Corona Virus Infection, COVID, Covid-19, SARS-CoV-2 Infection
Conditions
Keywords
Oxygen
Brief summary
The most severe manifestations of COVID-19 include respiratory failure, coagulation problems, and death. Inflammation and blood clotting are believed to play an important role in these manifestations. Research in humans has shown that dipyridamole can reduce blood clotting. This research study is being conducted to learn whether 14 days of treatment with dipyridamole will reduce excessive blood clotting in COVID-19. This study will enroll participants with confirmed coronavirus (SARS-CoV)-2 infection that are admitted. Eligible participants will be randomized to receive dipyridamole or placebo for 14 days in the hospital. In addition, data will be collected from the medical record, and there will also be blood draws during the hospitalization.
Interventions
DRUGDipyridamole 100 Milligram(mg)
Drug will be given for 14 days while in the hospital.
DRUGPlacebo oral tablet
Placebo will be given for 14 days while in the hospital.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Willing and able to provide informed consent prior to performing study procedures unless they have a legally authorized representative (LAR) * Confirmed coronavirus (SARS-CoV-2) infection * Currently hospitalized or anticipated hospitalization requiring supplemental oxygen
Exclusion criteria
* In the opinion of at least two investigators, unlikely to survive for \>48 hours from screening * Concurrent enrollment in a clinical trial with a cytokine inhibitor (targeting interleukin-6 (IL-6), Interleukin-6 Receptor (IL-6R), IL-1, or Janus kinase). Use of remdesivir is permitted. * Currently on invasive mechanical ventilation. * Hypotension defined as systolic blood pressure \< 90 mmHg on two sequential readings at least 4 hours apart * Pregnant or breastfeeding * Concurrent dual antithrombotic therapy (aspirin or P2Y12 inhibitor plus anticoagulation to treat deep venous thrombosis or pulmonary embolism (single antiplatelet or anticoagulant agent at prophylaxis or therapeutic dose is permitted) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5 times upper limit of normal, hemoglobin \< 8 grams per deciliter (g/dL), or platelets \<50,000 per cubic millimeter (mm3) * History of recent major bleeding, defined in accordance with the criteria of the International Society on Thrombosis and Hemostasis (ISTH). * Any physical examination findings and/or history of any illness that, in the opinion of the study investigator, might confound the results of the study or pose an additional risk to the patient by their participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in D-dimer | baseline, up to approximately 14 days after last study drug administration | average percent daily change in plasma D-dimer levels compared to baseline |
| Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | up to approximately 30 days after hospital discharge | Compare each dipyridamole patient head to head against each placebo patient using a hierarchical composite rank score 1. death 2. days on mechanical ventilation 3. dichotomized (yes/no) decrease in daily average SpO2/FiO2 of at least 50 units relative to day 1 at anytime during the observation period 4. cumulative sum of COVID ordinal score during study hospitalization. Ordinal scores could range 1-8. Levels 1 and 2 imply no hospitalization and 8 is the worst possible score (death); by definition, the subjects in the DICER study were hospitalized during the time period in which the study observed their ordinal scores. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Individual Component of Composite Endpoint- Days on Mechanical Ventilation | up to 14 days after study drug administration | The number of days spent on invasive mechanical ventilation during study hospitalization. |
| Days Alive and Free of Organ Support | up to approximately 28 days after last study drug administration score | Organ support is defined as receipt of invasive mechanical ventilation, vasopressor therapy, ECMO support, or dialysis. |
| Individual Component of Composite Endpoint- Cumulative Ordinal Score | Hospitalization up to 14 days after study drug administration | Cumulative sum of WHO Ordinal Scale for Clinical Improvement scores during hospitalization or through 14 days after study drug administration, whichever occurs first. The WHO Ordinal Scale ranges from 1 (no limitation of activities) through 8 (death). By definition, hospitalized patients score 3 or higher on the scale. The equation can be written: Cumulative Ordinal Score = (days in hospital up to 14) x (average ordinal score during hospitalization). Higher scores represent a combination of worse outcomes and longer hospitalizations. |
| Individual Component of Composite Endpoint- Sp02/Fi02 (as Shown by Participant Count) | up to 14 days after study drug administration | Binary outcome indicating patients whose Sp02/Fi02 dropped 50 points relative to baseline at any time during hospitalization. |
| Individual Component of Composite Endpoint- Death | up to approximately 30 days after hospital discharge | Death of any cause during duration of study participation |
Countries
United States
Participant flow
Recruitment details
Between May 2020 and January 2021, 99 eligible participants received at least one dose of study drug and were included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| Dipyridamole 100 Milligram(mg) 100 milligrams (mg) by mouth (PO) four times a day (QID)
Dipyridamole 100 Milligram(mg): Drug will be given for 14 days while in the hospital. | 49 |
| Placebo Placebo given by mouth four times a day
Placebo oral tablet: Placebo will be given for 14 days while in the hospital. | 50 |
| Total | 99 |
Baseline characteristics
| Characteristic | Placebo | Dipyridamole 100 Milligram(mg) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 18 Participants | 39 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 31 Participants | 60 Participants |
| D-Dimer | 1.24 mg/L STANDARD_DEVIATION 1.46 | 1.06 mg/L STANDARD_DEVIATION 0.8 | 1.15 mg/L STANDARD_DEVIATION 1.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 46 Participants | 94 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 4 Participants |
| Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) | 310 ratio STANDARD_DEVIATION 72 | 308 ratio STANDARD_DEVIATION 70 | 309 ratio STANDARD_DEVIATION 71 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 2 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 42 Participants | 45 Participants | 87 Participants |
| Sex: Female, Male Female | 17 Participants | 16 Participants | 33 Participants |
| Sex: Female, Male Male | 33 Participants | 33 Participants | 66 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 49 | 3 / 50 |
| other Total, other adverse events | 43 / 49 | 15 / 50 |
| serious Total, serious adverse events | 14 / 49 | 30 / 50 |
Outcome results
Primary
Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score
Compare each dipyridamole patient head to head against each placebo patient using a hierarchical composite rank score 1. death 2. days on mechanical ventilation 3. dichotomized (yes/no) decrease in daily average SpO2/FiO2 of at least 50 units relative to day 1 at anytime during the observation period 4. cumulative sum of COVID ordinal score during study hospitalization. Ordinal scores could range 1-8. Levels 1 and 2 imply no hospitalization and 8 is the worst possible score (death); by definition, the subjects in the DICER study were hospitalized during the time period in which the study observed their ordinal scores.
