Hemostasis in COVID-19: an Adaptive Clinical Trial

NCT ID: NCT04466670

Last Updated: 2021-06-09

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 379 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-11
• Study Completion Date: 2022-05-30

Brief Summary

Hypercoagulability has been demonstrated in COVID-19, leading to respiratory distress and increased mortality. This is an adaptive clinical trial to compare the efficacy and safety of two experimental strategies in patients with COVID-19: ASA or inhaled UFH associated with standard VTE prophylaxis.

Conditions

COVID-19

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

phase 1

Observational arm

Group Type: NO_INTERVENTION

No interventions assigned to this group

phase 2A

Acetylsalicylic acid

Group Type: EXPERIMENTAL

acetylsalicylic acid

Intervention Type: DRUG

acetylsalicylic acid (ASA) 100 mg daily PO up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.

phase 2B

inhaled unfractionated heparin

Group Type: EXPERIMENTAL

Unfractionated heparin nebulized

Intervention Type: DRUG

unfractionated heparin - 25,000 U/ 5 ml nebulized inhalation every 6 hours up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.

Placebo

Placebo arm for Phase 2A

Group Type: PLACEBO_COMPARATOR

acetylsalicylic acid

Intervention Type: DRUG

acetylsalicylic acid (ASA) 100 mg daily PO up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.

Interventions

acetylsalicylic acid

acetylsalicylic acid (ASA) 100 mg daily PO up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.

Intervention Type: DRUG

Unfractionated heparin nebulized

unfractionated heparin - 25,000 U/ 5 ml nebulized inhalation every 6 hours up to 14 days OR arterial oxygen saturation greater than or equal to 92% on room air OR PaO2 to FiO2 ratio greater than 200 for 2 consecutive days, whichever is first.

Intervention Type: DRUG

Other Intervention Names

aspirin

Eligibility Criteria

Inclusion Criteria

• Adult ≥18 years of age at time of enrollment
• Subjects with a positive COVID-19 diagnosis by RT-PCR or serologic testing
• Subject (or legally authorized representative) must be willing, understanding and able to provide written informed consent.
• Only at phase 2:

• onset of symptoms must not exceed 4 weeks
• ICU patients
• PaO2 to FiO2 ratio < 200

Exclusion Criteria

1. General

• Indications for therapeutic anticoagulation
• History of chronic lung disease oxygen dependent
• Pregnancy
• Death considered imminent and inevitable within 24 hours
• Patients under exclusive palliative care
• Participation in another trial of investigational drug
• Body weight < 40 Kg
• Total bilirubin > 20 mg/dL
• Severe active bleeding
• Persistent GI bleeding
• Known allergy to UFH or LMWH
• History of heparin-induced thrombocytopenia (HIT) within the past 6 months

• Platelet count < 25,000/mm3
• Bacterial endocarditis

• Platelet count < 50,000/mm3
• History of surgery in the last 30 days
• Intervention A: allergy to ASA and long-term use of antiplatelet drug
• Intervention B: inhaled nitric oxide use

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Sao Paulo General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Vanderson Geraldo Rocha

Full professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Vanderson Rocha

Role: PRINCIPAL_INVESTIGATOR

University of Sao Paulo General Hospital

Locations

Vanderson Rocha

São Paulo, , Brazil

Site Status: RECRUITING

Countries

Brazil

Facility Contacts

Vanderson Rocha, MD.PhD

Role: primary

vanderson.rocha@hc.fm.usp.br

+55-11-26617575

Yeh-Li Ho, MD.PhD

Role: backup

ho.yeh@hc.fm.usp.br

+55-11-26616045

References

Schulman S, Kearon C; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005 Apr;3(4):692-4. doi: 10.1111/j.1538-7836.2005.01204.x.

Reference Type: BACKGROUND

PMID: 15842354 (View on PubMed)

Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506. doi: 10.1016/S0140-6736(20)30183-5. Epub 2020 Jan 24.

Reference Type: RESULT

PMID: 31986264 (View on PubMed)

Fu L, Wang B, Yuan T, Chen X, Ao Y, Fitzpatrick T, Li P, Zhou Y, Lin YF, Duan Q, Luo G, Fan S, Lu Y, Feng A, Zhan Y, Liang B, Cai W, Zhang L, Du X, Li L, Shu Y, Zou H. Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: A systematic review and meta-analysis. J Infect. 2020 Jun;80(6):656-665. doi: 10.1016/j.jinf.2020.03.041. Epub 2020 Apr 10.

