypersensitivity to dipyridamole or any component of the formulation
Disease-related concerns:
●
Cardiovascular disease: Use with caution in patients with hypotension, unstable angina, 
and/or recent myocardial infarction; may enhance exercise induced myocardial ischemia 
in patients with chronic stable angina.
●
Coronary artery disease: : Dipyridamole has a vasodilatory effect and should be used 
with caution in patients with severe coronary artery disease, may exacerbate chest pain
●
Hepatic impairment: Use with caution in patients with hepatic impairment.
Concurrent drug therapy issues:
●
Antiplatelet agents/anticoagulants: Use with caution in patients on other antiplatelet 
agents or anticoagulation.
○
When dipyridamole was administered concomitantly with warfarin, bleeding was 
no greater in frequency or severity than that observed when warfarin was 
administered alone. In rare cases, increased bleeding during or after surgery has 
been observed
●
Pharmacologic stress testing: Interrupt oral dipyridamole therapy for 48 hours prior to 
stress testing with adenosine, IV dipyridamole, or regadenoson; may increase risk for 
cardiovascular adverse effects and impair the test sensitivity.
●
Adenosinergic agents (e.g., adenosine, regadenoson): dipyridamole can increase the 
plasma concentrations of adenosine, dose adjustment may be necessary
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●
Cholinesterase inhibitors: Dipyridamole may counteract the anticholinesterase effect of 
cholinesterase inhibitors
Drug Interaction Concerns:
An open-label, randomized, multiple-dose, crossover, drug-interaction study was carried out 
evaluating the theoretical risk of altered antiplatelet activity of aspirin and extended-release 
dipyridamole with concomitant use of omeprazole. A total of 6 healthy male and female 
participants aged 18-50 years were included in the study to evaluate the systemic pharmacokinetic 
exposure to extended release dipyridamole and aspirin inhibition of arachidonic acid-induced 
platelet aggregation.
Each participant was randomized to one of two possible treatment sequences where the received 
either aspirin and dipyridamole first, followed by omeprazole, and vice versa. Each treatment 
sequence was comprised of four 7-day treatments with a washout of > 14 days between the use of 
aspirin and dipyridamole monotherapy and combination therapy with omeprazole. Investigators 
reported similar systemic exposure to antiplatelet therapy with and without omeprazole. Using 
steady-state area under the concentration time curve (AUC) from 0-12 hours and maximum plasma 
concentration, researchers were able to show that pharmacokinetic and pharmacodynamic 
behavior of aspirin and extended-release dipyridamole was not altered by concurrent 
administration of omeprazole (Offman, 2013).
It is thought that dipyridamole has an inhibitory effect on p-glycoprotein exporters, which raises 
concern for concomitant administration with substrates of P-gp. Shalinski et al investigated how 
dipyridamole impacts the sensitivity of anticancer drugs, specifically in cell lines that either 
express the MDR1 (ABC1) gene or do not. MDR1 is the gene that encodes p-glycoprotein.
Researchers demonstrated that the presence of p-glycoprotein (multi-drug resistant cell lines) 
resulted in a much higher level of synergy with dipyridamole and vinblastine compared with cell 
lines that lack P-gp expression. (Shalinski, 1991)
Pregnancy and Teratogenic Considerations
●
There are no well controlled studies in human, pregnant, females
●
Dipyridamole should only be used in pregnancy if clearly needed
Breast-Feeding Considerations
●
Dipyridamole is excreted in breast milk. The manufacturer recommends that caution be 
exercised when administering dipyridamole to nursing women
Pediatric Considerations
●
Effectiveness in children less than 12 years of age have not been determined
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Pharmacokinetics
●
Following an oral dose of dipyridamole, the average time to peak concentration isabout 
75 minutes.
●
The decline in plasma concentration following a dose of dipyridamole tablets 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) isapproximately 
10 hours.
●
Dipyridamole is extensively protein bound
●
It is metabolized in the liver where it is conjugated as a glucuronide and excreted with the 
bile.
