Dipyridamole to Prevent Coronavirus Exacerbation of Respiratory Status (DICER) in COVID-19

Sponsor
University of Michigan (Other)
Overall Status
Completed
CT.gov ID
NCT04391179
Collaborator
(none)
99
Enrollment
1
Location
2
Arms
8.8
Actual Duration (Months)
11.3
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or DiseaseIntervention/TreatmentPhase
  • Drug: Dipyridamole 100 Milligram(mg)
  • Drug: Placebo oral tablet
Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
99 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Participant)
Primary Purpose:
Treatment
Official Title:
Dipyridamole to Prevent Coronavirus Exacerbation of Respiratory Status (DICER) in COVID-19
Actual Study Start Date :
May 31, 2020
Actual Primary Completion Date :
Feb 22, 2021
Actual Study Completion Date :
Feb 22, 2021

Arms and Interventions

ArmIntervention/Treatment
Experimental: Dipyridamole 100 Milligram(mg)

100 milligrams (mg) by mouth (PO) four times a day (QID)

Drug: Dipyridamole 100 Milligram(mg)
Drug will be given for 14 days while in the hospital.

Placebo Comparator: Placebo

Placebo given by mouth four times a day

Drug: Placebo oral tablet
Placebo will be given for 14 days while in the hospital.

Outcome Measures

Primary Outcome Measures

  1. 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

  2. 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 death days on mechanical ventilation dichotomized (yes/no) decrease in daily average SpO2/FiO2 of at least 50 units relative to day 1 at anytime during the observation period 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 Outcome Measures

  1. 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.

  2. Individual Component of Composite Endpoint- Death [up to approximately 30 days after hospital discharge]

    Death of any cause during duration of study participation

  3. 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.

  4. 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.

  5. 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.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts 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

Contacts and Locations

Locations

SiteCityStateCountryPostal Code
1University of MichiganAnn ArborMichiganUnited States48109

Sponsors and Collaborators

  • University of Michigan

Investigators

  • Principal Investigator: Jason Knight, MD, PhD, University of Michigan

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Jason Scott Knight, Associate Professor of Internal Medicine, University of Michigan
ClinicalTrials.gov Identifier:
NCT04391179
Other Study ID Numbers:
  • HUM00179783
First Posted:
May 18, 2020
Last Update Posted:
Mar 24, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Jason Scott Knight, Associate Professor of Internal Medicine, University of Michigan
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment DetailsBetween May 2020 and January 2021, 99 eligible participants received at least one dose of study drug and were included in the analysis.
Pre-assignment Detail
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Period Title: Overall Study
STARTED4950
COMPLETED3434
NOT COMPLETED1516

Baseline Characteristics

Arm/Group TitleDipyridamole 100 Milligram(mg)PlaceboTotal
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.Total of all reporting groups
Overall Participants495099
Age (Count of Participants)
<=18 years
0
0%
0
0%
0
0%
Between 18 and 65 years
31
63.3%
29
58%
60
60.6%
>=65 years
18
36.7%
21
42%
39
39.4%
Sex: Female, Male (Count of Participants)
Female
16
32.7%
17
34%
33
33.3%
Male
33
67.3%
33
66%
66
66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
1
2%
1
1%
Not Hispanic or Latino
46
93.9%
48
96%
94
94.9%
Unknown or Not Reported
3
6.1%
1
2%
4
4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
0
0%
Asian
2
4.1%
3
6%
5
5.1%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
Black or African American
2
4.1%
4
8%
6
6.1%
White
45
91.8%
42
84%
87
87.9%
More than one race
0
0%
1
2%
1
1%
Unknown or Not Reported
0
0%
0
0%
0
0%
D-Dimer (mg/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/L]
1.06
(.80)
1.24
(1.46)
1.15
(1.18)
Oxygen Saturation (SpO2)/Fraction of Inspired Oxygen (FiO2) (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]
308
(70)
310
(72)
309
(71)

Outcome Measures

1. Primary Outcome
TitlePercent Change in D-dimer
Descriptionaverage percent daily change in plasma D-dimer levels compared to baseline
Time Framebaseline, up to approximately 14 days after last study drug administration

