COVID-19 Pneumonia, Vascular Complications
Conditions
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.
Interventions
DRUGPlacebo
Daily dose while hospitalized up to 9 days
DRUGDipyridamole Tablets
Daily dose while hospitalized up to 9 days
Sponsors
UConn Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Randomized Open Label Study Standard Care vs. Standard Care with Dipyridamole
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
*
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| D-dimer | up to 9 days | Percent Change from Baseline \[Day Zero\] to last study measure (Day 3, Day 6 or Day 9) |
| Platelet Count | up to 9 days | Percent Change from Baseline \[Day Zero\] to last study measure (Day 3, Day 6 or Day 9) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Viral Detection | 9 days | Evaluate for a non-detection from nasopharyngeal swab and in stool |
Other
| Measure | Time frame | Description |
|---|---|---|
| PT PTT | 9 days | Coagulation System |
| Survival | 9 days | Survival Status Alive |
| Clinical Status | 9 days | Change in fever, cough, sputum |
| Pulmonary Status | 9 days | Change in SpO2/ imaging |
| Inflammatory Markers | 9 days | Change in the markers CRP/Ferritin |
| Blood Markers | 9 days | Change in Lymphocyte Count/ Fibrinogen/Cardiac Troponin |
Countries
United States
Participant flow
Recruitment details
Recruitment from Acute Care University Hospital Units May 2020 to March 2022
Pre-assignment details
At Consent, subjects are randomized to Placebo or Dipyridamole group.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 21 |
| 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.
Dipyridamole: Dipyridamole-100mg taken 3 times a day by mouth for 7 days. | 20 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | patients were discharged prior to Hospital Day 9 | 17 | 16 |
Baseline characteristics
| Characteristic | Standard Care | Standard Care With Dipyridamole | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 4 Participants | 11 Participants |
| Age, Categorical Between 18 and 65 years | 14 Participants | 16 Participants | 30 Participants |
| Age, Continuous | 59.62 years STANDARD_DEVIATION 14.06 | 60.75 years STANDARD_DEVIATION 13.89 | 60.17 years STANDARD_DEVIATION 13.81 |
| COVID-19 -moderate or severe | 21 Participants | 20 Participants | 41 Participants |
| Race/Ethnicity, Customized Race Asian | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Black/African American | 1 Participants | 4 Participants | 5 Participants |
| Race/Ethnicity, Customized Race Hispanic/Latino | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Race Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 18 Participants | 12 Participants | 30 Participants |
| Sex: Female, Male Female | 6 Participants | 10 Participants | 16 Participants |
| Sex: Female, Male Male | 15 Participants | 10 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 21 | 2 / 20 |
| other Total, other adverse events | 9 / 21 | 8 / 20 |
| serious Total, serious adverse events | 5 / 21 | 7 / 20 |
Outcome results
Primary
D-dimer
Percent Change from Baseline \[Day Zero\] to last study measure (Day 3, Day 6 or Day 9)
Time frame: up to 9 days
Population: Percent Change from Baseline
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard Care | D-dimer | 2.99 Percent Change of D-Dimer (ng/mL) |
| Standard Care With Dipyridamole | D-dimer | -10.09 Percent Change of D-Dimer (ng/mL) |
Primary
Platelet Count
Percent Change from Baseline \[Day Zero\] to last study measure (Day 3, Day 6 or Day 9)
Time frame: up to 9 days
Population: Percent Change (%) from Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Care | Platelet Count | 27.45 Percent Change of 10^3 Platelets/uL | Standard Deviation 34.94 |
| Standard Care With Dipyridamole | Platelet Count | 35.48 Percent Change of 10^3 Platelets/uL | Standard Deviation 37.52 |
Secondary
Viral Detection
Evaluate for a non-detection from nasopharyngeal swab and in stool
Time frame: 9 days
Other Pre-specified
Blood Markers
Change in Lymphocyte Count/ Fibrinogen/Cardiac Troponin
Time frame: 9 days
Other Pre-specified
Clinical Status
Change in fever, cough, sputum
Time frame: 9 days
Other Pre-specified
Inflammatory Markers
Change in the markers CRP/Ferritin
Time frame: 9 days
Other Pre-specified
PT PTT
Coagulation System
Time frame: 9 days
Other Pre-specified
Pulmonary Status
Change in SpO2/ imaging
Time frame: 9 days
Other Pre-specified
Survival
Survival Status Alive
Time frame: 9 days