Dipyridamole is metabolized via the liver to a monoglucuronide which is then subject to biliary 
and fecal excretion and simultaneous enterohepatic circulation. Pharmacokinetic analysis 
performed in four normal human volunteers found that the serum concentration curve following 
IV administration follows an open two-compartment model with first order, linear kinetics. Oral 
dipyridamole pharmacokinetics are described by the use of a corresponding pharmacokinetic 
model with two consecutive first order steps. The biological half-life of the drug was reported 
between 85 and 145minutes, with the systemic bioavailability of an oral, 100 mg dose varying 
from 37-66% (Nielsen-Kudsk, 1979)
Macgregor et al investigated the in vitro protein binding behavior of dipyridamole in plasma and 
buffered protein solutions. The drug was highly protein bound in heparinized human plasma 
(~98%) The extent of binding was consistent across the entire therapeutic range of drug 
concentrations (0.1 – 10 mcg/mL). Comparable binding results were found with a mixture of 80 
mg % α-1 acid glycoprotein and 40 g/L human serum albumin in pH 7.4 phosphate buffer 
solution. Binding in one or the other was significantly lower than in a combination of the two, 
indicating that both proteins are implicated in dipyridamole protein binding. The binding of 
dipyridamole to heparinized human plasma or human serum albumin was concentration 
independent up to 40 mcg/mL, at which point the free fraction of dipyridamole begins to increase 
(Macgregor, 1991).
Russell et. al investigated pH related changes in 11 healthy elderly adults on the absorption of 
dipyridamole. The subjects investigated were all over the age of 65 and 6 had a low gastric pH, 
which served as the control, while 5 had a gastric pH over 5. They all received 50 mg 
dipyridamole as a single dose. The control subjects were pretreated with 40 mg famotidine while 
the others were pretreated with 1360 mg glutamic acid. A Heidelberg radiotelemetric capsule 
monitored the gastric pH and emptying of radiolabeled orange juice was measured. The 
researchers noticed that an elevated gastric pH had a negative effect of dipyridamole absorption. 
The Tmax and Ka were slower in subjects with a pH over 5, however, this could be corrected by 
administration of glutamic acid before treatment. Additionally, gastric emptying seemed to be
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slower in patients with a pH above 5. Overall, it would be beneficial for patients with a 
higher gastric pH to pretreat with glutamic acid HCl before treatment with dipyridamole.
A study by Batista et al (2010) evaluated whether dipyridamole concentrations achieved in the 
plasma of patients taking an extended-release formulation of the medication through a 
gastrostomy tube (G-tube) are therapeutic and similar to those achieved in the plasma of patients 
who receive the drug orally. Patients included were those admitted following an acute cerebral 
infarction, with an indication for antiplatelet therapy for secondary prevention. Twelve patients 
with severe dysphagia requiring G-tube placement were cases, and 12 patients who were able to 
swallow safely served as controls and took the medication orally. The main outcome measure 
was dipyridamole plasma concentrations on day 5 at all three timepoints. The study found there 
was no significant difference in dipyridamole plasma concentrations between the groups found 
at 2 hours (p = 0.18), 6 hours (p = 0.92) or 12 hours (p = 0.69). Dipyridamole plasma 
concentrations obtained following administration of extended-release dipyridamole through a
G- tube in dysphagic patients achieved similar therapeutic levels to those obtained in patients 
taking the medication orally (Batista, 2010).
Preparation of Dipyridamole Suspension:
For patients who may be unable to swallow tablets or who have a feeding tube in place, the 
study drug tablets will be crushed and extemporaneous suspension will be prepared as follows:
A 10 mg/mL oral suspension may be made with tablets and one of three different vehicles 
(cherry syrup, a 1:1 mixture of Ora-Sweet and Ora-Plus, or a 1:1 mixture of Ora-Sweet SF and 
Ora-Plus). Crush twenty-four 50 mg tablets in a mortar and reduce to a fine powder. Add 20 
mL of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in 
incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with 
vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well" and 
"protect from light".
Stable for 60 days when stored in amber plastic prescription bottles in the dark at 
room temperature or refrigerated.
Reference: Allen LV and Erickson III MA, "Stability of Baclofen, Captopril, Diltiazem, 
Hydrochloride, Dipyridamole, and Flecainide Acetate in Extemporaneously Compounded 
Oral Liquids," Am J Health Syst Pharm, 1996, 53:2179-84.8879325
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References
1. Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, et.al. Clinical Characteristics of 
Coronavirus Disease 2019 in China. NEJM 2020 Feb 28, 2020. 
https://www.nejm.org/doi/full/10.1056/NEJMoa2002032?url_ver=Z39.88- 
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
2. Insel PA, Murray F, Yokoyama U, et al. cAMP and Epac in the regulation of tissue 
fibrosis. Br J Pharmacol 2012; 444 166(2): 447-56. 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3417479/
3. Liu X, Hai-Bin Lou Z, et. al. Therapeutic effects of dipyridamole on COVID-19 patients 
with coagulation dysfunction. doi:https://doi.org/10.1101/2020.02.27.20027557 
https://www.medrxiv.org/content/10.1101/2020.02.27.20027557v1.full.pdf
4. Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Morgane M, Doudier B, Courjon J, 
Giordanengo V, Vieira VE, Dupont HT, Honore S, Colson P, Chabriere E, LaScola B, Rolain 
JM, Brouqui P, Raoult D. Hydroxychloroquine and azithromycin as a treatment of COVID- 
19: results of an open-label non-randomized clinical trial.Int J Antimicrob Agents. 2020 Mar 
20:105949. doi: 10.1016/j.ijantimicag.2020.105949. [Epub ahead of print] 
https://www.sciencedirect.com/science/article/pii/S0924857920300996?via%3Dihub
5. Product Information: dipyridamole IV injection, dipyridamole IV injection. 
Bedford Laboratories, Bedford, OH, 2007.