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4950
Mean (97.8% Confidence Interval) [percent daily change]
-5.6
-2.4
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.24
Comments
MethodMixed Models Analysis
Comments
Method of EstimationEstimation ParameterSlope
Estimated Value-.033
Confidence Interval (2-Sided) 95%
-.089 to .023
Parameter Dispersion Type: Standard Error of the Mean
Value: .027
Estimation CommentsEstimation represents log-scale difference between average daily change in D-Dimer for Dipyridamole patients minus placebo average daily change. Negative estimates indicate that D-Dimer levels decline faster in Dipyridamole versus placebo patients.
2. Primary Outcome
TitleNumber of Participants With Wins at Each Level of a Hierarchical Composite Rank Score
DescriptionCompare each dipyridamole patient head to head against each placebo patient using a hierarchical composite rank score death days on mechanical ventilation dichotomized (yes/no) decrease in daily average SpO2/FiO2 of at least 50 units relative to day 1 at anytime during the observation period 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 Frameup to approximately 30 days after hospital discharge

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4950
Composite endpoint- death
0
0%
3
6%
Composite endpoint- mechanical ventilation during hospitalization
3
6.1%
4
8%
Composite endpoint- 50+ unit drop SpO2/FiO2
13
26.5%
11
22%
Composite endpoint- remaining (ties among patients evaluated by ordinal score)
33
67.3%
32
64%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments 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.
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value.98
Comments
MethodMantel Haenszel
Comments
Method of EstimationEstimation Parameterwin ratio
Estimated Value1.00
Confidence Interval (2-Sided) 97.8%
0.78 to 1.29
Parameter Dispersion Type:
Value:
Estimation Commentswin ratio= (the probability of a win for the dipyridamole patient)/(probability of a win for the placebo patient)
3. Secondary Outcome
TitleDays Alive and Free of Organ Support
DescriptionOrgan support is defined as receipt of invasive mechanical ventilation, vasopressor therapy, ECMO support, or dialysis.
Time Frameup to approximately 28 days after last study drug administration score

Outcome Measure Data

Analysis Population Description
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/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4448
Median (Inter-Quartile Range) [days]
28
28
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value.08
Comments
MethodWilcoxon (Mann-Whitney)
Comments
4. Secondary Outcome
TitleIndividual Component of Composite Endpoint- Death
DescriptionDeath of any cause during duration of study participation
Time Frameup to approximately 30 days after hospital discharge

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4950
Count of Participants [Participants]
0
0%
3
6%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value.09
Comments
MethodLog Rank
Comments
5. Secondary Outcome
TitleIndividual Component of Composite Endpoint- Days on Mechanical Ventilation
DescriptionThe number of days spent on invasive mechanical ventilation during study hospitalization.
Time Frameup to 14 days after study drug administration

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4950
Mean (Standard Deviation) [days]
0.33
(1.36)
0.88
(2.74)
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value0.36
Comments
Methodregression, negative binomial
Comments
Method of EstimationEstimation ParameterMean Difference (Net)
Estimated Value0.29
Confidence Interval (2-Sided) 95%
0.02 to 3.94
Parameter Dispersion Type:
Value:
Estimation Commentsestimated ratio of days on mechanical ventilation for dipyridamole and placebo
6. Secondary Outcome
TitleIndividual Component of Composite Endpoint- Sp02/Fi02 (as Shown by Participant Count)
DescriptionBinary outcome indicating patients whose Sp02/Fi02 dropped 50 points relative to baseline at any time during hospitalization.
Time Frameup to 14 days after study drug administration

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4950
Count of Participants [Participants]
14
28.6%
14
28%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value.94
Comments
MethodRegression, Logistic
Comments
Method of EstimationEstimation ParameterOdds Ratio (OR)
Estimated Value1.04
Confidence Interval (2-Sided) 95%
0.43 to 2.51
Parameter Dispersion Type:
Value:
Estimation CommentsOdds of a 50 point drop in the dipyridamole group relative to the placebo group.
7. Secondary Outcome
TitleIndividual Component of Composite Endpoint- Cumulative Ordinal Score
DescriptionCumulative 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 FrameHospitalization up to 14 days after study drug administration

Outcome Measure Data

Analysis Population Description
excluded patients that died or withdrew from the study
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants4448
Median (Inter-Quartile Range) [score on a scale * days]
14.3
15.0
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Dipyridamole 100 Milligram(mg), Placebo
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesisp-Value.95
Comments
MethodWilcoxon (Mann-Whitney)
Comments

