key: cord-0948071-qcdxks09
authors: Eikelboom, John; Rangarajan, Sumathy; Jolly, Sanjit S.; Belley-Cote, Emilie P.; Whitlock, Richard; Beresh, Heather; Lewis, Gayle; Xu, Lizhen; Chan, Noel; Bangdiwala, Shrikant; Diaz, Rafael; Orlandini, Andres; Hassany, Mohamed; Tarhuni, Wadea M.; Yusufali, A.M.; Sharma, Sanjib Kumar; Konstsevaya, Anna; Jaramillo, Patricio Lopez; Avezum, Alvaro; Dans, Antonio L.; Wasserman, Sean; Camilo, Felix; Kazmi, Khawar; Pais, Prem; Xavier, Denis; Lopes, Renato D.; Berwanger, Otavio; Nkeshimana, Menelas; Harper, William; Loeb, Mark; Choudhri, Shurjeel; Farkouh, Michael E.; Bosch, Jackie; Anand, Sonia S.; Yusuf, Salim
title: The Anti-Coronavirus Therapy (ACT) trials: design, baseline characteristics, and challenges.
date: 2022-03-01
journal: CJC Open
DOI: 10.1016/j.cjco.2022.02.010
sha: 6f7d6a5efd2d74011864c23de0969c5d3ef2a50f
doc_id: 948071
cord_uid: qcdxks09

BACKGROUND: Effective treatments for COVID-19 are urgently needed but conducting randomized trials during the pandemic has been challenging. METHODS: The Anti-Coronavirus Therapy (ACT) trials are parallel factorial international trials that aimed to enroll 3,500 outpatients and 2,500 inpatients with symptomatic COVID-19. The outpatient trial is evaluating colchicine versus usual care, and aspirin versus usual care. The primary outcome for the colchicine randomization is hospitalization or death, and for the aspirin randomization is major thrombosis, hospitalization, or death. The inpatient trial is evaluating colchicine versus usual care, and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily versus usual care. The primary outcome for the colchicine randomization is need for high flow oxygen, mechanical ventilation, or death, and for the rivaroxaban plus aspirin randomization is major thrombotic events, need for high flow oxygen, mechanical ventilation, or death. RESULTS: At the completion of enrolment on February 10, 2022, the outpatient trial had enrolled 3,917 patients and the inpatient trial 2,754 patients. Challenges encountered included lack of preliminary data about the interventions under evaluation, uncertainties related to the expected event rates, delays in regulatory and ethics approvals and in obtaining study interventions, as well as the changing pattern of the COVID-19 pandemic. CONCLUSIONS: The ACT trials will determine the efficacy of anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin given alone or in combination with rivaroxaban across the spectrum of mild, moderate, and severe COVID-19. Lessons learned from the conduct of these trials will inform planning of future trials.

Patients with coronavirus disease 2019 (COVID-19) most commonly experience mild symptoms.

Increasing severity of disease is accompanied by a hypercoagulable state and dysregulated immune response, and can result in respiratory failure, multi-organ dysfunction, and death. 1, 2 Initial efforts to identify effective therapies for COVID-19 focused on repurposing of existing drugs to target the virus, hypercoagulability, or inflammation, but most trials have been inadequately powered, and few treatments have been shown to be effective. [3] [4] [5] In combination with non-pharmaceutical methods, vaccines are expected the most effective way to reduce the burden of COVID-19, 6 but many countries have only limited access to vaccines, and even where the vaccine is widely available, hesitancy has limited uptake and breakthrough infections still occur. 7 Continued evaluation of potential therapies for COVID-19 therefore remains important.