6. Product Information: dipyridamole oral tablets, dipyridamole oral tablets. 
Zydus Pharmaceuticals USA, Inc, Princeton, NJ, 2008.
7. Angelides S, Van der Wall H, Freedman SB. Acute Reaction to Dipyridamole during 
Mycardial Scintigrapy. N. Engl. Med. 340: 394, 1999. DOI: 
10.1056/NEJM199902043400517 
https://www.nejm.org/doi/full/10.1056/NEJM199902043400517?url_ver=Z39.88- 
2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed
8. Weinmann P, Morret JL, Leynadier F. Anaphylaxis-like reaction induced by 
dipyridamole during myocardial scintigraphy. Am. J. Med. 97: 448, 1994. 
https://doi.org/10.1016/0002-9343(94)90331-X 
https://www.sciencedirect.com/science/article/pii/000293439490331X?via%3Dihu 
b
9. Cogen F, Zweiman B. Dipyridamole (Persantine)-induced asthma during thallium 
stress testing. J. Allergy Clin. Immunol. 115: 203-204, 2005. 
doi:10.1016/j.jaci.2004.09.041 
https://www.sciencedirect.com/science/article/pii/S0091674904026284?via%3Dihub
Literature pertaining to Dipyridamole
Dipyridamole (Persantine) [package insert]. Ridgefield, CT 06877. Boehringer 
Ingelheim Pharmaceuticals Inc. 2019
https://docs.boehringer- 
ingelheim.com/Prescribing%20Information/PIs/Persantine%20Tabs/PersTab.pdf
Henzlova MJ, Duvall WL, Einstein AJ, et al. ASNC imaging guidelines for SPECT Nuclear 
Cardiology Procedures: Stress, Protocols, and Tracers J Nucl Cardiol. 2016.[PubMed 
26914678]
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https://link.springer.com/article/10.1007/s12350-015-0387-x
Macgregor TR, Sardi ED. In Vitro Protein Binding Behavior of Dipyridamole. Journal of 
Pharmaceutical Sciences. 1991;80(2):119-120. doi:10.1002/jps.2600800206. 
https://www.sciencedirect.com/science/article/abs/pii/S0022354915484710?via%3Dihub
Offman E, Schobelock MJ, Brickl R, VanderMaelen CP, Ehrlich J, Eisert W. Pharmacokinetics 
and pharmacodynamics of the antiplatelet combination aspirin (acetylsalicylic acid) plus 
extended-release dipyridamole are not altered by coadministration with the potent CYP2C19 
inhibitor omeprazole. Am J Cardiovasc Drugs. 2013;13(2):113-120. doi: 10.1007/s40256-013- 
0018-3 [doi].
https://link.springer.com/article/10.1007%2Fs40256-013-0018-3
Nielsen-Kudsk F, Pedersen AK. Pharmacokinetics of dipyridamole. Acta Pharmacol Toxicol 
(Copenh). 1979;44(5):391-399. doi: 10.1111/j.1600-0773.1979.tb02350.x [doi].
https://www.ncbi.nlm.nih.gov/pubmed/474151
Batista, Leonardo M, et al. “Pharmacokinetics of Extended-Release Dipyridamole Following 
Administration through a Gastrostomy Tube.” Clinical Drug Investigation, vol. 30, no. 7, 2010, 
pp. 483–488., doi:10.2165/11536220-000000000-00000.
https://link.springer.com/article/10.2165%2F11536220-000000000-00000
Russell TL, Berardi RR, Barnett JL, O'Sullivan TL, Wagner JG, Dressman JB. “PH-Related 
Changes in the Absorption of Dipyridamole in the Elderly.” Pharmaceutical Research, U.S. 
National Library of Medicine, pubmed.ncbi.nlm.nih.gov/7908130/. 
https://deepblue.lib.umich.edu/bitstream/handle/2027.42/41435/11095_2004_Article_304414.pd 
f?sequence=1&isAllowed=y
Shalinsky D, Slovak M, Howell S. Modulation of vinblastine sensitivity by dipyridamole in 
multidrug resistant fibrosarcoma cells lacking mdr1 expression. British Journal of Cancer. 
