Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC)

• Sponsor: University of Manitoba (Other)
• Overall Status: Completed
• CT.gov ID: NCT04372589
• Collaborator: University Health Network, Toronto (Other)
• Enrollment: 1,200
• Locations: 60
• Arms: 2
• Actual Duration (Months): 11.9
• Patients Per Site: 20
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

Endothelial injury as a consequence of SARS-CoV-2 infection leads to a dysregulated host inflammatory response and activation of coagulation pathways. Macro- and micro-vascular thrombosis may contribute to morbidity, organ failure, and death. Therapeutic anticoagulation with heparin may improve clinical outcomes in patients with COVID-19 through anti-thrombotic, anti-inflammatory, and anti-viral activities of heparins. This pragmatic, Bayesian adaptive randomized controlled trial will determine whether therapeutic anticoagulation with heparin (subcutaneous low molecular weight heparin or intravenous unfractionated heparin) versus usual care reduces the need for intubation or death in hospitalized patients with COVID-19. The trial uses an adaptive design which was chosen to overcome limitations in available data to inform a priori estimation of event rates and possible effect sizes. The adaptive design also includes response-adaptive randomization based on baseline D-dimer level, probing for differential efficacy across subgroups defined based on initial D-dimer level. This Bayesian adaptive randomized trial will stop at a conclusion 1) when the posterior probability that the proportional odds ratio is greater than 1.0 reaches 99% (definition of benefit); 2) when the posterior probability that the proportional odds ratio is greater than 1.2 is less than 10% (definition of futility) or; 3) when the posterior probability that the proportional odds ratio is less than 1.0 is greater than 90% (definition of harm). The trial will enroll a maximum of 3,000 patients, although in many simulations the trial may require fewer patients. The trial is strategically aligned with the international REMAP-CAP/COVID platform trial to accelerate evidence generation.

Condition or Disease	Intervention/Treatment	Phase
COVID-19; Pneumonia	Drug: Heparin	Phase 2/Phase 3

Detailed Description

This is a prospective, open-label, multicentre, Bayesian adaptive randomized clinical trial to establish whether therapeutic-dose parenteral anticoagulation improves outcomes for patients hospitalized with COVID-19 (e.g., reduces intubation or mortality). Participants will be randomized either to the investigational arm (therapeutic anticoagulation with heparin for 14 days or until "recovery" [defined as hospital discharge or liberation from supplemental oxygen if initially required], whichever comes first), or to the control arm (usual care, including thromboprophylactic dose anticoagulation according to local practice).

Study Design

• Study Type: Interventional
• Actual Enrollment: 1200 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Pragmatic, Bayesian adaptive randomized controlled trialPragmatic, Bayesian adaptive randomized controlled trial
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Antithrombotic Therapy to Ameliorate Complications of COVID-19 (ATTACC), in Collaboration With Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-4)
• Actual Study Start Date: May 20, 2020
• Actual Primary Completion Date: May 17, 2021
• Actual Study Completion Date: May 17, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Investigational arm Participants randomized to the investigational arm will receive therapeutic anticoagulation for 14 days (or until hospital discharge or liberation from supplemental oxygen >24 hours if previously required, whichever comes first) with heparin, with preference for subcutaneous low molecular weight heparin (enoxaparin preferred, although dalteparin or tinzaparin are also acceptable, as available) if no contraindication is present; alternatively, intravenous unfractionated heparin infusion may be used.	Drug: Heparin; Low molecular weight heparin (LMWH) Preferred therapeutic anticoagulant is enoxaparin. Generally regimens: 1.5 mg/kg subcutaneous once daily or 1 mg/kg subcutaneous twice daily. Alternatively, other subcutaneous LMWH used, including tinzaparin (175 anti-Xa IU/kg subcutaneous once daily) or dalteparin (200 IU/kg subcutaneous once daily or 100 IU/kg subcutaneous twice a day). Unfractionated heparin (UFH) Commenced, administered, and monitored according to local hospital policy, and guidelines that are used for the treatment of venous thromboembolism (i.e. not for acute coronary syndrome). Intravenous infusion of UFH is according to total body weight and pragmatically adjusted according to local institutional policy to achieve an activated partial thromboplastin time (aPTT) of 1.5-2.5x the reference value. If UFH is used, the availability of a local hospital policy that has specifies an aPTT target in this range or an anti-Xa value is a requirement.
No Intervention: Control arm Participants will receive usual care of thromboprophylactic dose anticoagulation according to local practice.

Outcome Measures

Primary Outcome Measures

1. Mortality and days free of organ support [21 days]

   The primary endpoint in the trial is days alive and free of organ support at day 21. This endpoint is defined as the number of days that a patient is alive and free of organ support through the first 21 days after trial entry. Organ support is defined as receipt of invasive or non-invasive mechanical ventilation, high flow nasal oxygen (>30 L/min), vasopressor therapy, or ECMO support. Death at any time (including beyond 21 days) during the index hospital stay is assigned the worst possible score of -1.