Targeting inflammation using glucocorticoids 3 (e.g., dexamethasone) or immunomodulators 4, 5 (e.g., tocilizumab, baricitinib) reduces mortality in hospitalized patients with COVID-19. The advantage of glucocorticoids is that they are inexpensive and widely available, but they have many side effects including increased susceptibility to life-threatening infections, 8 whereas immunomodulators are unaffordable in many parts of the world. To date, anti-inflammatory therapies have not been shown to be effective in outpatients. Colchicine is a simple, inexpensive anti-inflammatory drug that has been used for more than 40 years at low doses for treatment of gout and familial Mediterranean fever. Colchicine accumulates in neutrophils and monocytes and inhibits the NLR3P inflammasome which is activated by the SARS-CoV-2 virus. 9 The randomized COLCORONA (n=4,488) trial testing colchicine (0.5 mg twice daily for 3 day followed by 0.5 mg once daily for 27 days) in outpatients 10 and the COLCOVID trial (n=1,279) testing colchicine (loading dose followed by 0.5 mg once daily for up to 14 days) in inpatients, 11 J o u r n a l P r e -p r o o f produced promising but not definitive results, whereas the much larger RECOVERY trial (n=11,340) did not demonstrate a benefit of colchicine in inpatients. 12 In the RECOVERY trial patients received a loading dose of colchicine followed by 0.5 mg twice daily for up to 10 days.

In the ACT outpatient trial, we are evaluating colchicine 0.6 mg twice daily for 3 days followed by 0.6 mg once daily for an additional 25 days in outpatients, which is similar to doses that were tested in COLCORONA. In the ACT inpatient trial, we are testing colchicine give as a loading dose of 1.2 mg followed by 0.6 mg 2 hours later and then 0.6 mg twice daily for 28 days in inpatients (with dose reduction in patients with severe renal impairment), which is a higher dose than that tested in RECOVERY and a longer duration of treatment than that tested in both RECOVERY and COLCOVID.

Hypercoagulability in patients with COVID-19 is accompanied by activation of blood coagulation including a marked increase in blood levels of D-Dimer. 13 Observational studies report high rates of venous thromboembolism (VTE) in hospitalized patients with COVID- 19, 14 whereas postmortem studies demonstrate extensive endothelial dysfunction and platelet and fibrin rich microvascular thrombosis involving the lungs and other organs. 15 Several randomized trials have evaluated the use of antithrombotic strategies in outpatients and inpatients with COVID-19, to prevent venous and arterial thromboembolic events and mortality, but results have been conflicting, with reductions in VTE accompanied by increases in bleeding and no mortality benefits. 16, 17 Aspirin and rivaroxaban are effective anti-thrombotic drugs when used alone or in combination. Aspirin alone prevents both venous and arterial thromboembolism, including stroke and myocardial infarction (MI). 18 Rivaroxaban 2.5 mg twice daily in combination with aspirin is substantially more effective than aspirin alone for prevention of both arterial events and VTE, 19 J o u r n a l P r e -p r o o f and the combination may prove to be an ideal antithrombotic regimen to target microvascular thrombosis. In the ACT trials, we are evaluating aspirin 100 mg once daily in outpatients and the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily in inpatients.

The ACT program includes outpatient and inpatient randomized trials, testing the effects of antiinflammatory and antithrombotic therapies in complementary populations. The comparison between anti-inflammatory therapy and control, and between antithrombotic therapy and control, will be examined separately in each trial, and will also be combined across the trials, thereby providing information on the value of these interventions in a broad range of patients with mild, moderate, or severe COVID-19 disease.

The primary objective of the anti-inflammatory randomization is to evaluate if colchicine compared to usual care prevents hospitalization or death. The primary objective for the antithrombotic randomization is to evaluate if aspirin compared to usual care prevents major thrombotic clinical events (myocardial infarction, stroke, acute limb ischemia, pulmonary embolism), hospitalization or death. The primary objectives will be evaluated during the first 45 days after randomization.

The ACT outpatient trial is a multi-centre, international, open label, parallel group randomized controlled trial with a 2 x 2 factorial design of symptomatic patients with COVID-19 ( Table 1 ).

The detailed inclusion and exclusion criteria are summarized in Table 2 .

Potentially eligible patients are screened by telephone and those eligible are randomized using a central interactive web randomization system in a 1:1 ratio to colchicine versus usual care, and in a 1:1 ratio to aspirin versus usual care, stratified by site and using randomly permuted blocks.

The dosing regimens of study interventions are detailed in Table 3 .

The primary objective of the anti-inflammatory randomization is to evaluate if colchicine compared with usual care prevents the need for high flow oxygen, mechanical ventilation, or death. The primary objective for the antithrombotic randomization is to evaluate whether the combination of rivaroxaban and aspirin compared with usual care prevents major thrombotic clinical events (myocardial infarction, stroke, acute limb ischemia, pulmonary embolism), the need for high flow oxygen (non-invasive respiratory support that delivers warmed, humidified, oxygen-enriched air to patients typically at a rate of at least 15 litres per minute), mechanical ventilation, or death. The primary objectives will be evaluated during the first 45 days after randomization.

