Trial of Open Label Dipyridamole- In Hospitalized Patients With COVID-19 (TOLD)

A Randomized, Open-label Study of the Vascular and Microbiologic Efficacy of Dipyridamole Plus Standard Care vs. Standard Care in Hospitalized COVID19 Patients

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

Study Overview

• Status: Terminated
• Conditions: COVID-19 Pneumonia; Vascular Complications
• Intervention / Treatment: Drug: Placebo; Drug: Dipyridamole Tablets

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.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sheila Thurlow, RN; Phone Number: 860-679-4637; Email: thurlow@uchc.edu
• Study Contact Backup: Name: Elizabeth Laska, RN; Phone Number: 860-679-1707; Email: laska@uchc.edu

Study Locations

• United States
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • UConn Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults ≥18 years of age.

2. COVID-19 positive by PCR and hospitalized for 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

   • No clinical signs indicative of Severe or Critical Illness Severity

   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

   • No criteria for Critical Severity

   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:

     • Respiratory failure defined based on resource utilization requiring at least 1 of the following:

       ◙, 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, 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)

     • Shock (defined by SBP < 90 mm Hg, or Diastolic BP < 60 mm Hg or requiring vasopressors)
     • Multiple organ dysfunction/failure

3. Able to give written informed consent in English to participate in the study by patient.

   -

Exclusion Criteria:

• Exclusion Criteria:

  1. Inability to swallow or ingest oral medication in either tablet form or in suspension form.
  2. Patient is known to be pregnant
  3. Patients with a history of allergy or hypersensitivity to dipyridamole
  4. Patient is unable to consent -intubated, on mechanical ventilation
  5. Bleeding disorders (e.g. thrombocytopenia with platelet counts < 50,000)

  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.

     Metastatic cancer as well as those with severe coronary artery disease, unstable angina, STEMI, NSTEMI, hypotension (systolic blood pressure <90mmHg), myocarditis, bradycardia with resting heart rate less than 60 bpm, atrioventricular block without pacemaker.

     Those with myasthenia gravis and those treated with cholinesterase inhibitors

  7. Patient is enrolled in a clinical trial for another investigational drug designed to test for efficacy for SARS-CoV-2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Standard Care with Dipyridamole; 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.	Drug: Dipyridamole Tablets; Daily dose while hospitalized up to 9 days; Other Names: Persantine
Placebo Comparator: Standard Care; 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.	Drug: Placebo; Daily dose while hospitalized up to 9 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
D-dimer	Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)	up to 9 days
Platelet Count	Percent Change from Baseline [Day Zero] to last study measure (Day 3, Day 6 or Day 9)	up to 9 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Viral Detection	Evaluate for a non-detection from nasopharyngeal swab and in stool	9 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Survival	Survival Status Alive	9 days
Inflammatory Markers	Change in the markers CRP/Ferritin	9 days
Blood Markers	Change in Lymphocyte Count/ Fibrinogen/Cardiac Troponin	9 days
Pulmonary Status	Change in SpO2/ imaging	9 days
Clinical Status	Change in fever, cough, sputum	9 days
PT PTT	Coagulation System	9 days

Collaborators and Investigators

• Sponsor: UConn Health

Study record dates

Study Major Dates

• Study Start (Actual): May 3, 2020
• Primary Completion (Actual): March 22, 2022
• Study Completion (Actual): April 24, 2022

Study Registration Dates

• First Submitted: May 29, 2020
• First Submitted That Met QC Criteria: June 8, 2020
• First Posted (Actual): June 11, 2020

Study Record Updates

• Last Update Posted (Actual): April 21, 2023
• Last Update Submitted That Met QC Criteria: April 20, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Phosphodiesterase Inhibitors; Dipyridamole
• Other Study ID Numbers: 20-192-2.F

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No