Secondary Outcome Measures

1. Arterial and venous thrombotic conditions [28 days and 90 days]

   A composite endpoint of death, deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke collected during hospitalization or at 28 days and 90 days after enrollment (whichever is earlier).

2. Intubation and mortality [30 days]

   Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization: no invasive mechanical ventilation, invasive mechanical ventilation, or death.

3. All-cause mortality [28 days and 90 days]

4. Intubation [30 days]

   Invasive mechanical ventilation.

5. Hospital-free days [28 days]

   Days alive outside of the hospital through 28 days following randomization.

6. Ventilator-free days [28 days]

   Days alive not on a ventilator assessed at 28 days following randomization.

7. Myocardial infarction [28 days and 90 days]

8. Ischaemic stroke [28 days and 90 days]

9. Venous thromboembolism [28 days and 90 days]

   Symptomatic proximal venous thromboembolism (DVT or PE).

10. Vasopressor-free days [28 days]

    Days alive not on a vasopressor assessed at 28 days following randomization.

11. Renal replacement free days [28 days]

    Days alive not on renal replacement assessed at 28 days following randomization.

12. Hospital re-admission [28 days]

    Hospital re-admission within 28 days.

13. Acute kidney injury [Duration of study]

    As defined by KDIGO criteria.

14. Systemic arterial thrombosis or embolism [28 days and 90 days]

15. ECMO support [Duration of study]

    Use of extracorporeal membrane oxygenation (ECMO) support.

16. Mechanical circuit thrombosis [Duration of study]

    Dialysis or ECMO.

17. WHO ordinal scale [28 days]

    Peak scale over 28 days, scale at 14 days, and proportion with improvement by at least 2 categories compared to enrollment, at 28 days.

18. Major bleeding [Intervention period (maximum 14 days)]

    As defined by the International Society on Thrombosis and Haemostasis (ISTH).

19. Heparin-induced thrombocytopenia (HIT) [Intervention period (maximum 14 days)]

    Laboratory-confirmed.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients ≥18 years of age providing (possibly through a substitute decision maker) informed consent who require hospitalization anticipated to last ≥72 hours, for microbiologically-confirmed COVID-19, enrolled < 72 hours of hospital admission or of COVID-19 confirmation

• If the patient is already hospitalized and the COVID-19 diagnosis is due to an outbreak or an incidental finding, then enrollment can occur within 72 hours of a clinical syndrome attributable to COVID-19 that requires continued hospitalization (e.g. new or worsening oxygen requirements or acute kidney injury) which is further anticipated to extend the hospital admission by an additional 72 hours from randomization.

Exclusion Criteria:

1. Patients admitted to an ICU AND receiving organ support (i.e. high flow nasal oxygen, receiving non-invasive or invasive mechanical ventilation, or are requiring vasopressor/inotrope)

2. Patients for whom the intent is to not use pharmacologic thromboprophylaxis

3. Active bleeding

4. Risk factors for bleeding, including:

5. intracranial surgery or stroke within 3 months;

6. history of intracerebral arteriovenous malformation;

7. cerebral aneurysm or mass lesions of the central nervous system;

8. intracranial malignancy

9. history of intracranial bleeding

10. history of bleeding diatheses (e.g., hemophilia)

11. history of gastrointestinal bleeding within previous 3 months

12. thrombolysis within the previous 7 days

13. presence of an epidural or spinal catheter

14. recent major surgery <14 days

15. uncontrolled hypertension (sBP >200 mmHg, dBP >120 mmHg)

16. other physician-perceived contraindications to anticoagulation

17. Platelet count <50 x10^9/L, INR >2.0, or baseline aPTT >50 (if available per SOC testing)

18. Hemoglobin <80 g/L (to minimize the likelihood of requiring red blood cell transfusion if potential bleeding were to occur)