1991;64(4):705-709. doi:10.1038/bjc.1991.385.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1977708/pdf/brjcancer00074-0107.pdf
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ICF_001.pdf: 
UConnHealth IRB# 20-192-2.F
Trial of Open Label Dipyridamole for COVID-19
1
Version 5; 5/26/2021
Consent for Participation in Research Activities 
at UCONN Health
Sponsor Investigator: Dr. Liang 860-679-7541
Site Co-Investigators: Drs. Kevin Dieckhaus, Jeff Aeschlimann, Mark Metersky, Eric Mortensen, 
Christopher Pickett
Project Title: A randomized, open-label study of the vascular and microbiologic efficacy of dipyridamole 
plus standard care vs. standard care in hospitalized COVID19 patients.
Expected Duration of Participation: 9 days
IRB Study #: 20-192-2.F
Funding Source: UConn Health School of Medicine
Name of Research Participant:  
In this consent form, “you” always refers to the subject. If you are a legally authorized representative, 
please remember that “you” refers to the study subject. This consent form is intended for the patient 
who is eligible to participate in this study. However, if the patient is incapable of providing consent due 
to the severity of his/her illness, the consent of a relative or other authorized representative will be 
sought.
If at any time during the study, the patient becomes capable of providing consent, informed consent will 
be sought from the subject as a condition of their continuing participation
OVERVIEW OF THE RESEARCH
You are being asked to provide consent to participate in a research study. Participation is voluntary. You 
can say yes or no. If you say yes now you can still change your mind later. Some key points to consider 
are summarized in this overview, but you should consider all of the information in this document carefully 
before making your decision.
This study is an open-label drug study to examine potential benefit to hospitalized COVID-19 patients. 
This means that you and your doctor will know if you are taking the study drug. The drug is Dipyridamole 
which is already FDA approved for the prevention of clots in heart valve patients. It may also have anti- 
viral effects. The Principal Investigator is conducting this research under an Investigational New Drug 
review by the FDA. Dipyridamole is not currently approved for COVID-19 patients.
This research is being done to determine if Dipyridamole is safe and effective for helping to reduce 
complications in those hospitalized for COVID-19. The use of this drug in January 2020, during the 
outbreak of the pandemic in China, was reported in a small study to reduce complications arising in those 
hospitalized. When given 3 times a day as a pill or liquid, if necessary, Dipyridamole has been found to 
protect platelets (cells that help with clotting) from being destroyed throughout the body by the virus.
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Researchers are also looking to see if the drug can stop this virus from reactivating in the body, and help 
as people do recover. The results of this research are to be promptly shared with the FDA by the Sponsor 
Investigator, Dr. Liang, for possible consideration as a new use for this drug. DNA is analyzed to learn 
more about differences in patient susceptibility to COVID-19 and how this medicine may act in the body. 
Results are not disclosed you individually.
In this UConn Health Trial of Open Label Dipyridamole (TOLD) for COVID-19, 100 subjects are 
expected to participate. Half of the participants will have the study medication added to their UConn 
Health standard care for COVID-19 (taken by mouth, 3 times a day); the other half will receive standard 
care (without study medication).
Participation will involve your review of this form and if you are enrolled, we will collect all hospital care 
information about you and any possible effects on that care from Dipyridamole.
50 of the 100 UConn patients on this study will receive the drug; the other 50 will receive standard care. 
This is determined like a coin flip after you join. You have a 50/50 chance of receiving study drug for 7 
days, while hospitalized. Your care will be monitored for 2 days after you finish the drug, as part of the 
study. 
Up to 3 sets of research blood, nasal swab and stool sample collections will be done on day 3, day 6 and 
day 9. The research blood will be collected along with your Standard of Care blood draw.  However, if 
you are discharged before Day 9, a final day sample set will be collected.   Standard of Care blood will 
be collected on Day 0 (the day you sign consent) for research purposes if not already done. Any 
procedures that are research related are paid for by the study. You can withdraw at any time. Women 
with childbearing potential will be screened with a pregnancy test.
You are asked to allow the researchers to collect and analyze all the information from your Standard, 
Hospital care for the next 9 days along with samples for research purposes. The research is about your 
infection and your body response. COVID-19 research only test results can be provided to you upon 
your request, at any time. After 9 days, your study participation with collection of samples, is over
The most common risk associated with the study medication in pill form is dizziness (14%). Other 
possible risk associated with medication are stomach ache (6%), headache (2%) and skin rash (2%). Less 
frequent side effects reported are: vomiting, diarrhea, flushing or itching. Potentially serious effects of the 
study drug are chest pain and liver function deterioration are rarely seen.