Adverse Events

Time FrameThe collection period for adverse events began after informed consent and ended 30 days after administration of the last dose of study drug.
Adverse Event Reporting Description
Arm/Group TitleDipyridamole 100 Milligram(mg)Placebo
Arm/Group Description100 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.Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
All Cause Mortality
Dipyridamole 100 Milligram(mg)Placebo
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total0/49 (0%) 3/50 (6%)
Serious Adverse Events
Dipyridamole 100 Milligram(mg)Placebo
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total14/49 (28.6%) 30/50 (60%)
Cardiac disorders
Atrial Fibrillation0/49 (0%) 1/50 (2%)
Heart failure1/49 (2%) 0/50 (0%)
Cardiac Arrest0/49 (0%) 1/50 (2%)
Myocardial infarction0/49 (0%) 1/50 (2%)
Paroxysmal artrial tachycardia0/49 (0%) 1/50 (2%)
Stroke0/49 (0%) 1/50 (2%)
Musculoskeletal and connective tissue disorders
Pneumothorax0/49 (0%) 1/50 (2%)
Psychiatric disorders
Delirium1/49 (2%) 0/50 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure7/49 (14.3%) 14/50 (28%)
Lung infection2/49 (4.1%) 7/50 (14%)
Pulmonary edema1/49 (2%) 0/50 (0%)
Vascular disorders
Hypotension1/49 (2%) 2/50 (4%)
Thromboembolic event1/49 (2%) 1/50 (2%)
Other (Not Including Serious) Adverse Events
Dipyridamole 100 Milligram(mg)Placebo
Affected / at Risk (%)# EventsAffected / at Risk (%)# Events
Total43/49 (87.8%) 15/50 (30%)
Blood and lymphatic system disorders
Thrombocytopenia0/49 (0%) 1/50 (2%)
Cardiac disorders
Bradycardia0/49 (0%) 1/50 (2%)
Heart failure0/49 (0%) 1/50 (2%)
Ventricular arrhythmia0/49 (0%) 1/50 (2%)
Electrocardiogram QT corrected interval prolonged0/49 (0%) 1/50 (2%)
Palpitations1/49 (2%) 0/50 (0%)
Gastrointestinal disorders
Diarrhea1/49 (2%) 0/50 (0%)
Emesis1/49 (2%) 0/50 (0%)
Aspartate aminotransferase increased0/49 (0%) 1/50 (2%)
General disorders
Delirium2/49 (4.1%) 1/50 (2%)
Abdominal pain2/49 (4.1%) 0/50 (0%)
Body pain0/49 (0%) 1/50 (2%)
Fall0/49 (0%) 1/50 (2%)
Non-cardiac chest pain1/49 (2%) 0/50 (0%)
Diaphoresis1/49 (2%) 0/50 (0%)
Tremor1/49 (2%) 0/50 (0%)
Musculoskeletal and connective tissue disorders
Back pain3/49 (6.1%) 0/50 (0%)
Neck pain1/49 (2%) 0/50 (0%)
Ankle pain1/49 (2%) 0/50 (0%)
Nervous system disorders
Headache17/49 (34.7%) 3/50 (6%)
Paresthesia1/49 (2%) 1/50 (2%)
Psychiatric disorders
Anxiety2/49 (4.1%) 0/50 (0%)
Renal and urinary disorders
Edema limbs0/49 (0%) 1/50 (2%)
Acute kidney injury1/49 (2%) 0/50 (0%)
Kidney infection1/49 (2%) 0/50 (0%)
Atypical urothelial cells in urine1/49 (2%) 0/50 (0%)
Incontinence1/49 (2%) 0/50 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular1/49 (2%) 0/50 (0%)
Vascular disorders
Epistaxis2/49 (4.1%) 0/50 (0%)
Vaginal hemorrhage0/49 (0%) 1/50 (2%)
Hypotension1/49 (2%) 0/50 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/TitleJason Knight, MD, PhD
OrganizationUniversity of Michigan
Phone734-763-3031
Emailjsknight@med.umich.edu
Responsible Party:
Jason Scott Knight, Associate Professor of Internal Medicine, University of Michigan
ClinicalTrials.gov Identifier:
NCT04391179
Other Study ID Numbers:
  • HUM00179783
First Posted:
May 18, 2020
Last Update Posted:
Mar 24, 2022
Last Verified:
Mar 1, 2022