19. Acute or subacute bacterial endocarditis

20. History of heparin induced thrombocytopenia (HIT) or other heparin allergy including hypersensitivity

21. Current use of dual antiplatelet therapy

22. Patients with an independent indication for therapeutic anticoagulation

23. Patients in whom imminent demise is anticipated and there is no commitment to active ongoing intervention

24. Anticipated transfer to another hospital that is not a study site within 72 hours

25. Enrollment in other trials related to anticoagulation or antiplatelet therapy

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Emory University Hospital Midtown	Atlanta	Georgia	United States	30308
2	University of Chicago	Chicago	Illinois	United States	60637
3	Ochsner Clinic	Jefferson	Louisiana	United States	70121
4	Maine Medical Center	Portland	Maine	United States	04102
5	Henry Ford University	Dearborn	Michigan	United States	48128
6	Beaumont Hospital	Royal Oak	Michigan	United States	48336
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Saint Louis University School of Medicine/Saint Louis Veterans Affairs Medical Center	Saint Louis	Missouri	United States	63104
9	Cooper University Health Care	Camden	New Jersey	United States	08103
10	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
11	Saint Barnabas Medical Center	Livingston	New Jersey	United States	07039
12	Montefiore-Einstein Center for Heart and Vascular Care	New York	New York	United States	10467
13	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
14	Santa Casa de Misericordia de Itabuna	Itabuna	BA	Brazil
15	Hospital Unimed do Cariri	Juazeiro do Norte	CE	Brazil
16	Instituto Goiano de Oncologia e Hematologia - INGOH	Goiania	Goias	Brazil
17	Centro de Pesquisas Clínicas Humap - UFMS	Campo Grande	Mato Grosso Do Sul	Brazil
18	Hospital Felício Rocho	Belo Horizonte	MG	Brazil
19	Clinica de Campo Grande S/A	Campo Grande	MS	Brazil
20	Unimed Campo Grande	Campo Grande	MS	Brazil
21	Hospital Agamenon Magalhaes	Recife	Pernanbuco	Brazil
22	Hospital das Clinicas da UFPR	Curitiba	PR	Brazil
23	Pontifícia Universidade Católica do Paraná	Curitiba	PR	Brazil
24	Parana Medical Research Center	Maringa	PR	Brazil
25	Hospital Sao Vicente de Paulo	Passo Fundo	Rio Grande Do Sul	Brazil
26	Hospital Universitario Pedro Ernesto	Rio de Janeiro	RJ	Brazil
27	Hospital de Clinicas de Porto Alegre	Porto Alegre	RS	Brazil
28	Instituto de Cardiologia do Rio Grande do Sul	Porto Alegre	RS	Brazil
29	Instituto de Medicina Vascular	Porto Alegre	RS	Brazil
30	AngioCor Blumenau	Blumenau	Santa Catarina	Brazil
31	Instituto de Cardiologia de Santa Catarina	Sao Jose	Santa Catarina	Brazil
32	Instituto de Pesquisa Clínica de Campinas	Campinas	Sao Paulo	Brazil
33	Praxis Pesquisa Medica	Santo Andre	Sao Paulo	Brazil
34	Santa Casa de Votuporanga	Votuporanga	Sao Paulo	Brazil
35	Casa de Saúde Santa Marcelina	Sao Paulo	SP	Brazil
36	Instituto de Molestias Cardio Vasculares de Tatui	Tatui	SP	Brazil
37	Hospital 9 de Julho	São Paulo		Brazil
38	Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo		Brazil
39	Instituto de Infectologia Emilio Ribas	São Paulo		Brazil
40	Instituto do Coração do Estado de São Paulo	São Paulo		Brazil
41	Sociedade Beneficente Israelita Hospital Albert Einstein	São Paulo		Brazil
42	Victoria General Hospital	Victoria	British Columbia	Canada
43	Health Sciences Center Winnipeg	Winnipeg	Manitoba	Canada	R3A 1R9
44	Grace General Hospital	Winnipeg	Manitoba	Canada
45	St. Boniface General Hospital	Winnipeg	Manitoba	Canada
46	Hamilton Health Sciences	Hamilton	Ontario	Canada
47	St. Joseph's Healthcare Hamilton	Hamilton	Ontario	Canada
48	Hôpital Montfort	Ottawa	Ontario	Canada
49	The Ottawa Hospital	Ottawa	Ontario	Canada
50	University Health Network	Toronto	Ontario	Canada	M5G2C4
51	McGill University Health Centre	Montréal	Quebec	Canada	H4A3J1
52	Centre Hospitalier de l'université de Montréal (CHUM)	Montréal	Quebec	Canada
53	Jewish General Hospital	Montréal	Quebec	Canada
54	CHU de Quebec-University Laval	Québec	Quebec	Canada
55	Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ)	Québec	Quebec	Canada
56	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec	Canada
57	Regina General Hospital	Regina	Saskatchewan	Canada
58	Hospital de Infectolog´ñia Centro Médico Nacional La Raza	Azcapotzalco	Mexico City	Mexico
59	Hospital General Regional 1 Carlos MacGregor Sánchez Navarro	Benito Juárez	Mexico City	Mexico
60	Hospital General regional 2 El Marqués	Querétaro		Mexico

Sponsors and Collaborators

• University of Manitoba
• University Health Network, Toronto

Investigators

• Principal Investigator: Patrick R. Lawler, MD, MPH, Peter Munk Cardiac Centre/University Health Network
• Principal Investigator: Ewan C. Goligher, MD, PhD, University Health Network, Toronto
• Principal Investigator: Ryan Zarychanski, MD, MSc, University of Manitoba

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Manitoba
• ClinicalTrials.gov Identifier: NCT04372589
• Other Study ID Numbers: ATTACC; OZM-113
• First Posted: May 4, 2020
• Last Update Posted: Jul 27, 2021
• Last Verified: Jan 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: COVID-19; Heparin

Study Results

No Results Posted as of Jul 27, 2021