While on the study your care team providers will ask about your overall health to include any of these 
possible side effects. Your care by providers may stop the drug for your overall safety.
If you join the study you may leave it at any time. There will be no negative effect on the care or services 
provided to you UConn Health in the Hospital. If a commercially viable product is developed you will 
not share in any financial gains.
Why am I Invited to Participate?
You are 18 year old and hospitalized at UConn Health with COVID-19.
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What Procedures Will Be Done?
You are asked to review and sign this consent to participate in the study.
After that, the study team will inspect all your hospitalization records for up to 9 days. There are no study 
visits. All patients get Standard Clinical Care with their providers giving the care for COVID19 in 
Hospital. After joining, ½ of patients will be assigned to receive the study drug. The use of the study drug, 
when assigned is considered experimental at this time. At 3, 6 and 9 days (+ or – 1 day) after starting the 
study, samples of blood, nasal swab and stool are obtained when for research analyses. All samples are 
obtained by your providers when available. The research swab (when available) and stool samples are 
collected to examine COVID-19 viral shedding; the blood tests for the research are included in monitoring 
your overall health while hospitalized.
What Alternative Procedures or Treatments Are Available To Me?
There is no FDA approved therapy for COVID-19. You may decline participation. You may choose to be 
in another study if available to you
What Are the Costs To Me For Participating In This Study?
There is no charge for participating in this research study. There is no charge for the sample collections 
conducted as part of your hospital care and there are no charges to you or your insurance for participating 
in this research. Regular standard of care charges for hospital treatment are billed to your insurance. This 
study is funded by a grant from the University of Connecticut, School of Medicine.
Is Participation Voluntary?
Participation in this study is voluntary. Before making a decision about whether to participate in this research 
study, read this consent form carefully and discuss any questions you have with an investigator listed above. 
You may also want to talk with family members, your primary care physician or a friend before making a 
decision.
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If you decide to participate in the study, you are free to withdraw from it at any time. If you choose to 
withdraw from this study, the data and any specimens that have already been collected from you prior to 
withdrawing will continue to be used and remain in our study Research database.
If you decide not to participate and withdraw from the study, your decision will not affect your present or 
future medical care you receive at UConn Health and there will be no penalty or loss of benefits to which 
you are otherwise entitled.
How Many People Will Participate?
We expect 100 people to enroll in this study. By chance, 50 will receive the study drug added to their 
Standard Care.
How Long Will My Participation In This Study Last?
Your information will be collected for up to 9 days. Research samples are collected on day 3, day 6 and 
day 9 (+ or – 1 day); they will be collected on your last hospital day if necessary. Each day, the Study 
Team staff with the Investigators will review your hospital care progress in the EPIC medical record for 
this research. They will collect information about your condition and blood work and interact with your 
providers to monitor your safety whether on the drug or not. If you withdraw from the study we continue 
to collect medical record information, if you permit, until discharge or day 9, whichever is later. If you 
are discharged, recovered before 9 days, we will call you for follow up information, if you allow. 
We will follow-up by phone at 30 and 60 days after study enrollment (Day 1) to check on your 
wellbeing. If we cannot contact you, we will check EPIC medical records and/or public health records if 
needed.
You can receive results of your research COVID-19 tests from the Hospitalization whenever you request 
from the study team. If you are a Department of Corrections participant, you will not be contacted after 
discharge.
Medication Dosing: If you are selected by chance to receive the drug, you will take 100 mg 3 times a 
day in pill form, for 7 days, when you are randomized to the Standard Care plus Dipyridamole group. If 
you are on a breathing tube initially or at some point, you are unable to swallow the medication. There is 
a liquid form which may be given to you when your standard care includes a tube passed through your 
nose into your stomach for nutrition and medications.
What Drug Will I Be Asked to Take? Is it Safe?
If you choose to participate in this study you may be assigned to take study medication- Dipyridamole 
which goes by the brand name, Persantine. For this research, all medicines and treatments which your 
providers consider using to treat you in the Hospital are permissible except overlapping use of other 
COVID-19 research drugs under another research study. All medication that you use will be recorded to 
our Research Records.
There may be risks related to use of Dipyridamole that are not now known. You will be notified of any 
new significant findings regarding the medication that might affect your willingness to continue in the 
study.
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What is Dipyridamole?
Dipyridamole has FDA approval now when it is added to treatment with the blood thinner (warfarin) for 
the prevention of clotting complications with cardiac valve replacement. The investigators at UConn 
Health are familiar with its use. It is also FDA approved for combination with aspirin to reduce the risk of 
stroke in patients who have had transient ischemia (TIA) of the brain or stroke due to clotting.
