Anti-Coronavirus Therapies to Prevent Progression of Coronavirus Disease 2019 (COVID-19) Trial

Study Overview
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Brief Summary
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ACT is a randomized clinical trial to assess therapies to reduce the clinical progression of COVID-19.

Detailed Description
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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.

Official Title
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Anti-Coronavirus Therapies to Prevent Progression of COVID-19, a Randomized Trial

Conditions
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Coronavirus, Severe Acute Respiratory Syndrome

Intervention / Treatment
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* Drug: Colchicine
* Drug: Interferon-Beta
* Drug: Aspirin
* Drug: Rivaroxaban


Participation Criteria
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Eligibility Criteria
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Outpatient trial: Inclusion criteria: Symptomatic and laboratory-confirmed diagnosis of COVID-19. Age ≥ 30 years. High risk: either age ≥70 or one of the following: male; obesity (BMI ≥30); chronic cardiovascular, respiratory or renal disease; active cancer; diabetes. Within 7 days (ideally 72 hours) of diagnosis, or worsening clinically. Exclusion criteria: General: advanced kidney disease; advanced liver disease; pregnancy (known or potential) or lactation. Colchicine: allergy or planned use; current or planned use of cyclosporine, verapamil, HIV protease inhibitor, azole antifungal, or macrolide antibiotic (except azithromycin). 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: Symptomatic and laboratory-confirmed diagnosis of COVID-19. Age ≥18 years. Within 72 hours (ideally 24 hours) of admission, or worsening clinically. Exclusion criteria: General: advanced kidney disease; advanced liver disease, pregnancy (known or potential) or lactation, already ventilated for >72 hours. Colchicine: allergy or planned use; current or planned use of cyclosporine, verapamil, HIV protease inhibitors, azole antifungals, or macrolide antibiotics (except azithromycin). 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Open-label, parallel group, factorial, randomized controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Colchicine<br>Outpatients: 0.6 mg twice daily for 3 days, then 0.6 mg once daily for 25 days (total 28 days). Inpatients: 1.2 mg followed by 0.6 mg 2 hours later, then 0.6 mg twice daily for 28 days. (*Depending on availability, 0.6 mg tablets can be substituted by 0.5 mg tablets for a regimen in outpatients of 0.5 mg twice daily for 3 days, then 0.5 mg once daily for 25 days [total 28 days]; and in inpatients of 1.0 mg followed by 0.5 mg 2 hours later, then 0.5 mg twice daily for 28 days). | Drug: Colchicine<br>* oral medication<br>|
| Experimental: Interferon Beta [This arm is now closed to recruitment]<br>Inpatients Only: 0.25 mg by subcutaneous injection on days 1, 3, 5 & 7 | Drug: Interferon-Beta<br>* subcutaneous injection<br>|
| Experimental: Aspirin (ASA)<br>Outpatients: 75 to 100 mg once daily for 28 days. Inpatients: 75 to 100 mg once daily for 28 days | Drug: Aspirin<br>* oral medication<br>|
| Experimental: Rivaroxaban<br>Inpatients Only: 2.5 mg twice daily for 28 days. | Drug: Rivaroxaban<br>* oral medication<br>|
| No Intervention: Usual Care (Control)<br>Outpatients and Inpatients: No constraints for treating physicians on the therapies within the standard of care arm. All key co-interventions will be documented. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Outpatient trial - Colchicine vs. control: Time from randomization to first occurrence of the composite of hospitalization or death |  | 45 days post randomization | 
| 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) |  | 45 days post randomization | 
| Inpatient trial - Colchicine vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, or death |  | 45 days post randomization | 
| 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) |  | 45 days post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Outpatient trial - Aspirin vs. control: Time from randomization to first occurrence of any thrombosis (MI, stroke, ALI, PE, or DVT) |  | 45 days post randomization | 
| Inpatient trial - Colchicine vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, or respiratory death |  | 45 days post randomization | 
| Inpatient trial - Aspirin vs. control: Time from randomization to first occurrence of the composite of high flow oxygen, mechanical ventilation, or respiratory death |  | 45 days post randomization | 
| Inpatient trial - Aspirin vs. control: Time from randomization to first occurrence of any thrombosis (MI, stroke, ALI, PE, or DVT) |  | 45 days post randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, coronavirus, interferon, colchicine, aspirin, rivaroxaban, anti-inflammatory, antithrombotic, anti-viral