ATTACC-CAP: AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia

• Sponsor: University of Manitoba (Other)
• Overall Status: Not yet recruiting
• CT.gov ID: NCT05848713
• Collaborator: Canadian Institutes of Health Research (CIHR) (Other), Research Manitoba (Other), Ozmosis Research Inc. (Industry), Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network (Other), Canadian Critical Care Trials Group (Other)
• Enrollment: 4,000
• Locations: 34
• Arms: 2
• Anticipated Duration (Months): 71
• Patients Per Site: 117.6
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

This is an international, open-label, stratified randomized controlled trial with Bayesian adaptive stopping rules to compare the effects of therapeutic-dose heparin vs. usual care pharmacological thromboprophylaxis on outcomes in patients admitted to hospital with community acquired pneumonia (CAP).

Condition or Disease	Intervention/Treatment	Phase
Community-acquired Pneumonia	Drug: Heparin	Phase 3

Detailed Description

The global incidence of hospitalization due to CAP is high and associated with substantive morbidity and mortality. Thrombotic complications - including venous, arterial, and possibly microvascular - occur commonly in hospitalized patients across many etiologies of CAP. Poor outcomes may be mediated by both inflammatory and thrombotic processes leading to respiratory, cardiac, and other end organ dysfunction. There are currently no established therapies that modify the potentially maladaptive immunothrombosis pathway in CAP.

Therapeutic-dose anticoagulation with heparin reduces disease progression and mortality in non-critically ill patients hospitalized with COVID-19 with an acceptable safety profile. COVID-19 shares pathogenic features, including activation of the inflammatory and coagulation cascades, with other pneumonias. Whether therapeutic-dose heparin confers similar clinical benefits in non-COVID-19 CAP is unknown.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 4000 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Adaptive stratified randomized clinical trial with Bayesian stopping rulesAdaptive stratified randomized clinical trial with Bayesian stopping rules
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia
• Anticipated Study Start Date: May 1, 2023
• Anticipated Primary Completion Date: Mar 31, 2028
• Anticipated Study Completion Date: Mar 31, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Therapeutic-Dose Heparin Participants randomized to the investigational arm will receive a pragmatic strategy of therapeutic-dose low molecular-weight heparin (LMWH) or unfractionated heparin (UFH) administered daily for up to 14 days or until hospital discharge, whichever occurs first. Participants should start receiving study drug as soon as possible following randomization.	Drug: Heparin; Preference is for LMWH given ease of administration and possibility of a more favorable safety profile, if no contraindication is present. Enoxaparin, dalteparin, or tinzaparin are acceptable LMWHs to be used for patients in the investigational arm and dose should be based on measured or estimated weight of the patient. Alternatively, intravenous UFH may be used and may be preferred in the presence of significant renal compromise. Intravenous UFH is typically dosed 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, or a corresponding UFH anti-Xa level. If UFH is used, the availability of a local site policy that specifies an aPTT target in this range or a corresponding anti-Xa value is a requirement.
No Intervention: Usual Care Participants randomized to the control arm will receive usual care thromboprophylactic dose anticoagulation according to local practice. To ensure adequate separation between the study groups, the dose of heparin/LMWH used in the usual care arm should not equal more than half of the approved therapeutic dose for that agent according to local VTE treatment protocols.

Outcome Measures

Primary Outcome Measures

1. Ordinal endpoint reflecting survival [30 days]

   Survival to hospital discharge without ICU-level organ support. Organ support is defined as receipt of high flow nasal oxygen, invasive or non-invasive mechanical ventilation, vasopressor/inotropic therapy, or extracorporeal life support (ECLS) within an ICU. This outcome reflects disease progression to ICU-level organ failure or the worst possible outcome (death). It was chosen because of its importance to patients, clinicians, and other stakeholders. Given the limited number of ICU beds, reducing the burden of critical illness has important health system capacity implications.

Secondary Outcome Measures

1. Bleeding events [14 days]

   Number of participants with major bleeds as defined by the ISTH definition.

2. HIT events [14 days]

   Number of participants with laboratory confirmed heparin induced thrombocytopenia (HIT)

3. Thrombotic events [30 days and 90 days]

   Number of participants with deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke

4. Invasive mechanical ventilation [30 days]

   Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization

5. All cause mortality [30 days, 90 days, and 180 days]

6. Hospital-free days [30 days, 90 days, and 180 days]

   Days alive outside hospital

7. Health related quality of life [30 days, 90 days, and 180 days]

   Using the EQ-5D-5L instrument

8. Health related quality of life [30 days, 90 days, and 180 days]

   Using the Clinical Frailty Scale instrument

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

2. Admitted to hospital for a suspected or confirmed diagnosis of CAP defined by:

3. Radiographic evidence of new or worsening infiltrate

4. One or more of the following signs and/or symptoms of lower respiratory tract infection

1. New or increased cough or sputum production ii. Fever of > 37.8C or temperature < 36C iii. WBC > 11 x 109/L or < 4 x 109/L c. The primary diagnosis is believed to be CAP as per the attending physician

