AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia

Community-acquired Pneumonia Clinical Trial

— ATTACC-CAP  

Official title:

AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05848713
• Other study ID #: ATTACC-CAP
• Secondary ID: OZM-129
• Status: Recruiting
• Phase: Phase 3
• Start date: October 10, 2023
• Est. completion date: March 31, 2029

Study information

• Verified date: November 2023
• Source: University of Manitoba
• Contact: Chantale Pineau
• Phone: 2042353223
• Email: attacc.cap[@]umanitoba.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 4000
• Est. completion date: March 31, 2029
• Est. primary completion date: March 31, 2028
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Patients =18 years of age

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

1. Radiographic evidence of new or worsening infiltrate

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

i. 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

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

4. 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:

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

2. History of an inherited or acquired bleeding disorder

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

4. Ischemic stroke within 3 months of hospital admission

5. Gastrointestinal bleeding within 3 months of hospital admission

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

7. Other physician-perceived contraindications to therapeutic anticoagulation

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

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

10. Patients in whom imminent death is anticipated

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

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

Related Conditions & MeSH terms

• Community-acquired Pneumonia
• Pneumonia

Intervention

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.

Locations

Country	Name	City	State
Brazil	Hospital de Reabilitacao de Anomalias Craniofaciais	Bauru	SP
Brazil	Hospital Felicio Rocho	Belo Horizonte	MG
Brazil	NUPEC-Orizonti	Belo Horizonte	MG
Brazil	UPECLIN - Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu	Botucatu	SP
Brazil	Hospital Universitario Sao Francisco na Providencia na Deus	Bragança Paulista	Sao Paulo
Brazil	Hospital Brasilia	Brasília	DF
Brazil	Hospital Sao Brasilia	Brasília	DF
Brazil	Instituto de Cardiologia e Transplantes do Distrito Federal	Brasília	DF
Brazil	IPECC	Campinas	SP
Brazil	Hospital do Coração - MS	Campo Grande	MS
Brazil	Hospital Sao Jose	Criciúma	SC
Brazil	Hospital Santa Cruz	Curitiba	PR
Brazil	PUCPR	Curitiba	PR
Brazil	Instituto Goiano de Oncologia e Hematologia - INGOH	Goiania	GO
Brazil	Hospital de Messejana Dr. Carlos Alberto Studart Gomes	Goiânia	GO
Brazil	Hospital Ruy Azeredo	Goiânia	GO
Brazil	Santa Casa de Misericordia de Itabuna	Itabuna	BA
Brazil	Hospital Bruno Born	Lajeado	RS
Brazil	CiTen - Centro Hospital Municipal Antonio Giglio	Osasco	Sao Paulo
Brazil	Hospital Sao Vicente de Paulo	Passo Fundo	RS
Brazil	Hospital de Clínicas de Porto Alegre	Porto Alegre	RS
Brazil	Hospital Regional de Presidente Prudente	Presidente Prudente	SP
Brazil	Hospital Estadual de Serrana	Ribeirão Preto	SP
Brazil	Hospital Universitario de Santa Maria	Santa Maria	RS
Brazil	Hospital Regional Homero Miranda Gomes	São José	SC
Brazil	Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo	São Paulo	SP
Brazil	Santa Casa de Misericordia de Sao Paulo	São Paulo	SP
Brazil	Hospital Evangelico de Vila Velha	Vila Velha	ES
Brazil	Hospital Evangelico de Vila Velha	Vila Velha	ES
Brazil	Hospital Universitário Cassiano Antonio Moraes	Vitória	ES
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Hamilton Health Sciences	Hamilton	Ontario
Canada	Hamilton Health Sciences - Juravinski	Hamilton	Ontario
Canada	Kingston General Hospital	Kingston	Ontario
Canada	Markham Stouffville Hospital	Markham	Ontario
Canada	Centre Hospitalier de l'université de Montréal (CHUM)	Montréal	Quebec
Canada	Jewish General Hospital	Montréal	Quebec
Canada	McGill University Health Centre	Montréal	Quebec
Canada	Nanaimo Regional General Hospital	Nanaimo	British Columbia
Canada	Hôpital Montfort	Ottawa	Ontario
Canada	The Ottawa Hospital	Ottawa	Ontario
Canada	CHU de Quebec-University Laval	Québec	Quebec
Canada	Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)	Québec	Quebec
Canada	Memorial University	Saint John's	Newfoundland and Labrador
Canada	Centre Hospitalier Universitaire de Sherbrooke	Sherbrooke	Quebec
Canada	Niagara Health System - St Catharines Site	St. Catherines	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University Health Network	Toronto	Ontario
Canada	Vancouver General Hospital	Vancouver	British Columbia
Canada	Grace General Hospital	Winnipeg	Manitoba
Canada	Health Sciences Center Winnipeg	Winnipeg	Manitoba
Canada	St. Boniface General Hospital	Winnipeg	Manitoba
United States	University of Chicago	Chicago	Illinois
United States	Henry Ford University	Dearborn	Michigan
United States	Ochsner Clinic	Jefferson	Louisiana
United States	Maine Medical Center	Portland	Maine
United States	Maine Medical Centre	Portland	Maine

Sponsors (6)

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

Countries where clinical trial is conducted

United States,  Brazil,  Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Ordinal endpoint reflecting survival	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.	30 days
Secondary	Bleeding events	Number of participants with major bleeds as defined by the ISTH definition.	14 days
Secondary	HIT events	Number of participants with laboratory confirmed heparin induced thrombocytopenia (HIT)	14 days
Secondary	Thrombotic events	Number of participants with deep vein thrombosis, pulmonary embolism, systemic arterial thromboembolism, myocardial infarction, or ischemic stroke	30 days and 90 days
Secondary	Invasive mechanical ventilation	Ordered categorical endpoint with three possible outcomes based on the worst status of each patient through day 30 following randomization	30 days
Secondary	All cause mortality		30 days, 90 days, and 180 days
Secondary	Hospital-free days	Days alive outside hospital	30 days, 90 days, and 180 days
Secondary	Health related quality of life	Using the EQ-5D-5L instrument	30 days, 90 days, and 180 days
Secondary	Health related quality of life	Using the Clinical Frailty Scale instrument	30 days, 90 days, and 180 days