Clinical trial NCT04324463: Anti-Coronavirus Therapies to Prevent Progression of Coronavirus Disease 2019 (COVID-19) Trial
Official title: Anti-Coronavirus Therapies to Prevent Progression of COVID-19, a Randomized Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Coronavirus
Severe Acute Respiratory Syndrome
Keywords: COVID-19
coronavirus
interferon
colchicine
aspirin
rivaroxaban
anti-inflammatory
antithrombotic
anti-viral
Lead sponsor: Population Health Research Institute
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2020-03-27
Enrollment: 6667
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Open-label, parallel group, factorial, randomized controlled trial
Primary purpose: TREATMENT

Brief summary: ACT is a randomized clinical trial to assess therapies to reduce the clinical progression of COVID-19.

Detailed description: The ACT COVID-19 program consists of two parallel trials testing the effects of interventions in complementary populations in outpatients and inpatients.

In the outpatient study, symptomatic patients in the community who are COVID-19 positive and at high risk of disease progression: colchicine compared with control (anti-inflammatory); and ASA compared with control (anti-thrombotic); using a 2 x 2 factorial design. The primary outcome for colchicine vs. control is the composite of hospitalization or death. The primary outcome for ASA vs. control is the composite of hospitalization, death, or major thrombosis \[myocardial infarction(MI), stroke, acute limb ischemia(ALI), or pulmonary embolism (PE)\].

For inpatients, in symptomatic patients who are COVID-19 positive and who are hospitalized: colchicine is compared with control (anti-inflammatory), and the combination of ASA and rivaroxaban is compared with control (anti-thrombotic); using a 2 x 2 factorial design. The primary outcome for colchicine vs. control is the composite of high flow oxygen, mechanical ventilation, or death. The primary outcome for the combination of ASA and rivaroxaban vs. control is the composite of high flow oxygen, mechanical ventilation, death, or major thrombosis (MI, stroke, ALI, or PI).

\*The Inpatient study previously also included a comparison of Interferon-β with control in a 2x2x2 design. The Interferon-β arm was closed to recruitment in November 2020.

Eligibility criteria: Outpatient trial:

Inclusion criteria:

1. Symptomatic and laboratory-confirmed diagnosis of COVID-19.
2. Age ≥ 30 years.
3. High risk: either age ≥70 or one of the following: male; obesity (BMI ≥30); chronic cardiovascular, respiratory or renal disease; active cancer; diabetes.
4. Within 7 days (ideally 72 hours) of diagnosis, or worsening clinically.

Exclusion criteria:

1. General: advanced kidney disease; advanced liver disease; pregnancy (known or potential) or lactation.
2. Colchicine: allergy or planned use; current or planned use of cyclosporine, verapamil, HIV protease inhibitor, azole antifungal, or macrolide antibiotic (except azithromycin).
3. ASA: allergy; high risk of bleeding, current or planned use of other anti-thrombotic drugs (e.g., P2Y12 inhibitors, direct oral anticoagulants, vitamin K antagonists, heparins)

Inpatient trial:

Inclusion criteria:

1. Symptomatic and laboratory-confirmed diagnosis of COVID-19.
2. Age ≥18 years.
3. Within 72 hours (ideally 24 hours) of admission, or worsening clinically.

Exclusion criteria:

1. General: advanced kidney disease; advanced liver disease, pregnancy (known or potential) or lactation, already ventilated for \>72 hours.
2. Colchicine: allergy or planned use; current or planned use of cyclosporine, verapamil, HIV protease inhibitors, azole antifungals, or macrolide antibiotics (except azithromycin).
3. ASA and rivaroxaban: allergy; high risk of bleeding; estimated GFR \<15 ml/min; current or planned use of P2Y12 inhibitors or therapeutic doses of anticoagulants\* (e.g., direct oral anticoagulants, vitamin K antagonists, heparin, LMWH), current or planned use of strong inhibitors of both CYP 3A4 and P-gp (e.g., lopinavir/ritonavir, carbamazepine, ketoconazole). \*Note that prophylactic doses of anticoagulants can be used in patients who are randomized to control.

