Aggrenox To Treat Acute Covid-19 (ATTAC-19)

A Randomized Controlled Trial to Evaluate the Outcomes With Aggrenox in Patients With SARS-CoV-2 Infection

The purpose of this study is to explore the efficacy of Aggrenox in patients with SARS-CoV-2 infection with symptoms consistent with COVID-19. An anticipated total of 132 participants will be randomly divided almost equally into 2 groups: one group will receive Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally along with the standard of care and the other group with receive the standard of care only but no Dipyridamole ER 200mg/ Aspirin 25mg. Participants will be screened, enrolled, receive treatment, and followed for 28 days. The clinical and laboratory outcomes of all the participants enrolled in the study will be evaluated at the end of the study to explore if there is any difference in the outcomes between 2 groups.

Study Overview

• Status: Completed
• Conditions: Covid19
• Intervention / Treatment: Drug: Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally AND Standard of care; Other: Standard of care

Detailed Description

Purpose/Specific Aims: The purpose of this study is to explore the efficacy of Aggrenox in patients with SARS-CoV-2 infection with symptoms consistent with COVID-19.

Among 132 SARS-CoV-2 patients (66 patients in each randomized arm), we will determine the efficacy of Aggrenox on clinical outcomes.

Hypotheses / Research Question(s) Compared to standard care, the addition of Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg), to standard care will result in improvement in the composite COVID ordinal scale at day 15. Additionally, combined Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally), and standard care will reduce the need for ventilation, length of mechanical ventilation, hospital length of stay, ICU length of stay, decrease risk of thromboembolic complications and improve survival more than standard care alone in SARS-CoV-2 patients.

Research Design and Methods Randomized design. Participants will be randomized 1:1 to Aggrenox or standard treatment. Arm 1: Active Comparator: (Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally).

Participants will receive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally), 2 times daily (FDA-recommended dose) starting on the day of enrollment for a total of 2 weeks + standard care.

Arm 2: Standard care Comparator: Participants will receive standard care starting on the day of enrollment for a total of 2 weeks.

The investigators will perform a randomized, 2-arm, open-label single-site pilot study to evaluate the effect of oral Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally), on clinical outcomes in patients with SARS-CoV-2. In this research proposal, investigators will randomly assign 132 consenting participants with diagnosis of SARS-CoV-2 to two treatment groups: 1) Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) + standard care and 2) standard care alone. Participants will be screened, enrolled, receive treatment and followed for 28 days. The study aim and procedure will be explained to every eligible subject and informed consent will be obtained from interested subjects or authorized proxy to participate in the study. The investigators will collect demographic, clinical, laboratory and radiological data. The patients would be followed daily for 2 weeks after enrollment while the patient is in the hospital and once discharged, they will be called every 3rd day to follow up on the symptoms.

• Study Type: Interventional
• Enrollment (Actual): 99
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New Jersey
    • Newark, New Jersey, United States, 07103
      • Rutgers New Jersey Medical School University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 years.
2. Hospitalization.
3. SARS-CoV-2 viral nucleic acid positive within 3 days.
4. Lab test result pending plus a high clinical suspicion for SARS-CoV-2 (fever and cough for ≤ 7 days, bilateral pulmonary infiltrates on imaging or new hypoxemia with spO2 ≤94% on room air or no alternative explanation for respiratory symptoms).
5. Willing and able to provide consent or by authorized proxy.