What are Potential Risks and Side Effects Associated with Dypyridamole?
Side effects are usually mild and don’t last long. In studies looking at long term use of Dipyridamole 
tablets, initial side effects usually disappear.
The following reactions were reported in two heart valve replacement studies, comparing Dipyridamole 
tablets and warfarin (Blood thinner) therapy to either warfarin alone or warfarin with placebo:
Dizziness (13.6% vs. 8.2%)
Abdominal distress (6.1% vs. 3.5%)
Headache (2.3% vs. 0.0%)
Rash (2.3% vs. 1.1%)
Other reactions from uncontrolled studies include- diarrhea, vomiting, flushing and pruritus. 
In addition, chest pain related to the heart and liver test elevations have been reported rarely. 
Safeguards Taken:
You will be asked by your providers each day if you are experiencing any potential medication related 
adverse effects, as above or otherwise, as part of Standard Care. If you experience any side effects, you 
may also contact the study coordinator by Dr. Bruce Liang at 860-679-7541.
What Other Types of Risk Are Involved If I Choose To Participate? 
Risks Associated with Confidentiality
•
Your participation is confidential. There is a chance that people outside of the research team may 
learn of your participation in a study. Despite our best efforts we cannot guarantee 100% 
confidentiality.
•
Safeguards Taken: Paper research records will be locked in a secure location in the 
Clinical Research Center, apart from your medical record. The records will be identifiable, 
which means they will include a research code such as “753-XXX”. Your name and/or medical 
record number may be on some documents, such as the consent form and any images of it, as 
transmitted by fax or electronically, via cell phone image obtained and then provided to study 
team by email. All UConn Health issued phones and fax machines are secure. If you are the 
LAR providing consent, your device may not be secure to guarantee confidentiality. All 
electronic files (e.g., emails, database, spreadsheet) containing identifiable information will be 
retained in study files which are password protected and encrypted. Any computer receiving or 
hosting such files will also have password protection. Only research staff will have access to the 
electronic files. A master list that links the code on the paper records to your name will be kept 
in electronic format.
•
The research samples will be labeled with your research code only. You cannot be identified since 
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lab researchers will not have access to the master list which contains your personal information. .
Risks Associated with Blood Draws, Nasal Swabs and Stool Collection:
•
Arrangements are made so that your study blood tube (about ¾ of tablespoon on day 3, 6 & 9) is 
taken as part of your scheduled blood draw to monitor your progress. There is a total of about two 
and half tablespoons of blood needed for this study. There can be some mild discomfort during 
the blood draw, if not done through a line you may already have. Some people develop a bruise at 
the needle site; some people report dizziness or even faint after having their blood drawn; and, 
some people develop minor infections. You may be uncomfortable temporarily while nasal swab 
is being obtained, but this is not harmful. There is no discomfort to you associated with our 
collection of a stool sample for research.
•
Safeguards Taken: If you do not have an IV to draw sample, the area where the blood drawing 
needle is to be inserted will be wiped with a disinfectant before the needle is inserted. Only sterile 
needles will be used. The puncture site will be covered with a bandage. Experienced staff draw 
your blood obtain your swab and let them know if you if you feel faint and you can be assisted. 
You may decline if you wish.
Risks related to Genetic (DNA) Testing:
•
The principal risk of genetic testing is a loss of confidentiality, with sensitive information 
concerning your genetic risk for disease becoming known. Such information, if available to you, 
could cause distress and if available to health or life insurers could adversely affect your access 
to insurance or its benefits.
•
Variation in some genes is known to be directly related to risk for certain illnesses, and other 
genes we may encounter in our study with your DNA may be shown at some point in the future, to 
be related to illness. For example, genetic research could potentially reveal that you are at risk for 
certain diseases or that you are a carrier of a genetic disorder. This could mean that you or 
members of your extended family may have an increased likelihood of developing the disorder, or 
may be carriers.
•
Safeguards Taken (related to genetic testing): To guard against these risks, confidentiality will 
be closely protected. All study information will be kept in a research record. The research record is 
separate from your medical record (EPIC). The research record is not available to insurance 
companies.
•
We will not make any of our genetic testing results available to you, nor will we add them to your 
medical record
•
If you want to know your risk for genetic diseases, we can refer you to a genetic counselor. You 
(or your insurance carrier) would be responsible for the cost of any genetic counseling.
•
While complete confidentiality of research records cannot be guaranteed 100%, we strongly 
protect our information and work constantly so that these safeguards will prevent any research 
genetic testing information that could cause you trouble in the future, from becoming known to 
anyone other than the scientists working on this study.
What Are the Benefits Of Participating In This Study?
