Clinical trial NCT05848713: AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia
Official title: AntiThrombotic Therapy to Ameliorate Clinical Complications in Community Acquired Pneumonia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Community-acquired Pneumonia
Keywords: Pneumonia
Heparin
Anticoagulation
Community acquired pneumonia
Unfractionated Heparin
Low Molecular Weight Heparin
Dalteparin
Enoxaparin
Tinzaparin
Lead sponsor: University of Manitoba
Sponsor class: OTHER
Collaborators: name: Canadian Institutes of Health Research (CIHR)
name: Research Manitoba
name: Ozmosis Research Inc.
name: Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network
name: Canadian Critical Care Trials Group
name: AVANTI
First posted: 2023-05-08
Enrollment: 4000
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Adaptive stratified randomized clinical trial with Bayesian stopping rules
Primary purpose: TREATMENT

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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Ordinal endpoint reflecting survival
timeFrame: 30 days
Secondary outcomes:
measure: Bleeding events
timeFrame: 14 days
measure: HIT events
timeFrame: 14 days
measure: Thrombotic events
timeFrame: 30 days and 90 days
measure: Invasive mechanical ventilation
timeFrame: 30 days
measure: All cause mortality
timeFrame: 30 days, 90 days, and 180 days
measure: Hospital-free days
timeFrame: 30 days, 90 days, and 180 days
measure: Health related quality of life
timeFrame: 30 days, 90 days, and 180 days
measure: Health related quality of life
timeFrame: 30 days, 90 days, and 180 days
Other outcomes:
Locations:
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Jefferson
country: United States
facility: Ochsner Clinic
state: Louisiana
city: Portland
country: United States
facility: Maine Medical Centre
state: Maine
city: Dearborn
country: United States
facility: Henry Ford University
state: Michigan
city: Camden
country: United States
facility: Cooper University Health Care
state: New Jersey
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Itabuna
country: Brazil
facility: Santa Casa de Misericordia de Itabuna
state: BA
city: Brasília
country: Brazil
facility: Hospital Brasilia
state: DF
city: Brasília
country: Brazil
facility: Hospital Sao Brasilia
state: DF
city: Brasília
country: Brazil
facility: Instituto de Cardiologia e Transplantes do Distrito Federal
state: DF
city: Serra
country: Brazil
facility: Hospital Estadual Dr. Jayme Santos Neves
state: ES
city: Vila Velha
country: Brazil
facility: Hospital Evangelico de Vila Velha
state: ES
city: Vitória
country: Brazil
facility: Hospital Universitário Cassiano Antonio Moraes
state: ES
city: Goiania
country: Brazil
facility: Instituto Goiano de Oncologia e Hematologia - INGOH
state: GO
city: Goiânia
country: Brazil
facility: Hospital de Messejana Dr. Carlos Alberto Studart Gomes
state: GO
city: Goiânia
country: Brazil
facility: Hospital Ruy Azeredo
state: GO
city: Belo Horizonte
country: Brazil
facility: Hospital Felicio Rocho
state: MG
city: Belo Horizonte
country: Brazil
facility: NUPEC-Orizonti
state: MG
city: Curitiba
country: Brazil
facility: Hospital Santa Cruz
state: PR
city: Curitiba
country: Brazil
facility: PUCPR
state: PR
city: Lajeado
country: Brazil
facility: Hospital Bruno Born
state: RS
city: Passo Fundo
country: Brazil
facility: Hospital Sao Vicente de Paulo
state: RS
city: Porto Alegre
country: Brazil
facility: Hospital de Clínicas de Porto Alegre
state: RS
city: Santa Maria
country: Brazil
facility: Hospital Universitario de Santa Maria
state: RS
city: Bragança Paulista
country: Brazil
facility: Hospital Universitario Sao Francisco na Providencia na Deus
state: Sao Paulo
city: Osasco
country: Brazil
facility: CiTen - Centro Hospital Municipal Antonio Giglio
state: Sao Paulo
city: Criciúma
country: Brazil
facility: Hospital Sao Jose
state: SC
city: São José
country: Brazil
facility: Hospital Regional Homero Miranda Gomes
state: SC
city: Bauru
country: Brazil
facility: Hospital de Reabilitacao de Anomalias Craniofaciais
state: SP
city: Botucatu
country: Brazil
facility: UPECLIN - Unidade de Pesquisa Clínica da Faculdade de Medicina de Botucatu
state: SP
city: Campinas
country: Brazil
facility: Fundação Centro Médico de Campinas
state: SP
city: Campinas
country: Brazil
facility: IPECC
state: SP
city: Presidente Prudente
country: Brazil
facility: Hospital Regional de Presidente Prudente
state: SP
city: Ribeirão Preto
country: Brazil
facility: Hospital Estadual de Serrana
state: SP
city: São Paulo
country: Brazil
facility: Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo
state: SP
city: São Paulo
country: Brazil
facility: Santa Casa de Misericordia de Sao Paulo
state: SP
city: São Paulo
country: Brazil
facility: HCFMUSP
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Grande Prairie
country: Canada
facility: Grand Prairie Regional Hospital
state: Alberta
city: Nanaimo
country: Canada
facility: Nanaimo Regional General Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: Health Sciences Center Winnipeg
state: Manitoba
city: Winnipeg
country: Canada
facility: Grace General Hospital
state: Manitoba
city: Winnipeg
country: Canada
facility: St. Boniface General Hospital
state: Manitoba
city: Saint John's
country: Canada
facility: Memorial University
state: Newfoundland and Labrador
city: Hamilton
country: Canada
facility: Hamilton Health Sciences - Juravinski
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: Markham
country: Canada
facility: Markham Stouffville Hospital
state: Ontario
city: Ottawa
country: Canada
facility: Hôpital Montfort
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital
state: Ontario
city: St. Catherines
country: Canada
facility: Niagara Health System - St Catharines Site
state: Ontario
city: Sudbury
country: Canada
facility: Health Sciences North Research Institute
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
city: Lévis
country: Canada
facility: Centre Hospitalier de Quebec - Hotel-Dieu de Levis
state: Quebec
city: Montréal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier de l'université de Montréal (CHUM)
state: Quebec
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Québec
country: Canada
facility: CHU de Quebec-University Laval
state: Quebec
city: Québec
country: Canada
facility: Institut universitaire de cardiologie et de pneumologie de Québec (IUCPQ)
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Regina General Hospital
state: Saskatchewan
Study officials:
affiliation: University of Manitoba
name: Ryan Zarychanski, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Health Network and McGill University
name: Patrick Lawler, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Manitoba
name: Sylvain Lother, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: L'Universite Laval
name: Alexis Turgeon, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.