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

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ClinicalTrials.gov Identifier: NCT04410328

Recruitment Status : Not yet recruiting

First Posted : June 1, 2020

Last Update Posted : July 7, 2020

See Contacts and Locations

Sponsor:

Collaborator:

Boehringer Ingelheim

Information provided by (Responsible Party):

Amit Singla, MD, FAANS, Rutgers, The State University of New Jersey

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Covid19	Drug: Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally AND Standard of care Other: Standard of care	Phase 3

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 Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	132 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	Arm 1: Aggrenox plus standard care. 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. Arm 2: Standard care. 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, the 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.
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Randomized Controlled Trial to Evaluate the Outcomes With Aggrenox in Patients With SARS-CoV-2 Infection
Estimated Study Start Date :	July 28, 2020
Estimated Primary Completion Date :	December 15, 2020
Estimated Study Completion Date :	December 15, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Aspirin Dipyridamole

U.S. FDA Resources

Arms and Interventions

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 Name: Aggrenox Other: Standard of care Participants will receive standard care starting on the day of enrollment for a total of 2 weeks.
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.

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 Name: Aggrenox

Other: Standard of care

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

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.

Outcome Measures

Primary Outcome Measures :

Covid (Coronavirus Disease-19) Ordinal Scale [ Time Frame: 15 days ]
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.

Secondary Outcome Measures :

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

Eligibility Criteria

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:	19 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age ≥18 years.
Hospitalization.
SARS-CoV-2 viral nucleic acid positive within 3 days.
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).
Willing and able to provide consent or by authorized proxy.

Exclusion Criteria:

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04410328

Contacts

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Contact: Amit Singla, MD	3195123558	as3321@njms.rutgers.edu
Contact: Olga Kovalenko, D, PhD, CCRC	973-972-3173	kovaleoa@njms.rutgers.edu

Sponsors and Collaborators

Rutgers, The State University of New Jersey

Boehringer Ingelheim

Investigators

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Principal Investigator:	Amit Singla, MD	Rutgers University

More Information

Publications of Results:

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.

Köhler D, Streienberger A, Morote-García JC, Granja TF, Schneider M, Straub A, Boison D, Rosenberger P. Inhibition of Adenosine Kinase Attenuates Acute Lung Injury. Crit Care Med. 2016 Apr;44(4):e181-9. doi: 10.1097/CCM.0000000000001370.

Fata-Hartley CL, Palmenberg AC. Dipyridamole reversibly inhibits mengovirus RNA replication. J Virol. 2005 Sep;79(17):11062-70.

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. Review.

Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, Ruan L, Song B, Cai Y, Wei M, Li X, Xia J, Chen N, Xiang J, Yu T, Bai T, Xie X, Zhang L, Li C, Yuan Y, Chen H, Li H, Huang H, Tu S, Gong F, Liu Y, Wei Y, Dong C, Zhou F, Gu X, Xu J, Liu Z, Zhang Y, Li H, Shang L, Wang K, Li K, Zhou X, Dong X, Qu Z, Lu S, Hu X, Ruan S, Luo S, Wu J, Peng L, Cheng F, Pan L, Zou J, Jia C, Wang J, Liu X, Wang S, Wu X, Ge Q, He J, Zhan H, Qiu F, Guo L, Huang C, Jaki T, Hayden FG, Horby PW, Zhang D, Wang C. A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19. N Engl J Med. 2020 May 7;382(19):1787-1799. doi: 10.1056/NEJMoa2001282. Epub 2020 Mar 18.

Other Publications:

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.

Fauci AS, Lane HC, Redfield RR. Covid-19 - Navigating the Uncharted. N Engl J Med. 2020 Mar 26;382(13):1268-1269. doi: 10.1056/NEJMe2002387. Epub 2020 Feb 28.

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.

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.

Ralevic V, Burnstock G. Receptors for purines and pyrimidines. Pharmacol Rev. 1998 Sep;50(3):413-92. Review.

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.

Parkinson FE, Ferguson J, Zamzow CR, Xiong W. Gene expression for enzymes and transporters involved in regulating adenosine and inosine levels in rat forebrain neurons, astrocytes and C6 glioma cells. J Neurosci Res. 2006 Sep;84(4):801-8.

Boswell-Casteel RC, Hays FA. Equilibrative nucleoside transporters-A review. Nucleosides Nucleotides Nucleic Acids. 2017 Jan 2;36(1):7-30. doi: 10.1080/15257770.2016.1210805. Epub 2016 Oct 19. Review.

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. Review.

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.

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. Review.

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. Review.

International Severe Acute Respiratory emergning Infection Consortium Case Reports. https://isaric.tghn.org.

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Responsible Party:	Amit Singla, MD, FAANS, Assistant Professor, Rutgers, The State University of New Jersey
ClinicalTrials.gov Identifier:	NCT04410328
Other Study ID Numbers:	Pro2020001399
First Posted:	June 1, 2020 Key Record Dates
Last Update Posted:	July 7, 2020
Last Verified:	July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

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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

Keywords provided by Amit Singla, MD, FAANS, Rutgers, The State University of New Jersey:


COVID-19 SARS-CoV Aggrenox Dipyridamole Aspirin

Additional relevant MeSH terms:

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Aspirin Dipyridamole Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents	Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action Platelet Aggregation Inhibitors Cyclooxygenase Inhibitors Enzyme Inhibitors Antipyretics Phosphodiesterase Inhibitors Vasodilator Agents

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