You may benefit from UConn Health Standard Care and the medical treatment during the 9 day study. 
You may have a good response to the study medication, if received. However, it is also possible that you 
may receive no direct health benefit from being in this study and it is possible that your health may 
decline.
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Other people who have COVID-19 requiring hospitalization may benefit in the future from the 
information learned from this study. However, there is also the possibility that no benefit will come from 
conducting this study.
Benefits related to genetic testing: You will not directly benefit from genetic testing done on your coded 
blood to explore immune or other response functions of people with COVID-19. Potential societal 
benefits may include a greater understanding of the genetic basis of susceptibility to or risks from 
COVID-19.
Will I Be Compensated For Participating In This Study?
There is no compensation available for participation in this study.
How Will My Personal Information Be Protected?
•
The following procedures will be used to protect the confidentiality of your data. Information 
related to your participation in this study will be kept in a research record, separate from you 
medical records. The image of this consent form and the orders for the study drug, may be part of 
your EPIC medical record to alert your care providers.
•
The study staff (principal investigator, co-investigators, research coordinator) will keep all 
research records (including any codes to your data) in a locked cabinet in a locked room. Each 
participant will have a unique sequentially assigned 3 digit study number. All research records will 
be labeled with this study ID (eg 753-XXX) rather than your name or other personal identifier.
•
A master key that links your name and your study ID will be securely maintained (in locked file) 
during the study but will be destroyed when the study and data analysis are completed.
•
All electronic files (e.g., database, spreadsheet, etc.) containing identifiable information will be 
encrypted and only be assessable via password protected logon to prevent access by un-authorized 
users. Samples and any research data that will be shared with others outside the immediate study 
team will be coded with a study ID in place of your name to protect your identity.
•
Any research lab results will be stored in your research record and upon completion of the study, 
the link between your personal identity and research information will be destroyed.
•
We will do our best to protect the confidentiality of the information we gather from you but we 
cannot guarantee 100% confidentiality. You should know that the Department of Health and 
Human Services, the Food and Drug Administration (FDA), and UConn Health’s Institutional 
Review Board and/or Human Subjects Protection Program may inspect records. They may inspect 
records to ensure that the study is being done correctly.
•
A description of this clinical study will be available on http://ClinicalTrials.gov, as required by
U.S. Law. The web site will not include information that can identify you. Following completion 
of this study, the web site will include a summary of study results. You can search the web site at 
any time.
•
At the conclusion of this study the researchers intend to publish one or more articles on their 
findings. Information will be presented in summary format and you will not be identified in any 
publications or presentations.
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What Will Happen to the Blood, Swab and Stool Samples I Give During the Study?
Once obtained, all blood samples (biochemical, proteins, DNA, RNA or plasma or serum from blood) 
stool samples (and DNA extracted from stool) and the infectious organisms/material (RNA) from swabs 
will become the property of UConn Health.
They will be used for research laboratory testing at UConn Health related to this study and/or will be 
stored in the laboratory of Dr. Liang, for later testing. Some are also distributed to Jackson Laboratories 
and the University of Michigan researchers. Your sample will be marked with your study ID but not 
your name or any other personal identifiers.
The link between your personally identifiable information and your assigned study ID will not be shared 
with anyone outside of the UConn Health research team, assisting in conduct of this study. The samples 
processed by collaborating scientists at Jackson Laboratory may include a code to allow results to be 
included in the research records when COVID-19 related testing is done there.
Prior to closure of the study, the link between your personal identity and your samples and information 
collected from you will be destroyed so that there will be no way, not even through codes, to link the 
samples and study results back to you.
The de-identified sample materials-DNA, RNA, blood cells, serum/plasma may be kept in storage 
indefinitely or until fully utilized by the Sponsor Investigator. These de-identified samples and any 
anonymized study information in the database, from you, may potentially be shared with other researchers 
and used in other projects. If such future research is done, additional informed consent will not be sought.
Your genomic data and health information will not be labeled with or contain your name or other 
information that could be used to identify you. However, it is possible that the information from your 
genome, when combined with information from other public sources could be used to identify you, 
though we believe it is unlikely that this will happen. Any researchers approved to access information in 
the database will agree not to attempt to identify you.
What Happens to the Blood, Stool and Swab Samples if I Withdraw from the Study?
If you choose to withdraw from the study, we will retain your samples in a coded format while the study 
is open. No further research will be conducted but we will use results of any sample data obtained before 
the time we are notified of your withdrawal.
The samples will be de-identified upon completion of the study and used as described above.
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UConnHealth IRB# 20-192-2.F
Trial of Open Label Dipyridamole for COVID-19
9
Version 5; 5/26/2021
What Happens if I Withdraw from the Study or I am discharged before 9 days?