1. Requires supplemental oxygen to treat hypoxemia (or requires an increased level of supplemental oxygen if on chronic oxygen therapy)

2. Hospital admission anticipated to last ≥72 hours from randomization

Exclusion Criteria:

1. Suspected or confirmed active COVID-19 infection

2. Hospital admission for >72 hours prior to randomization

3. Patients receiving non-invasive or invasive ventilation, vasopressors, or extracorporeal life support (ECLS) within an ICU at the time of enrollment

4. Requirement for chronic mechanical ventilation via tracheostomy prior to hospitalization

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

6. Patients with an independent indication for therapeutic-dose anticoagulation

7. Patients with a contraindication to therapeutic-dose anticoagulation, including:

8. Non-traumatic bleeding that requires medical evaluation or hospitalization within 30 days prior to CAP hospital admission

9. History of an inherited or acquired bleeding disorder

10. Cerebral aneurysm or mass lesions of the central nervous system

11. Ischemic stroke within 3 months of hospital admission

12. Gastrointestinal bleeding within 3 months of hospital admission

13. Platelet count <50 x109/L OR INR >2.0 OR hemoglobin <80 g/L at the time of screening

14. Other physician-perceived contraindications to therapeutic anticoagulation

15. History of heparin induced thrombocytopenia (HIT) or other heparin allergy

16. Current or recent (within 7 days of screening) use of dual anti-platelet inhibitors (For example; Aspirin + one of the following; clopidogrel, ticagrelor, prasugrel)

17. Patients in whom imminent death is anticipated

18. Anticipated transfer to another hospital that is not a study site within 72 hours of randomization

19. Enrollment in other interventional trials related to anticoagulation or antiplatelet therapy during current hospitalization

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago	Chicago	Illinois	United States	60637
2	Ochsner Clinic	Jefferson	Louisiana	United States	70121
3	Maine Medical Center	Portland	Maine	United States	04102
4	Maine Medical Centre	Portland	Maine	United States	04102
5	Henry Ford University	Dearborn	Michigan	United States	48128
6	Instituto Goiano de Oncologia e Hematologia - INGOH	Goiania	Goias	Brazil
7	Hospital do Coração - MS	Campo Grande	MS	Brazil
8	Hospital Angelina Caron	Curitiba	PR	Brazil
9	Hospital Sao Vicente de Paulo	Passo Fundo	Rio Grande Do Sul	Brazil
10	Hospital Universitário de Canoas	Canoas	RS	Brazil
11	UNIMAR	Marília	SP	Brazil
12	CRT-AIDS Santa Cruz	São Paulo	SP	Brazil
13	Hospital Municipal Bela Vista	São Paulo	SP	Brazil
14	UNIFESP	São Paulo	SP	Brazil
15	Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo		Brazil
16	Foothills Medical Centre	Calgary	Alberta	Canada	T2N 2T9
17	Vancouver General Hospital	Vancouver	British Columbia	Canada	V5Z 1M9
18	Health Sciences Center Winnipeg	Winnipeg	Manitoba	Canada	R3A 1R9
19	Grace General Hospital	Winnipeg	Manitoba	Canada
20	St. Boniface General Hospital	Winnipeg	Manitoba	Canada
21	Memorial University	Saint John's	Newfoundland and Labrador	Canada	A1C 5S7
22	St. Joseph's Healthcare Hamilton	Hamilton	Ontario	Canada
23	Kingston General Hospital	Kingston	Ontario	Canada	K7L 2V7
24	Markham Stouffville Hospital	Markham	Ontario	Canada	L3P 7P3
25	Hôpital Montfort	Ottawa	Ontario	Canada
26	The Ottawa Hospital	Ottawa	Ontario	Canada
27	Niagara Health System - St Catharines Site	St. Catherines	Ontario	Canada	L2S 0A9
28	Sunnybrook Health Sciences Centre	Toronto	Ontario	Canada	M4N 3M5
29	University Health Network	Toronto	Ontario	Canada	M5G2C4
30	McGill University Health Centre	Montréal	Quebec	Canada	H4A3J1
31	Centre Hospitalier de l'université de Montréal (CHUM)	Montréal	Quebec	Canada
32	Jewish General Hospital	Montréal	Quebec	Canada
33	CHU de Quebec-University Laval	Québec	Quebec	Canada
34	Institut universitaire de cardiologie et de pneumologie de Québec (CRIUCPQ)	Québec	Quebec	Canada

Sponsors and Collaborators

• University of Manitoba
• Canadian Institutes of Health Research (CIHR)
• Research Manitoba
• Ozmosis Research Inc.
• Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
• Canadian Critical Care Trials Group

Investigators

• Principal Investigator: Ryan Zarychanski, MD, University of Manitoba
• Principal Investigator: Patrick Lawler, MD, University Health Network and McGill University
• Principal Investigator: Sylvain Lother, MD, University of Manitoba
• Principal Investigator: Alexis Turgeon, MD, L'Universite Laval

Study Documents (Full-Text)

None provided.