The ACT inpatient trial is a multi-centre, international, open label, parallel group randomized controlled trial with a 2 x 2 factorial design in symptomatic inpatients with COVID-19 ( Table 1 ).

The detailed inclusion and exclusion criteria are summarized in Table 2 .

Potentially eligible patients are screened in person and those who are eligible are randomized using a central interactive web randomization system in a 1:1 ratio to colchicine versus control, and a 1:1 ratio to the combination of rivaroxaban and aspirin versus usual care, stratified by site, and using randomly permuted blocks. The dosing regimens of study interventions are detailed in Table 3 .

The protocol allows treating physicians to provide usual care according to local practice except that non-study treatments which could interact with the study drugs should be avoided unless a clear medical indication develops. In such cases, the study treatment would be interrupted. The duration of study treatments is 28 days, but the protocol makes provision to discontinue study treatments earlier when, in the judgment of the clinician, the patient has fully recovered from COVID-19 prior to completing 28 days of treatment.

Outcome assessors are not blinded to treatment allocation and trial outcomes are not adjudicated.

Primary, secondary, and other outcomes are summarized in Table 4 and outcome definitions are provided in Supplemental Table S1 . Participants will be followed in person or by telephone at J o u r n a l P r e -p r o o f Day 8, Day 45, and 6 months to evaluate adherence and possible use of non-study therapies, and to collect outcomes.

The ACT outpatient trial aimed to enroll 3,500 patients, which will provide 80% power with a 2sided alpha of 0.05 to detect a 30% relative risk reduction for each intervention versus control assuming an overall incidence rate of the primary outcome of 7.5% at 45 days and allowing for up to 2% loss to follow-up. The ACT inpatient trial aimed to enroll 2,500 patients, which will provide at least 80% power with a 2-sided alpha of 0.05 to detect a 20% relative risk reduction for each intervention versus usual care, assuming an overall incidence rate of the primary outcome of 22% at 45 days and allowing for up to 1% loss to follow-up. Because outpatients with COVID-19 are not as sick as those who are hospitalized, the Steering Committee felt that outpatients would need to achieve a larger risk reduction (i.e., 30% versus 20% in inpatients) to adopt a new treatment.

There will be no adjustment for multiplicity of testing because there is only one primary outcome for each randomization in each trial. Secondary outcomes will be considered as supportive evidence if the results are consistent with the primary outcome, and we will present p values so that the reader will know them. We will not make claims of significance for secondary outcomes unless the results are extreme (e.g., p<0.001).

In both trials, the primary hypothesis of efficacy will be tested under the intention to treat principle and will include all patients from the time of randomization. Colchicine and J o u r n a l P r e -p r o o f antithrombotic therapies have different targets and there is no biological or pharmacological rationale for expecting an interaction between these treatments when being co-administered.

However, in each trial separately, a possible interaction between the two treatment arms will be assessed by inclusion of an interaction term in the model. Kaplan-Meier curves will be used for a survival analysis and a Cox proportional hazards model will be used to estimate the hazard ratio and 95% confidence interval. We will perform subgroup analyses to explore whether the treatment effect is modified by age, sex, the laboratory tests used to confirm the diagnosis of COVID-19, vaccination status, timing of enrolment according to the phase of the pandemic, the presence or absence of co-morbidities at baseline, disease duration and severity at baseline, and, in the inpatient trial, admission to intensive care unit (ICU) at randomization and ventilation at randomization.

Analyses will be performed separately for each of the randomizations in the outpatient and inpatient trials, as well as a combined individual patient analysis of the outpatient and inpatient trials for anti-inflammatory and antithrombotic therapy comparisons. The combined analyses will provide >90% power with a 2-sided alpha of 0.05 to detect a 20% relative risk reduction with both anti-inflammatory and antithrombotic treatments.

The clinical manifestations of COVID-19 are well described but we do not know whether changes in blood biomarker levels are related to viral load, predict disease progression and/or end-organ damage, or can be used to evaluate responses to treatment. The specific objectives of the translational substudy are: Additional details are provided in a separate substudy protocol.