If you choose to withdraw from this study the data which has already been collected will continue to be 
used and remain in the research study database. We would like to be able to contact you in follow up if 
you are willing to continue to provide follow-up data for two days of information about status and any 
adverse events.
If you choose not to participate in the follow-up phase, your medical information or other confidential 
records will no longer be accessed for purposes of this research. However, investigators on this study may 
continue to review the study data collected prior to your withdrawal, and may consult public records, such 
as those establishing survival status.
Please indicate below whether you are willing to be contacted if discharged before Day 9 by 
the researchers in the future.
 I agree for the researchers contact me for the follow-up
 
(initials)
I do not agree for the researchers to contact me for follow up
 
(initials)
What If I Decide To Stop Participating In The Study?
You are free to stop taking part in this study at any time. If you decide to stop taking part in the study, 
your care and relationship with your doctors or the UConn Health will not be affected in any way. If you 
decide to withdraw we ask that you let us know by calling the Sponsor Investigator Dr. Liang at 860-679- 
7541.
Can Someone Else Make Me Stop Participating In This Study?
The Sponsor Investigator or Co-Investigators listed above may stop your participation in this study at any 
time, with or without your consent.
Reasons that might lead the study doctor to stop your participation in the study include:
1) if in their judgment medical, health problems should be addressed on an urgent basis including 
intensive treatment such that you are not able to express your consent to participate or 
withdraw; 2) if you experience a significant serious drug side effects, likely attributed to 
Dipyridamole; 3) there may be other reasons that are not specified here.
Will I Find Out the Results Of This Research Study?
We intend to publish results of this study shortly after we complete full analyses.
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UConnHealth IRB# 20-192-2.F
Trial of Open Label Dipyridamole for COVID-19
10
Version 5; 5/26/2021
What If I Experience An Adverse (Bad) Event or Injury Related To My Participation?
All research involves a risk that something bad might happen to you. In spite of all safety measures, you 
might develop a reaction or injury from participating in this study.
If you have an adverse event or study related injury, you should tell a Co-Investigator or Study staff or the 
Sponsor Investigator, Dr. Liang as soon as possible. You may contact Dr. Liang by calling 860-679- 
7541.
If the Sponsor Investigator determines that an injury you have experienced is possibly related to the study 
drug and requires medical intervention, you will receive care needed at UConn Health.
Financial compensation for such things as lost wages, disability or discomfort due to study drug injury is 
not offered. However, by signing this form you do not give up any of your legal rights.
UConn Health does not provide insurance coverage to compensate for injuries incurred during this 
research. However, compensation may still be available. A claim may be filed against the State of 
Connecticut seeking compensation. For a description of this process contact a representative of the UCH 
Institutional Review Board at 860-679-4849 and 860-679-8729.
UConn Health does not offer free care. However, treatment for a research related injury can be obtained 
at the UConn Health for the usual fee.
What If You Learn About Something That May Make Me Change My Mind?
We will tell you about any new information that may affect your willingness to participate. If you still 
want to participate we may ask you to sign a new consent form.
What if I Have Questions?
The Sponsor Investigator and Co-Investigators listed above and study staff are willing to answer any 
questions you have about the research. You are encouraged to ask questions before deciding whether to 
take part. You are also encouraged to ask questions during your study participation.
If you have questions, complaints or concerns about the research, you should call Dr. Liang, the Sponsor 
Investigator at 860-679-7541. If you have questions about your rights as a research subject you may 
contact the Institutional Review Board at 860-679-8729 or 860-679-4849.
You may also call the Institutional Review Board if you want to talk to someone who is not a member of 
the research team in order to pass along any suggestions, complaints, concerns or compliments about your 
involvement in the research, or to ask general questions or obtain information about participation in 
clinical research studies.
Please do not call the IRB number for medical related issues.
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UConnHealth IRB# 20-192-2.F
Trial of Open Label Dipyridamole for COVID-19
11
Version 5; 5/26/2021
Consent To Participate:
By signing this form you acknowledge that you have read, or have had read to you, this informed consent 
document, have talked with research personnel about this study, have been given the opportunity to ask 
questions and have them satisfactorily answered, and voluntarily consent to participate in this project as 
described in this form.
By signing this form the individual obtaining consent is confirming that the above information has been 
explained to the subject and that a copy of this document along with a copy of the Research Participant 
Feedback Form, will be provided to the participant The handout regarding the Genetic Information 
NonDiscrimination Act has also been provided to the subject.
Role
Printed Name
Signature
Date
Time
Subject
Legally 
Authorized 
Representative
Co-investigator
/Coordinator
Witness
(if telephonic)
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