Time frame: up to approximately 30 days after hospital discharge
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dipyridamole 100 Milligram(mg) | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- mechanical ventilation during hospitalization | 3 Participants |
| Dipyridamole 100 Milligram(mg) | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- 50+ unit drop SpO2/FiO2 | 13 Participants |
| Dipyridamole 100 Milligram(mg) | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- remaining (ties among patients evaluated by ordinal score) | 33 Participants |
| Dipyridamole 100 Milligram(mg) | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- death | 0 Participants |
| Placebo | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- remaining (ties among patients evaluated by ordinal score) | 32 Participants |
| Placebo | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- mechanical ventilation during hospitalization | 4 Participants |
| Placebo | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- 50+ unit drop SpO2/FiO2 | 11 Participants |
| Placebo | Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score | Composite endpoint- death | 3 Participants |
Comparison: A win ratio analysis of the hierarchical composite outcome requiring direct comparison of outcomes between each dipyridamole patient and placebo patient. The patient with the superior outcome is adjudicated the 'winner' and receives a +1 score, while the 'loser' scores -1.p-value: 0.9897.8% CI: [0.78, 1.29]Mantel Haenszel
Primary
Percent Change in D-dimer
average percent daily change in plasma D-dimer levels compared to baseline
Time frame: baseline, up to approximately 14 days after last study drug administration
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Dipyridamole 100 Milligram(mg) | Percent Change in D-dimer | -5.6 percent daily change |
| Placebo | Percent Change in D-dimer | -2.4 percent daily change |
p-value: 0.2495% CI: [-0.089, 0.023]Mixed Models Analysis
Secondary
Days Alive and Free of Organ Support
Organ support is defined as receipt of invasive mechanical ventilation, vasopressor therapy, ECMO support, or dialysis.
Time frame: up to approximately 28 days after last study drug administration score
Population: 5 participants on dipyridamole and 2 participants on placebo were excluded from this analysis because of their early withdrawal from the study (prior to 28 days after last study drug administration).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dipyridamole 100 Milligram(mg) | Days Alive and Free of Organ Support | 28 days |
| Placebo | Days Alive and Free of Organ Support | 28 days |
p-value: 0.08Wilcoxon (Mann-Whitney)
Secondary
Individual Component of Composite Endpoint- Cumulative Ordinal Score
Cumulative sum of WHO Ordinal Scale for Clinical Improvement scores during hospitalization or through 14 days after study drug administration, whichever occurs first. The WHO Ordinal Scale ranges from 1 (no limitation of activities) through 8 (death). By definition, hospitalized patients score 3 or higher on the scale. The equation can be written: Cumulative Ordinal Score = (days in hospital up to 14) x (average ordinal score during hospitalization). Higher scores represent a combination of worse outcomes and longer hospitalizations.
Time frame: Hospitalization up to 14 days after study drug administration
Population: excluded patients that died or withdrew from the study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dipyridamole 100 Milligram(mg) | Individual Component of Composite Endpoint- Cumulative Ordinal Score | 14.3 score on a scale * days |
| Placebo | Individual Component of Composite Endpoint- Cumulative Ordinal Score | 15.0 score on a scale * days |
p-value: 0.95Wilcoxon (Mann-Whitney)
Secondary
Individual Component of Composite Endpoint- Days on Mechanical Ventilation
The number of days spent on invasive mechanical ventilation during study hospitalization.
Time frame: up to 14 days after study drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dipyridamole 100 Milligram(mg) | Individual Component of Composite Endpoint- Days on Mechanical Ventilation | 0.33 days | Standard Deviation 1.36 |
| Placebo | Individual Component of Composite Endpoint- Days on Mechanical Ventilation | 0.88 days | Standard Deviation 2.74 |
p-value: 0.3695% CI: [0.02, 3.94]regression, negative binomial
Secondary
Individual Component of Composite Endpoint- Death
Death of any cause during duration of study participation
Time frame: up to approximately 30 days after hospital discharge
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dipyridamole 100 Milligram(mg) | Individual Component of Composite Endpoint- Death | 0 Participants |
| Placebo | Individual Component of Composite Endpoint- Death | 3 Participants |
p-value: 0.09Log Rank
Secondary
Individual Component of Composite Endpoint- Sp02/Fi02 (as Shown by Participant Count)
Binary outcome indicating patients whose Sp02/Fi02 dropped 50 points relative to baseline at any time during hospitalization.
Time frame: up to 14 days after study drug administration
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dipyridamole 100 Milligram(mg) | Individual Component of Composite Endpoint- Sp02/Fi02 (as Shown by Participant Count) | 14 Participants |
| Placebo | Individual Component of Composite Endpoint- Sp02/Fi02 (as Shown by Participant Count) | 14 Participants |
p-value: 0.9495% CI: [0.43, 2.51]Regression, Logistic