Primary outcomes:
measure: Outpatient trial - Colchicine vs. control: Time from randomization to first occurrence of the composite of hospitalization or death
timeFrame: 45 days post randomization
measure: Outpatient trial - Aspirin vs. control: Time from randomization to first occurrence of the composite of hospitalization, death or major thrombosis (MI, stroke, ALI, or PE)
timeFrame: 45 days post randomization
measure: Inpatient trial - Colchicine vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, or death
timeFrame: 45 days post randomization
measure: Inpatient trial - Aspirin and Rivaroxaban vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, death or major thrombosis (MI, stroke, ALI, or PE)
timeFrame: 45 days post randomization
Secondary outcomes:
measure: Outpatient trial - Aspirin vs. control: Time from randomization to first occurrence of any thrombosis (MI, stroke, ALI, PE, or DVT)
timeFrame: 45 days post randomization
measure: Inpatient trial - Colchicine vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, or respiratory death
timeFrame: 45 days post randomization
measure: Inpatient trial - Aspirin vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, or respiratory death
timeFrame: 45 days post randomization
measure: Inpatient trial - Aspirin vs. control: Time from randomization to first occurrence of any thrombosis (MI, stroke, ALI, PE, or DVT)
timeFrame: 45 days post randomization
Other outcomes:
Locations:
city: Manaus
country: Brazil
facility: Hospital Adventista de Manaus
state: Amazonas
city: Salvador
country: Brazil
facility: Prodal Saude S/A
state: BA
city: Vitoria
country: Brazil
facility: Hospital das Clinicas de Vitoria (Hospital Universitario Cassiano Antonio Moraes)
state: ES
city: Uberaba
country: Brazil
facility: Ubermed Serviços em Saúde Eireli - Hospital São Domingos
state: MG
city: Uberlândia
country: Brazil
facility: Hospital de Clínicas da Universidade Federal de Uberlândia
state: MG
city: Cuiabá
country: Brazil
facility: Hospital Universitario Julio Muller
state: Mount
city: Bento Goncalves
country: Brazil
facility: Instituto Tacchini de Pesquisa em Saude / Hospital Tacchini
state: Rio Grande Do Sul
city: Votuporanga
country: Brazil
facility: Santa Casa de Votuporanga
state: Sao Paulo
city: São Carlos
country: Brazil
facility: Hospital Universitario Prof. Dr. Horacio Carlos Panepucci da Universidade Federal de Sao Carlos (HU-UFSCar)
state: SP
city: São Paulo
country: Brazil
facility: Hospital Alemão Oswaldo Cruz
state: SP
city: Calgary
country: Canada
facility: CardiAI Inc.
state: Alberta
city: Hamilton
country: Canada
facility: Hamilton Health Sciences
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Newmarket
country: Canada
facility: Southlake Regional Health Centre
state: Ontario
city: Oakville
country: Canada
facility: Halton Healthcare/Oakville Trafalgar Memorial Hospital
state: Ontario
city: St. Catharines
country: Canada
facility: Niagara Health System-St. Catharine's
state: Ontario
city: Toronto
country: Canada
facility: Toronto Western Hospital Family Health Team
state: Ontario
city: Windsor
country: Canada
facility: Windsor Regional Hospital
state: Ontario
city: Woodstock
country: Canada
facility: Woodstock Hospital
state: Ontario
city: Montreal
country: Canada
facility: CIUSSS de L'est-de-l'ile de Montreal, Hopital Maisonneuve-Rosemont
state: Quebec
city: Montréal
country: Canada
facility: Centre Hospitalier de l'Université de Montréal (CHUM)
state: Quebec
city: Barranquilla
country: Colombia
facility: Biomelab SAS
state: Atlantico
city: Barranquilla
country: Colombia
facility: Clinica de la Costa LTDA
state: Atlantico
city: Bucaramanga
country: Colombia
facility: Instituto de Neumologico del Oriente
state: Santander
city: Guayaquil
country: Ecuador
facility: Unicormed
state: Guayas
city: Quito
country: Ecuador
facility: Hospital de Especialidades Eugenio Espejo
state: Pichincha
city: Quito
country: Ecuador
facility: Hospital Enrique Garces
state: Pichincha
city: Quito
country: Ecuador
facility: Hospital General Pablo Arturo Suarez
state: Pichincha
city: Ambato
country: Ecuador
facility: Oncoambato
state: Tungurahua
city: Giza
country: Egypt
facility: Giza Chest Hospital
state: Cairo
city: Cairo
country: Egypt
facility: Abbasia Chest Hospital
city: Cairo
country: Egypt
facility: Abbasia Fever Hospital
city: Cairo
country: Egypt
facility: National Hepatology and Tropical Medicine Research Institute
city: Fayoum
country: Egypt
facility: Fayoum University Hospital
city: Bangalore
country: India
facility: St. John's Medical College and Hospital
state: Karnataka
city: Pune