More Information

Publications

• ATTACC Investigators; ACTIV-4a Investigators; REMAP-CAP Investigators; Lawler PR, Goligher EC, Berger JS, Neal MD, McVerry BJ, Nicolau JC, Gong MN, Carrier M, Rosenson RS, Reynolds HR, Turgeon AF, Escobedo J, Huang DT, Bradbury CA, Houston BL, Kornblith LZ, Kumar A, Kahn SR, Cushman M, McQuilten Z, Slutsky AS, Kim KS, Gordon AC, Kirwan BA, Brooks MM, Higgins AM, Lewis RJ, Lorenzi E, Berry SM, Berry LR, Aday AW, Al-Beidh F, Annane D, Arabi YM, Aryal D, Baumann Kreuziger L, Beane A, Bhimani Z, Bihari S, Billett HH, Bond L, Bonten M, Brunkhorst F, Buxton M, Buzgau A, Castellucci LA, Chekuri S, Chen JT, Cheng AC, Chkhikvadze T, Coiffard B, Costantini TW, de Brouwer S, Derde LPG, Detry MA, Duggal A, Dzavik V, Effron MB, Estcourt LJ, Everett BM, Fergusson DA, Fitzgerald M, Fowler RA, Galanaud JP, Galen BT, Gandotra S, Garcia-Madrona S, Girard TD, Godoy LC, Goodman AL, Goossens H, Green C, Greenstein YY, Gross PL, Hamburg NM, Haniffa R, Hanna G, Hanna N, Hegde SM, Hendrickson CM, Hite RD, Hindenburg AA, Hope AA, Horowitz JM, Horvat CM, Hudock K, Hunt BJ, Husain M, Hyzy RC, Iyer VN, Jacobson JR, Jayakumar D, Keller NM, Khan A, Kim Y, Kindzelski AL, King AJ, Knudson MM, Kornblith AE, Krishnan V, Kutcher ME, Laffan MA, Lamontagne F, Le Gal G, Leeper CM, Leifer ES, Lim G, Lima FG, Linstrum K, Litton E, Lopez-Sendon J, Lopez-Sendon Moreno JL, Lother SA, Malhotra S, Marcos M, Saud Marinez A, Marshall JC, Marten N, Matthay MA, McAuley DF, McDonald EG, McGlothlin A, McGuinness SP, Middeldorp S, Montgomery SK, Moore SC, Morillo Guerrero R, Mouncey PR, Murthy S, Nair GB, Nair R, Nichol AD, Nunez-Garcia B, Pandey A, Park PK, Parke RL, Parker JC, Parnia S, Paul JD, Perez Gonzalez YS, Pompilio M, Prekker ME, Quigley JG, Rost NS, Rowan K, Santos FO, Santos M, Olombrada Santos M, Satterwhite L, Saunders CT, Schutgens REG, Seymour CW, Siegal DM, Silva DG Jr, Shankar-Hari M, Sheehan JP, Singhal AB, Solvason D, Stanworth SJ, Tritschler T, Turner AM, van Bentum-Puijk W, van de Veerdonk FL, van Diepen S, Vazquez-Grande G, Wahid L, Wareham V, Wells BJ, Widmer RJ, Wilson JG, Yuriditsky E, Zampieri FG, Angus DC, McArthur CJ, Webb SA, Farkouh ME, Hochman JS, Zarychanski R. Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19. N Engl J Med. 2021 Aug 26;385(9):790-802. doi: 10.1056/NEJMoa2105911. Epub 2021 Aug 4.

• Responsible Party: University of Manitoba
• ClinicalTrials.gov Identifier: NCT05848713
• Other Study ID Numbers: ATTACC-CAP; OZM-129
• First Posted: May 8, 2023
• Last Update Posted: May 8, 2023
• Last Verified: Apr 1, 2023

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by University of Manitoba: Pneumonia; Heparin; Anticoagulation; Community acquired pneumonia; Unfractionated Heparin; Low Molecular Weight Heparin; Dalteparin; Enoxaparin; Tinzaparin
• Additional relevant MeSH terms: Pneumonia; Heparin

Study Results

No Results Posted as of May 8, 2023