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)
• Enrollment: 99
• Location: 1
• Arms: 2
• Actual Duration (Months): 8.8
• Patients Per Site Per Month: 11.3

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 Disease	Intervention/Treatment	Phase
COVID; Corona Virus Infection; Covid-19; SARS-CoV-2 Infection	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

Arm	Intervention/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

	Site	City	State	Country	Postal Code
1	University of Michigan	Ann Arbor	Michigan	United States	48109

Sponsors and Collaborators

• University of Michigan

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Jul 12, 2021
• Statistical Analysis Plan - Feb 3, 2022

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: Oxygen
• Additional relevant MeSH terms: Infections; Communicable Diseases; COVID-19; Coronavirus Infections; Dipyridamole

Study Results

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.

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	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
STARTED	49	50
COMPLETED	34	34
NOT COMPLETED	15	16

Baseline Characteristics

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo	Total
Arm/Group Description	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.	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 Participants	49	50	99
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

Title	Percent Change in D-dimer
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	49	50
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 Hypothesis	p-Value	0.24
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Slope
	Estimated Value	-.033
	Confidence Interval	(2-Sided) 95%; -.089 to .023
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .027
	Estimation Comments	Estimation 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

Title	Number of Participants With Wins at Each Level of a Hierarchical Composite Rank Score
Description	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.
Time Frame	up to approximately 30 days after hospital discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	49	50
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 Hypothesis	p-Value	.98
	Comments
	Method	Mantel Haenszel
	Comments
Method of Estimation	Estimation Parameter	win ratio
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 97.8%; 0.78 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments	win ratio= (the probability of a win for the dipyridamole patient)/(probability of a win for the placebo patient)

3. Secondary Outcome

Title	Days Alive and Free of Organ Support
Description	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

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 Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	44	48
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 Hypothesis	p-Value	.08
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. Secondary Outcome

Title	Individual Component of Composite Endpoint- Death
Description	Death of any cause during duration of study participation
Time Frame	up to approximately 30 days after hospital discharge

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	49	50
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 Hypothesis	p-Value	.09
	Comments
	Method	Log Rank
	Comments

5. Secondary Outcome

Title	Individual Component of Composite Endpoint- Days on Mechanical Ventilation
Description	The number of days spent on invasive mechanical ventilation during study hospitalization.
Time Frame	up to 14 days after study drug administration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	49	50
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 Hypothesis	p-Value	0.36
	Comments
	Method	regression, negative binomial
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.29
	Confidence Interval	(2-Sided) 95%; 0.02 to 3.94
	Parameter Dispersion	Type: Value:
	Estimation Comments	estimated ratio of days on mechanical ventilation for dipyridamole and placebo

6. Secondary Outcome

Title	Individual Component of Composite Endpoint- Sp02/Fi02 (as Shown by Participant Count)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	49	50
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 Hypothesis	p-Value	.94
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.43 to 2.51
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds of a 50 point drop in the dipyridamole group relative to the placebo group.

7. Secondary Outcome

Title	Individual Component of Composite Endpoint- Cumulative Ordinal Score
Description	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

Outcome Measure Data

Analysis Population Description

excluded patients that died or withdrew from the study

Arm/Group Title	Dipyridamole 100 Milligram(mg)	Placebo
Arm/Group Description	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.	Placebo given by mouth four times a day Placebo oral tablet: Placebo will be given for 14 days while in the hospital.
Measure Participants	44	48
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 Hypothesis	p-Value	.95
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	The collection period for adverse events began after informed consent and ended 30 days after administration of the last dose of study drug.
Arm/Group Title	Dipyridamole 100 Milligram(mg)		Placebo
Arm/Group Description	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.		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 (%)	# Events	Affected / at Risk (%)	# Events
Total	0/49 (0%)		3/50 (6%)
Serious Adverse Events
	Dipyridamole 100 Milligram(mg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/49 (28.6%)		30/50 (60%)
Cardiac disorders
Atrial Fibrillation	0/49 (0%)		1/50 (2%)
Heart failure	1/49 (2%)		0/50 (0%)
Cardiac Arrest	0/49 (0%)		1/50 (2%)
Myocardial infarction	0/49 (0%)		1/50 (2%)
Paroxysmal artrial tachycardia	0/49 (0%)		1/50 (2%)
Stroke	0/49 (0%)		1/50 (2%)
Musculoskeletal and connective tissue disorders
Pneumothorax	0/49 (0%)		1/50 (2%)
Psychiatric disorders
Delirium	1/49 (2%)		0/50 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory failure	7/49 (14.3%)		14/50 (28%)
Lung infection	2/49 (4.1%)		7/50 (14%)
Pulmonary edema	1/49 (2%)		0/50 (0%)
Vascular disorders
Hypotension	1/49 (2%)		2/50 (4%)
Thromboembolic event	1/49 (2%)		1/50 (2%)
Other (Not Including Serious) Adverse Events
	Dipyridamole 100 Milligram(mg)		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	43/49 (87.8%)		15/50 (30%)
Blood and lymphatic system disorders
Thrombocytopenia	0/49 (0%)		1/50 (2%)
Cardiac disorders
Bradycardia	0/49 (0%)		1/50 (2%)
Heart failure	0/49 (0%)		1/50 (2%)
Ventricular arrhythmia	0/49 (0%)		1/50 (2%)
Electrocardiogram QT corrected interval prolonged	0/49 (0%)		1/50 (2%)
Palpitations	1/49 (2%)		0/50 (0%)
Gastrointestinal disorders
Diarrhea	1/49 (2%)		0/50 (0%)
Emesis	1/49 (2%)		0/50 (0%)
Aspartate aminotransferase increased	0/49 (0%)		1/50 (2%)
General disorders
Delirium	2/49 (4.1%)		1/50 (2%)
Abdominal pain	2/49 (4.1%)		0/50 (0%)
Body pain	0/49 (0%)		1/50 (2%)
Fall	0/49 (0%)		1/50 (2%)
Non-cardiac chest pain	1/49 (2%)		0/50 (0%)
Diaphoresis	1/49 (2%)		0/50 (0%)
Tremor	1/49 (2%)		0/50 (0%)
Musculoskeletal and connective tissue disorders
Back pain	3/49 (6.1%)		0/50 (0%)
Neck pain	1/49 (2%)		0/50 (0%)
Ankle pain	1/49 (2%)		0/50 (0%)
Nervous system disorders
Headache	17/49 (34.7%)		3/50 (6%)
Paresthesia	1/49 (2%)		1/50 (2%)
Psychiatric disorders
Anxiety	2/49 (4.1%)		0/50 (0%)
Renal and urinary disorders
Edema limbs	0/49 (0%)		1/50 (2%)
Acute kidney injury	1/49 (2%)		0/50 (0%)
Kidney infection	1/49 (2%)		0/50 (0%)
Atypical urothelial cells in urine	1/49 (2%)		0/50 (0%)
Incontinence	1/49 (2%)		0/50 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/49 (2%)		0/50 (0%)
Vascular disorders
Epistaxis	2/49 (4.1%)		0/50 (0%)
Vaginal hemorrhage	0/49 (0%)		1/50 (2%)
Hypotension	1/49 (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.