The ACT trials are overseen by an international Steering Committee and managed by the 

When the ACT trials were first designed, there were very few data on event rates, or potential treatment effects of the planned interventions. Many of the treatments being evaluated were supported by theoretical considerations and some experimental data but lacked even preliminary clinical data in patients with COVID-19, and little was known about the expected event rates in this population. To accommodate these uncertainties, the ACT trial protocols made provision for modifications to study design based on emerging data, including dropping treatments and replacing or adding new treatments as well as changing the sample size. The preparation of detailed responses to address the hundreds of questions and comments took many hours and contributed substantially to delays in study start up in many countries.

As the pandemic evolved, sensationalized media reporting, misleading claims by politicians, and conspiracy theories circulating on social media, fueled community distrust and made patient enrolment even more difficult in many countries. At local sites, access by potential participants was limited by restrictions and lockdowns, and concerns about the risk of COVID-19 infection for site personnel added to the challenges. At the same time, the pandemic varied in its intensity in different regions of the world and even within countries. Where the pandemic was severe, clinical services were overwhelmed, and clinicians found it difficult to devote time for research, and when the severity of the pandemic waned, there were fewer eligible patients. As a result, the trial initially experienced much slower than expected recruitment.

The rapidly changing pattern of the COVID-19 pandemic and emerging data regarding the efficacy and safety of novel therapies required several protocol modifications during the course of the ACT trials.

As originally designed in April 2020, the ACT outpatient trial tested hydroxychloroquine or chloroquine in combination with azithromycin versus usual care, and the ACT inpatient trial used a 2 x 2 factorial design to test hydroxychloroquine or chloroquine plus azithromycin versus usual care, and beta-interferon versus usual care. In June 2020, evaluation of hydroxychloroquine or chloroquine in combination with azithromycin was discontinued in both the outpatient and inpatient trials because of data indicating no benefit from a large, randomized trial, 22 and ongoing concerns about the potential for harm. Patients enrolled in the initial phase of J o u r n a l P r e -p r o o f the ACT trials and who were randomized to hydroxychloroquine or chloroquine in combination with azithromycin versus usual care and interferon versus usual care are not included in the current design and their results are being reported separately. Randomization to new treatments were added to both the outpatient trial, which began testing in a 2 x 2 factorial design colchicine versus usual care and aspirin versus usual care, and the inpatient trial, which began testing in a 2

x 2 x 2 factorial design colchicine versus usual care and combination of rivaroxaban and aspirin versus usual care, in addition to continuing beta-interferon versus usual care. In October 2020, beta-interferon was dropped from the inpatient trial because of emerging evidence that it did not provide benefit, 23 and ongoing concerns about safety.

In July 2021, further changes were made to the protocol based on an evaluation of blinded event rates. Although at this time recruitment was progressing at a rate of 300-400 patients per month in each of the outpatient and inpatient trials, the overall proportion of patients who had experienced a primary outcome was lower in both the outpatient (blinded overall event rates 6-7% versus 12% originally projected) and inpatient trial (blinded overall event rates 15% versus 30% originally projected). Furthermore, the proportion of outpatients under the age of 30 who were experiencing a primary outcome was < 2%. Accordingly, the Steering Committee (without knowledge of any emerging trends in the results) decided to increase the sample size in the outpatient trial (from 2,500 to 3,500) and inpatient trial (from 1,500 to 2,500), modify the primary outcomes for the antithrombotic comparison in the outpatient trial (original primary outcome: hospitalization or death; revised primary outcome: major thrombotic events, hospitalization or death), and in the inpatient trial for the colchicine comparison (original primary outcome: mechanical ventilation or death; revised primary outcome: requirement for J o u r n a l P r e -p r o o f high flow oxygen, mechanical ventilation or death) and the antithrombotic comparison (original primary outcome: mechanical ventilation or death; revised primary outcome: major thrombotic events, requirement for high flow oxygen, mechanical ventilation or death), and introduced a 30

year lower age cutoff in the outpatient trial.

At the completion of enrollment on February 10, 2022 the ACT trials had enrolled 3,917 patients in the outpatient trial and 2,754 patients in the inpatient trial. The numbers enrolled varied markedly over the course of the trial reflecting the changing patterns of the pandemic (Figure 1 ).