Reference Type: RESULT

PMID: 32283155 (View on PubMed)

Arachchillage DRJ, Laffan M. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 May;18(5):1233-1234. doi: 10.1111/jth.14820. No abstract available.

Reference Type: RESULT

PMID: 32291954 (View on PubMed)

Lillicrap D. Disseminated intravascular coagulation in patients with 2019-nCoV pneumonia. J Thromb Haemost. 2020 Apr;18(4):786-787. doi: 10.1111/jth.14781. Epub 2020 Mar 24. No abstract available.

Reference Type: RESULT

PMID: 32212240 (View on PubMed)

Lippi G, Favaloro EJ. D-dimer is Associated with Severity of Coronavirus Disease 2019: A Pooled Analysis. Thromb Haemost. 2020 May;120(5):876-878. doi: 10.1055/s-0040-1709650. Epub 2020 Apr 3. No abstract available.

Reference Type: RESULT

PMID: 32246450 (View on PubMed)

Feng Y, Ling Y, Bai T, Xie Y, Huang J, Li J, Xiong W, Yang D, Chen R, Lu F, Lu Y, Liu X, Chen Y, Li X, Li Y, Summah HD, Lin H, Yan J, Zhou M, Lu H, Qu J. COVID-19 with Different Severities: A Multicenter Study of Clinical Features. Am J Respir Crit Care Med. 2020 Jun 1;201(11):1380-1388. doi: 10.1164/rccm.202002-0445OC.

Reference Type: RESULT

PMID: 32275452 (View on PubMed)

Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost. 2020 Jun;18(6):1421-1424. doi: 10.1111/jth.14830. Epub 2020 May 6.

Reference Type: RESULT

PMID: 32271988 (View on PubMed)

Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, Kaptein FHJ, van Paassen J, Stals MAM, Huisman MV, Endeman H. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020 Jul;191:145-147. doi: 10.1016/j.thromres.2020.04.013. Epub 2020 Apr 10.

Reference Type: RESULT

PMID: 32291094 (View on PubMed)

Helms J, Tacquard C, Severac F, Leonard-Lorant I, Ohana M, Delabranche X, Merdji H, Clere-Jehl R, Schenck M, Fagot Gandet F, Fafi-Kremer S, Castelain V, Schneider F, Grunebaum L, Angles-Cano E, Sattler L, Mertes PM, Meziani F; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020 Jun;46(6):1089-1098. doi: 10.1007/s00134-020-06062-x. Epub 2020 May 4.

Reference Type: RESULT

PMID: 32367170 (View on PubMed)

Lodigiani C, Iapichino G, Carenzo L, Cecconi M, Ferrazzi P, Sebastian T, Kucher N, Studt JD, Sacco C, Bertuzzi A, Sandri MT, Barco S; Humanitas COVID-19 Task Force. Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Milan, Italy. Thromb Res. 2020 Jul;191:9-14. doi: 10.1016/j.thromres.2020.04.024. Epub 2020 Apr 23.

Reference Type: RESULT

PMID: 32353746 (View on PubMed)

Middeldorp S, Coppens M, van Haaps TF, Foppen M, Vlaar AP, Muller MCA, Bouman CCS, Beenen LFM, Kootte RS, Heijmans J, Smits LP, Bonta PI, van Es N. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost. 2020 Aug;18(8):1995-2002. doi: 10.1111/jth.14888. Epub 2020 Jul 27.

Reference Type: RESULT

PMID: 32369666 (View on PubMed)

Llitjos JF, Leclerc M, Chochois C, Monsallier JM, Ramakers M, Auvray M, Merouani K. High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients. J Thromb Haemost. 2020 Jul;18(7):1743-1746. doi: 10.1111/jth.14869. Epub 2020 May 27.

Reference Type: RESULT

PMID: 32320517 (View on PubMed)

Gralinski LE, Bankhead A 3rd, Jeng S, Menachery VD, Proll S, Belisle SE, Matzke M, Webb-Robertson BJ, Luna ML, Shukla AK, Ferris MT, Bolles M, Chang J, Aicher L, Waters KM, Smith RD, Metz TO, Law GL, Katze MG, McWeeney S, Baric RS. Mechanisms of severe acute respiratory syndrome coronavirus-induced acute lung injury. mBio. 2013 Aug 6;4(4):e00271-13. doi: 10.1128/mBio.00271-13.

Reference Type: RESULT

PMID: 23919993 (View on PubMed)

Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell. 2020 Apr 16;181(2):281-292.e6. doi: 10.1016/j.cell.2020.02.058. Epub 2020 Mar 9.