Exclusion Criteria:

1. Pregnancy.
2. G-6PD deficiency.
3. Use of antiplatelet agents including inhibitor of P2Y12 ADP platelet receptors, phosphodiesterase inhibitors, and Glycoprotein IIB/IIIA inhibitors.
4. On therapeutic anticoagulation with coumadin, heparin and direct oral anticoagulants.
5. Vasodilatory shock.
6. Patient with known ongoing angina, recent myocardial infarction and sub-valvular aortic stenosis.
7. Active gastric or duodenal ulcer or any bleeding disorder.
8. Hemoglobin <9 mg/dL, platelet count of <30,000 /mm3.
9. Acute respiratory infection for >10 days.
10. Known allergy/hypersensitivity to Dipyridamole and/or Aspirin.
11. Severe hepatic or renal insufficiency.
12. Uncontrolled hypertension defined as systolic > 180 mm Hg or diastolic > 100 mm Hg.
13. Patients with known allergy to NSAIDs

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: Participants receiving Dipyridamole and Aspirin; Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally plus standard care. Participants will receive Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally), 2 times daily starting on the day of enrollment for a total of 2 weeks.	Drug: Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally AND Standard of care; Participants in the experimental group will receive Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally (if they have a feeding tube), 2 times daily starting on the day of enrollment for a total of 2 weeks.; Other Names: Aggrenox; Other: Standard of care; Participants will receive standard care starting on the day of enrollment for a total of 2 weeks.
Other: Participants receiving standard of care; Participants will receive standard care starting on the day of enrollment for a total of 2 weeks.	Other: Standard of care; Participants will receive standard care starting on the day of enrollment for a total of 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Covid (Coronavirus Disease-19) Ordinal Scale	Change in composite COVID ordinal scale at day 15. Ordinal scale: 1) not hospitalized with resumption of normal activities; 2) not hospitalized, but unable to resume normal activities; 3) hospitalized, not requiring oxygen; 4) hospitalized, requiring oxygen; 5) hospitalized, requiring high-flow oxygen therapy, or noninvasive ventilation; 6) hospitalized, requiring invasive ventilation; 7) ventilation plus additional organ support such as pressors, renal replacement therapy and ECMO and 8) death. COVID Ordinal Scale ranges from 1 to 8, with score 1 on the scale corresponds to an ambulatory patient with minimal symptoms and score 8 on the scale corresponds to death.	15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	All-cause mortality assessed on day 15.	15 days
Mortality	All-cause mortality assessed on day 28.	28 days
Supplemental Oxygen	Supplemental Oxygen-free days	28 days
Invasive-ventilator	Invasive-ventilator-free days	28 days
ICU stay	ICU-free days	28 days
Hospital stay	Hospital-free days	28 days
Inflammatory markers	Decrease in the markers D-dimer/ Ferritin/ C-reactive protein	15 days
Thromboembolic complications	Thromboembolic complications including stroke	28 days
COVID ordinal scale	COVID ordinal scale	28 days

Collaborators and Investigators

• Sponsor: Rutgers, The State University of New Jersey
• Collaborators: Boehringer Ingelheim
• Investigators: Principal Investigator: Amit Singla, MD, Rutgers University