The baseline characteristics of the patients recruited into the trial are summarized in Table 6 . In the outpatient trial, mean age was 44.6 years (SD 13.6) and 56.5% were male. In the inpatient trial, mean age was 56.5 years (SD 19.3) and 59.2% were male. Reflecting their younger age and less severe illness, patients enrolled in the outpatient compared with the inpatient trial generally had fewer cardiovascular comorbidities (diabetes: 11.5 vs 20.7%; hypertension: 20.2 vs 34.5%; cerebrovascular disease: 0.2 vs 1.6%, and active cancer 0.5 vs 0.7%).

The ACT trials are testing whether anti-inflammatory therapy with colchicine and antithrombotic therapy with aspirin in outpatients or the combination of rivaroxaban and aspirin in inpatients can reduce major thrombotic events, hospitalization, high flow oxygen, mechanical ventilation, and mortality.

The promise of colchicine suggested by the results of the COLCORONA trial in outpatients (primary outcome: relative risk 0.79, p=0.081) 10 and the COLCOVID trial in inpatients (primary outcome: relative risk 0.83, p=0.08) 11 was not supported by the results of the larger RECOVERY trial (primary outcome: relative risk 1.01, p=0.77) 12 of inpatients with COVID-19. It is unclear whether differences in the severity of COVID-19 may have influenced the apparently divergent results of the inpatient trials, but comparison of mortality rates in the COLCOVID trial conducted in Argentina (21%) and the RECOVERY trial conducted in the UK (21%) suggest a similar risk profile. It is possible that longer duration of colchicine treatment evaluated in the COLCORONA trial (30 days) and COLCOVID trial (up to 14 days) is more effective than up to 10 days of treatment in the RECOVERY trial. Although colchicine works rapidly and in previous trials most events occurred within the first 7 to 14 days after randomization, patients may benefit from extended treatment because there is evidence of a prolonged inflammatory state in patients with COVID-19. Finally, it is possible that the widespread use of glucocorticoids (>90% in both inpatient trials) masked any potential benefit of colchicine. The ACT trial is well positioned to further inform the potential efficacy of colchicine, which is being tested for up to 28 days across the spectrum of mild, moderate, or severe disease and in more diverse populations than previously studied. 24, 25 J o u r n a l P r e -p r o o f

The lack of convincing evidence from randomized trials of a net benefit of antithrombotic therapy in patients with COVID-19 has several possible explanations. The largest completed trial to date involved 2,219 inpatients, 26 and although VTE event rates were generally lower with the use of intensified antithrombotic therapy, most of the differences were not significant and accompanied by increases in bleeding, with no mortality benefit. In the ACTION trial involving hospitalized patients with COVID-19, therapeutic anticoagulation with rivaroxaban 20 mg once daily (or therapeutic parenteral anticoagulation in those who were unstable) was not more efficacious than prophylactic anticoagulation, and increased bleeding. 27 The lower 2.5 mg twice daily dose of rivaroxaban being tested in combination with aspirin the ACT inpatient trial was chosen because of proven efficacy in previous trials for the prevention of both venous and arterial thrombosis. 19, 28 Furthermore, by targeting both platelets and fibrin this combination has the potential to prevent microvascular thrombosis and related organ dysfunction in patients with COVID-19.

Investigator awareness of treatment allocation in an open label trial could affect decisions about patient management (e.g., non-study treatments for COVID-19, decisions regarding hospitalization) and may also influence ascertainment and reporting of outcomes. To address these issues, we will compare the use of cointerventions and the severity of illness at the time of hospitalization by treatment group. To further mitigate risk, we provide objective criteria for study outcomes and we monitor data quality, including the reporting of outcomes. J o u r n a l P r e -p r o o f eGFR, estimated glomerular filtration rate; m2, square meter; mL, milliliters; min, minute *Depending on availability, 0.5 mg tablets can be used instead of 0.6 mg tablets. †If eGFR drops to 15 to 29 ml/min/1.73m 2 the dose of colchicine will be reduced to once daily.

If eGFR drops below 15 ml/min/1.73m 2 or creatinine rises by 60% over 24 hours or 100% over 48 hours, or creatinine rise is accompanied by oliguria or anuria, colchicine and rivaroxaban will be discontinued. ‡ Depending on availability, 75 or 81 mg tablets can be used instead of 100 mg tablets.