Reference Type: RESULT

PMID: 32155444 (View on PubMed)

Hoffmann M, Kleine-Weber H, Schroeder S, Kruger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Muller MA, Drosten C, Pohlmann S. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020 Apr 16;181(2):271-280.e8. doi: 10.1016/j.cell.2020.02.052. Epub 2020 Mar 5.

Reference Type: RESULT

PMID: 32142651 (View on PubMed)

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. doi: 10.1002/path.1570.

Reference Type: RESULT

PMID: 15141377 (View on PubMed)

Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin-Angiotensin-Aldosterone System Inhibitors in Patients with Covid-19. N Engl J Med. 2020 Apr 23;382(17):1653-1659. doi: 10.1056/NEJMsr2005760. Epub 2020 Mar 30. No abstract available.

Reference Type: RESULT

PMID: 32227760 (View on PubMed)

Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, Vanstapel A, Werlein C, Stark H, Tzankov A, Li WW, Li VW, Mentzer SJ, Jonigk D. Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19. N Engl J Med. 2020 Jul 9;383(2):120-128. doi: 10.1056/NEJMoa2015432. Epub 2020 May 21.

Reference Type: RESULT

PMID: 32437596 (View on PubMed)

Dolhnikoff M, Duarte-Neto AN, de Almeida Monteiro RA, da Silva LFF, de Oliveira EP, Saldiva PHN, Mauad T, Negri EM. Pathological evidence of pulmonary thrombotic phenomena in severe COVID-19. J Thromb Haemost. 2020 Jun;18(6):1517-1519. doi: 10.1111/jth.14844. No abstract available.

Reference Type: RESULT

PMID: 32294295 (View on PubMed)

Panigada M, Bottino N, Tagliabue P, Grasselli G, Novembrino C, Chantarangkul V, Pesenti A, Peyvandi F, Tripodi A. Hypercoagulability of COVID-19 patients in intensive care unit: A report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost. 2020 Jul;18(7):1738-1742. doi: 10.1111/jth.14850. Epub 2020 Jun 24.

Reference Type: RESULT

PMID: 32302438 (View on PubMed)

Escher R, Breakey N, Lammle B. Severe COVID-19 infection associated with endothelial activation. Thromb Res. 2020 Jun;190:62. doi: 10.1016/j.thromres.2020.04.014. Epub 2020 Apr 15. No abstract available.

Reference Type: RESULT

PMID: 32305740 (View on PubMed)

Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ; HLH Across Speciality Collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020 Mar 28;395(10229):1033-1034. doi: 10.1016/S0140-6736(20)30628-0. Epub 2020 Mar 16. No abstract available.

Reference Type: RESULT

PMID: 32192578 (View on PubMed)

Whyte CS, Morrow GB, Mitchell JL, Chowdary P, Mutch NJ. Fibrinolytic abnormalities in acute respiratory distress syndrome (ARDS) and versatility of thrombolytic drugs to treat COVID-19. J Thromb Haemost. 2020 Jul;18(7):1548-1555. doi: 10.1111/jth.14872. Epub 2020 Jun 3.

Reference Type: RESULT

PMID: 32329246 (View on PubMed)

White D, MacDonald S, Bull T, Hayman M, de Monteverde-Robb R, Sapsford D, Lavinio A, Varley J, Johnston A, Besser M, Thomas W. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020 Aug;50(2):287-291. doi: 10.1007/s11239-020-02145-0.

Reference Type: RESULT

PMID: 32445064 (View on PubMed)

Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e24S-e43S. doi: 10.1378/chest.11-2291.

Reference Type: RESULT

PMID: 22315264 (View on PubMed)

Barrett CD, Moore HB, Yaffe MB, Moore EE. ISTH interim guidance on recognition and management of coagulopathy in COVID-19: A comment. J Thromb Haemost. 2020 Aug;18(8):2060-2063. doi: 10.1111/jth.14860. Epub 2020 Jun 14. No abstract available.

Reference Type: RESULT

PMID: 32302462 (View on PubMed)

Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, Nigoghossian C, Ageno W, Madjid M, Guo Y, Tang LV, Hu Y, Giri J, Cushman M, Quere I, Dimakakos EP, Gibson CM, Lippi G, Favaloro EJ, Fareed J, Caprini JA, Tafur AJ, Burton JR, Francese DP, Wang EY, Falanga A, McLintock C, Hunt BJ, Spyropoulos AC, Barnes GD, Eikelboom JW, Weinberg I, Schulman S, Carrier M, Piazza G, Beckman JA, Steg PG, Stone GW, Rosenkranz S, Goldhaber SZ, Parikh SA, Monreal M, Krumholz HM, Konstantinides SV, Weitz JI, Lip GYH; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-Up: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020 Jun 16;75(23):2950-2973. doi: 10.1016/j.jacc.2020.04.031. Epub 2020 Apr 17.