Publications and helpful links

General Publications

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• Weiss P, Murdoch DR. Clinical course and mortality risk of severe COVID-19. Lancet. 2020 Mar 28;395(10229):1014-1015. doi: 10.1016/S0140-6736(20)30633-4. Epub 2020 Mar 17. No abstract available.
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• Cucinotta D, Vanelli M. WHO Declares COVID-19 a Pandemic. Acta Biomed. 2020 Mar 19;91(1):157-160. doi: 10.23750/abm.v91i1.9397.
• McPherson JA, Barringhaus KG, Bishop GG, Sanders JM, Rieger JM, Hesselbacher SE, Gimple LW, Powers ER, Macdonald T, Sullivan G, Linden J, Sarembock IJ. Adenosine A(2A) receptor stimulation reduces inflammation and neointimal growth in a murine carotid ligation model. Arterioscler Thromb Vasc Biol. 2001 May;21(5):791-6. doi: 10.1161/01.atv.21.5.791.
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• Wang C, Lin W, Playa H, Sun S, Cameron K, Buolamwini JK. Dipyridamole analogs as pharmacological inhibitors of equilibrative nucleoside transporters. Identification of novel potent and selective inhibitors of the adenosine transporter function of human equilibrative nucleoside transporter 4 (hENT4). Biochem Pharmacol. 2013 Dec 1;86(11):1531-40. doi: 10.1016/j.bcp.2013.08.063. Epub 2013 Sep 7.
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• Chakrabarti S, Freedman JE. Dipyridamole, cerebrovascular disease, and the vasculature. Vascul Pharmacol. 2008 Apr-Jun;48(4-6):143-9. doi: 10.1016/j.vph.2007.12.004. Epub 2008 Feb 15.
• Mustafa SJ. Effects of coronary vasodilator drugs on the uptake and release of adenosine in cardiac cells. Biochem Pharmacol. 1979 Sep 1;28(17):2617-24. doi: 10.1016/0006-2952(79)90037-6. No abstract available.
• Adedeji AO, Sarafianos SG. Antiviral drugs specific for coronaviruses in preclinical development. Curr Opin Virol. 2014 Oct;8:45-53. doi: 10.1016/j.coviro.2014.06.002. Epub 2014 Jul 2.
• Huang B, Chen Z, Geng L, Wang J, Liang H, Cao Y, Chen H, Huang W, Su M, Wang H, Xu Y, Liu Y, Lu B, Xian H, Li H, Li H, Ren L, Xie J, Ye L, Wang H, Zhao J, Chen P, Zhang L, Zhao S, Zhang T, Xu B, Che D, Si W, Gu X, Zeng L, Wang Y, Li D, Zhan Y, Delfouneso D, Lew AM, Cui J, Tang WH, Zhang Y, Gong S, Bai F, Yang M, Zhang Y. Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways. Cell. 2019 Nov 14;179(5):1160-1176.e24. doi: 10.1016/j.cell.2019.10.027.
• Insel PA, Murray F, Yokoyama U, Romano S, Yun H, Brown L, Snead A, Lu D, Aroonsakool N. cAMP and Epac in the regulation of tissue fibrosis. Br J Pharmacol. 2012 May;166(2):447-56. doi: 10.1111/j.1476-5381.2012.01847.x.
• International Severe Acute Respiratory emergning Infection Consortium Case Reports. https://isaric.tghn.org.
• Macatangay BJC, Jackson EK, Abebe KZ, Comer D, Cyktor J, Klamar-Blain C, Borowski L, Gillespie DG, Mellors JW, Rinaldo CR, Riddler SA. A Randomized, Placebo-Controlled, Pilot Clinical Trial of Dipyridamole to Decrease Human Immunodeficiency Virus-Associated Chronic Inflammation. J Infect Dis. 2020 Apr 27;221(10):1598-1606. doi: 10.1093/infdis/jiz344.
• Li Z LX, Huang Yi-Y et al. FEP-based screening prompts drug repositioning against COVID-19. 2020.
• Liu X LZ, Liu S et al. . Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction. 2020.
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• Weyrich AS, Skalabrin EJ, Kraiss LW. Targeting the inflammatory response in secondary stroke prevention: a role for combining aspirin and extended-release dipyridamole. Am J Ther. 2009 Mar-Apr;16(2):164-70. doi: 10.1097/MJT.0b013e31814b17bf.

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2020
• Primary Completion (Actual): October 15, 2021
• Study Completion (Actual): October 15, 2021

Study Registration Dates

• First Submitted: May 28, 2020
• First Submitted That Met QC Criteria: May 29, 2020
• First Posted (Actual): June 1, 2020

Study Record Updates

• Last Update Posted (Actual): February 16, 2022
• Last Update Submitted That Met QC Criteria: January 31, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Aspirin; Dipyridamole; COVID-19; SARS-CoV; Aggrenox
• 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; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Phosphodiesterase Inhibitors; Aspirin; Dipyridamole
• Other Study ID Numbers: Pro2020001469

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: Yes
• product manufactured in and exported from the U.S.: No