J o u r n a l P r e -p r o o f J o u r n a l P r e -p r o o f Table 5 

• The title of the protocol should include the place, study population, the time, and the principal aim of the study.

• The protocol should contain a single aim for the outpatient and inpatient trials.

• We do not agree with an open label design

• Please clarify the factorial design. Is the intent to have 4 treatment groups?

• The interpretation of these evaluations of each treatment that include comparisons where the other treatment is also being administered is unclear if that other treatment is not expected to be widely used in the proposed patient population (e.g., if one treatment is found to be not effective and/or safe based on the results of this study).

• The proposed factorial analysis relies on an assumption of no statistical interaction between the treatments which may not be reasonable and, if violated, may lead to unreliable information on the effectiveness of the treatment.

• Clarify why verbal consent is proposed.

J o u r n a l P r e -p r o o f

Mild or moderate COVID-19

Severe COVID-19

Association between administration of systemic corticosteroids and mortality among patients with COVID-19. A meta-analysis

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Metaanalysis

The use of janus kinase inhibitors in hospitalized patients with COVID-19: Systematic review and meta-analysis

The Combined Effect of Vaccination and Nonpharmaceutical Public Health Interventions-Ending the COVID-19 Pandemic

SARS-CoV-2 vaccines

The "Black Fungus" in India: The emerging syndemic of COVID-19-associated mucormycosis

Colchicine in COVID-19: an old drug

Colchicine for community-treated patients with COVID-19 (COLCORONA): a phase 3, randomised, double-blinded, adaptive, placebo-controlled, multicentre trial

Randomized Trial of Colchicine in Patients Hospitalized with COVID-19

Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label

COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year

Venous Thromboembolism in hospitalized critical and noncritical COVID-19 patients: A systematic review and meta-analysis

Autopsy findings in COVID-19-related deaths: a literature review

Safety and efficacy of different prophylactic anticoagulation dosing regimens in critically and non-critically ill patients with COVID-19: A systematic review and meta-analysis of randomized controlled trials

Hypercoagulability and thrombosis in COVID-19: a modifiable cause for mortality?

Aspirin in the Primary and Secondary Prevention of Vascular Disease: collaborative meta-analysis of individual participant data from randomized trials

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease

Repeated assessments of results in clinical trials of cancer treatment

Design and analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and design

Effect of hydroxychloroquine in hospitalized patients with Covid-19

Repurposed Antiviral Drugs for Covid-19 -Interim WHO Solidarity Trial Results

Relationship of SARS-CoV-2-specific CD4 response to COVID-19 severity and impact of HIV-1 and Tuberculosis co-infection

Western Cape Department of Health in collaboration with the National Institute for Communicable Diseases, South Africa

Therapeutic Anticoagulation with Heparin in Noncritically Ill Patients with Covid-19

Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

Rivaroxaban in Peripheral Artery Disease after Revascularization

Challenges and lessons learned from COVID-19 trials: Should we be doing clinical trials differently?

Interventions • The committee questions the safety of long-term colchicine as it is usually given for a shorter period. • Why test colchicine in mild disease?

• Are there any studies using aspirin and colchicine together? Will this combination work better than single use? • The committee believes that the rivaroxaban and aspirin treatments in inpatients should be separated out • Clarify the goal of your development program and whether you intend to develop colchicine and ASPIRIN as a co

• We do not agree with your proposed follow up schedule

• Clarify in both protocol and informed consent, how follow-ups will be carried out on days 8, 45 and 6 months. Benefits of participation • What special measures will be taken to protocol the rights, well-being, and safety of subjects in a vulnerable situation

• How have the ethical principles of respect, justice, beneficence and nonmaleficence been applied in the selection of participants?

• Clarify who, when, how, and where the participants will receive the direct benefits of participating in the ACT trial

Why is a 12% control event rate assumed? How is this percentage calculated? • What statistical tests will be used to analyze the potential drug interactions?

• The ethics committee would like to analyze the country data after 50 patients have been recruited

ACT, anti-coronavirus therapy; n, number; SD, standard deviation

At the time of writing, baseline data are not yet available for all patients enrolled in the ACT

The ACT Trial is an investigator-initiated study that is funded by the Population Health Research