country: India
facility: Bharathi Hospital and Research Center
state: Maharashtra
city: Pune
country: India
facility: Sanjeevan Hospital
state: Maharashtra
city: Doraha
country: India
facility: Sidhu Hospital Pvt.Ltd
state: Punjab
city: Chengalpattu
country: India
facility: SRM Medical College Hospital & Research Center
state: Tamil Nadu
city: Hyderabad
country: India
facility: AIG Hospital
state: Telangana
city: Secunderabad
country: India
facility: KIMS
state: Telangana
city: Bharatpur-10
country: Nepal
facility: Chitwan Medical College
state: Bagmati
city: Kathmandu
country: Nepal
facility: Sahid Gangalal National Heart Center
state: Bagmati
city: Surkhet
country: Nepal
facility: Province Hospital, Karnali Province
state: Karnali
city: Bhadrapur
country: Nepal
facility: Mechi Zonal Hospital
state: Province No. 1
city: Biratnagar
country: Nepal
facility: Koshi Zonal Hospital
state: Province No. 1
city: Kathmandu
country: Nepal
facility: B.P. Koirala Institute of Health Sciences
state: Province No.1
city: Karachi
country: Pakistan
facility: Aga Khan University Hospital
state: Sindh
city: Karachi
country: Pakistan
facility: Jinnah Postgraduate Medical Center
state: Sindh
city: Karachi
country: Pakistan
facility: Tabba Heart Institute
state: Sindh
city: Manila
country: Philippines
facility: Philippine General Hospital
state: Metro Manila
city: Ekaterinburg
country: Russian Federation
facility: State Budgetary Health Care Institution of Sverdlovsk region "Central city clinical hospital # 6 Ekaterinburg"
state: Sverdlovsk Region
city: Yekaterinburg
country: Russian Federation
facility: Central City Clinical Hospital No. 24
state: Sverdlovsk Region
city: Tver
country: Russian Federation
facility: Tver State Medical University
state: Tver Oblast
city: Voronezh
country: Russian Federation
facility: Voronezh State Medical University named after N.N. Burdenko
state: Voronezh Region
city: Barnaul
country: Russian Federation
facility: Altai Regional Center for Medical Prevention
city: Moscow
country: Russian Federation
facility: City Clinical Hospital No. 15 named after O.M. Filatova
city: Moscow
country: Russian Federation
facility: National Medical Research Center for Therapy and Preventive Medicine
city: Nizhny Novgorod
country: Russian Federation
facility: City Clinical Hospital No. 3
city: Rostov-on-Don
country: Russian Federation
facility: Rostov State Medical University
city: Cape Town
country: South Africa
facility: Tiervlei Trial Centre
state: Western Cape
city: Cape Town
country: South Africa
facility: University of Cape Town- Groote Schuur Hospital
state: Western Cape
city: George
country: South Africa
facility: TASK Eden
state: Western Cape
city: Hatta
country: United Arab Emirates
facility: Hatta Hospital
state: Dubai
city: Dubai
country: United Arab Emirates
facility: Rashid Hospital, Dubai Health Authority
city: Dubai
country: United Arab Emirates
facility: Thumbay Hospital Dubai
Study officials:
affiliation: Population Health Research Institute
name: Richard Whitlock, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Population Health Research Institute
name: Emilie Belley-Cote, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Population Health Research Institute
name: John Eikelboom, MBBS MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: Eikelboom JW, Jolly SS, Belley-Cote EP, Whitlock RP, Rangarajan S, Xu L, Heenan L, Bangdiwala SI, Luz Diaz M, Diaz R, Yusufali A, Kumar Sharma S, Tarhuni WM, Hassany M, Avezum A, Harper W, Wasserman S, Almas A, Drapkina O, Felix C, Lopes RD, Berwanger O, Lopez-Jaramillo P, Anand SS, Bosch J, Choudhri S, Farkouh ME, Loeb M, Yusuf S. Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial. Lancet Respir Med. 2022 Dec;10(12):1169-1177. doi: 10.1016/S2213-2600(22)00298-3. Epub 2022 Oct 10.
citation: Eikelboom JW, Jolly SS, Belley-Cote EP, Whitlock RP, Rangarajan S, Xu L, Heenan L, Bangdiwala SI, Tarhuni WM, Hassany M, Kontsevaya A, Harper W, Sharma SK, Lopez-Jaramillo P, Dans AL, Palileo-Villanueva LM, Avezum A, Pais P, Xavier D, Felix C, Yusufali A, Lopes RD, Berwanger O, Ali Z, Wasserman S, Anand SS, Bosch J, Choudhri S, Farkouh ME, Loeb M, Yusuf S. Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial. Lancet Respir Med. 2022 Dec;10(12):1160-1168. doi: 10.1016/S2213-2600(22)00299-5. Epub 2022 Oct 10.
citation: Mikolajewska A, Fischer AL, Piechotta V, Mueller A, Metzendorf MI, Becker M, Dorando E, Pacheco RL, Martimbianco ALC, Riera R, Skoetz N, Stegemann M. Colchicine for the treatment of COVID-19. Cochrane Database Syst Rev. 2021 Oct 18;10(10):CD015045. doi: 10.1002/14651858.CD015045.