Reference Type: RESULT

PMID: 32311448 (View on PubMed)

Maatman TK, Jalali F, Feizpour C, Douglas A 2nd, McGuire SP, Kinnaman G, Hartwell JL, Maatman BT, Kreutz RP, Kapoor R, Rahman O, Zyromski NJ, Meagher AD. Routine Venous Thromboembolism Prophylaxis May Be Inadequate in the Hypercoagulable State of Severe Coronavirus Disease 2019. Crit Care Med. 2020 Sep;48(9):e783-e790. doi: 10.1097/CCM.0000000000004466.

Reference Type: RESULT

PMID: 32459672 (View on PubMed)

Nahum J, Morichau-Beauchant T, Daviaud F, Echegut P, Fichet J, Maillet JM, Thierry S. Venous Thrombosis Among Critically Ill Patients With Coronavirus Disease 2019 (COVID-19). JAMA Netw Open. 2020 May 1;3(5):e2010478. doi: 10.1001/jamanetworkopen.2020.10478.

Reference Type: RESULT

PMID: 32469410 (View on PubMed)

Tremblay D, van Gerwen M, Alsen M, Thibaud S, Kessler A, Venugopal S, Makki I, Qin Q, Dharmapuri S, Jun T, Bhalla S, Berwick S, Feld J, Mascarenhas J, Troy K, Cromwell C, Dunn A, Oh WK, Naymagon L. Impact of anticoagulation prior to COVID-19 infection: a propensity score-matched cohort study. Blood. 2020 Jul 2;136(1):144-147. doi: 10.1182/blood.2020006941. No abstract available.

Reference Type: RESULT

PMID: 32462179 (View on PubMed)

Paranjpe I, Fuster V, Lala A, Russak AJ, Glicksberg BS, Levin MA, Charney AW, Narula J, Fayad ZA, Bagiella E, Zhao S, Nadkarni GN. Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. J Am Coll Cardiol. 2020 Jul 7;76(1):122-124. doi: 10.1016/j.jacc.2020.05.001. Epub 2020 May 6. No abstract available.

Reference Type: RESULT

PMID: 32387623 (View on PubMed)

Juschten J, Tuinman PR, Juffermans NP, Dixon B, Levi M, Schultz MJ. Nebulized anticoagulants in lung injury in critically ill patients-an updated systematic review of preclinical and clinical studies. Ann Transl Med. 2017 Nov;5(22):444. doi: 10.21037/atm.2017.08.23.

Reference Type: RESULT

PMID: 29264361 (View on PubMed)

Dixon B, Schultz MJ, Smith R, Fink JB, Santamaria JD, Campbell DJ. Nebulized heparin is associated with fewer days of mechanical ventilation in critically ill patients: a randomized controlled trial. Crit Care. 2010;14(5):R180. doi: 10.1186/cc9286. Epub 2010 Oct 11.

Reference Type: RESULT

PMID: 20937093 (View on PubMed)

Viecca M, Radovanovic D, Forleo GB, Santus P. Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study. Pharmacol Res. 2020 Aug;158:104950. doi: 10.1016/j.phrs.2020.104950. Epub 2020 May 23.

Reference Type: RESULT

PMID: 32450344 (View on PubMed)

Connor JT, Elm JJ, Broglio KR; ESETT and ADAPT-IT Investigators. Bayesian adaptive trials offer advantages in comparative effectiveness trials: an example in status epilepticus. J Clin Epidemiol. 2013 Aug;66(8 Suppl):S130-7. doi: 10.1016/j.jclinepi.2013.02.015.

Reference Type: RESULT

PMID: 23849147 (View on PubMed)

Gsponer T, Gerber F, Bornkamp B, Ohlssen D, Vandemeulebroecke M, Schmidli H. A practical guide to Bayesian group sequential designs. Pharm Stat. 2014 Jan-Feb;13(1):71-80. doi: 10.1002/pst.1593. Epub 2013 Aug 24.

Reference Type: RESULT

PMID: 24038922 (View on PubMed)

Other Identifiers

33788820.9.0000.0068

Identifier Type: -

Identifier Source: org_study_id