The COVID-19 pandemic triggered an unprecedented surge in clinical research, leading to thousands of studies aimed at understanding, managing, and ultimately controlling the virus. As healthcare systems worldwide faced the immense challenge of treating patients, researchers raced against time to generate evidence-based strategies that could save lives. Among this flood of data, certain clinical trials emerged as pivotal, fundamentally shaping our approach to COVID-19 treatment and prevention.
With so much information available, it’s crucial to identify and focus on the most impactful studies. In this post, we’ve distilled 40 landmark clinical trials that not only provided vital insights but also changed the course of COVID-19 management. These trials stand out for their contributions to understanding the virus, improving patient outcomes, and guiding global health policies. Whether you’re a healthcare professional, researcher, or simply interested in the science behind the pandemic, these summaries offer a concise look at the studies that made a difference.
To explore the visual summaries (like the one below) of these trials, download the Visualmed app (iPhone) Visualmed for Android. Visualmed offers visual abstracts and infographic-based summaries of clinical trials, making it easy for you to stay up-to-date on the go. We have listed the first 18 trials here and the remaining on our app!
- ACTION Trial: Therapeutic versus prophylactic anticoagulation in hospitalized COVID-19 patients with elevated D-dimer concentration
In this multicenter, randomized trial conducted at 31 sites in Brazil, the efficacy and safety of therapeutic versus prophylactic anticoagulation in hospitalized COVID-19 patients with elevated D-dimer levels were compared. A total of 615 patients were randomly assigned to receive either therapeutic anticoagulation (rivaroxaban or enoxaparin) or standard prophylactic anticoagulation. The study found no significant difference in clinical outcomes between the two groups, but therapeutic anticoagulation was associated with a higher risk of major or clinically relevant bleeding. Consequently, therapeutic-dose rivaroxaban or other direct oral anticoagulants should not be used in these patients without a clear evidence-based indication.
(Source) - ACTIVE-4B: Effect of Antithrombotic Therapy on Clinical Outcomes in Outpatients With Clinically Stable Symptomatic COVID-19
In a randomized trial involving 657 symptomatic but clinically stable outpatients with COVID-19 in the US, researchers assessed whether adding antithrombotic therapy (aspirin or apixaban) compared with placebo could reduce major cardiopulmonary outcomes over a 45-day period. The trial was stopped early due to an unexpectedly low event rate. The results showed no significant differences in the composite outcome of all-cause mortality, thromboembolism, myocardial infarction, stroke, or hospitalization between those treated with aspirin, apixaban, or placebo. These findings do not support the use of aspirin or apixaban to reduce major adverse cardiovascular or pulmonary events in this patient population.
(Source) - ACTIV-3 Trial: Neutralizing Monoclonal Antibody for Hospitalized Patients with COVID-19
In a platform trial assessing the efficacy of the monoclonal antibody LY-CoV555 in hospitalized COVID-19 patients without end-organ failure, 314 patients were randomly assigned to receive either LY-CoV555 or a placebo, along with standard care, including remdesivir, supplemental oxygen, and glucocorticoids. The trial was halted early for futility as there was no significant difference in pulmonary outcomes at day 5 or sustained recovery over 90 days between the two groups. Additionally, the safety outcomes were similar, with no efficacy demonstrated for LY-CoV555 in this patient population.
(Source) - ACTIV-6 Trial: Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19
In a decentralized, double-blind, randomized trial conducted in the US, the effectiveness of inhaled fluticasone furoate (200 μg daily for 14 days) was compared with placebo in nonhospitalized adults with mild-to-moderate COVID-19. Among the 1407 participants, there was no significant difference in the time to symptom resolution between the fluticasone and placebo groups. Additionally, the rates of urgent-care visits, emergency department visits, or hospitalization were slightly higher in the fluticasone group, but no deaths occurred in either group. The study concluded that inhaled fluticasone furoate did not shorten recovery time compared to placebo.
(Source) - ACTT-1 Trial: Remdesivir for the Treatment of Covid-19
In a double-blind, randomized, placebo-controlled trial involving 1062 hospitalized COVID-19 patients with lower respiratory tract infections, remdesivir was tested for efficacy. Patients received either remdesivir or a placebo for up to 10 days. Those treated with remdesivir had a median recovery time of 10 days, compared to 15 days for the placebo group. Additionally, remdesivir was associated with higher odds of clinical improvement by day 15 and a lower mortality rate by day 29, although the difference in mortality was not statistically significant. The study concluded that remdesivir significantly shortened the time to recovery compared to placebo.
(Source) - ACTT-2 Trial: Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19
In a double-blind, randomized, placebo-controlled trial involving 1033 hospitalized COVID-19 patients, the combination of baricitinib, a Janus kinase inhibitor, and remdesivir was compared to remdesivir alone. Patients receiving the combination treatment had a median recovery time of 7 days, compared to 8 days for the control group, with a 30% higher likelihood of clinical improvement by day 15. Notably, among patients requiring high-flow oxygen or noninvasive ventilation, the recovery time was significantly shorter with the combination treatment (10 days vs. 18 days). The study also found lower 28-day mortality rates and fewer serious adverse events in the combination group, concluding that baricitinib plus remdesivir was more effective than remdesivir alone in improving outcomes for COVID-19 patients.
(Source) - ACTT-4 Trial: Baricitinib versus dexamethasone for adults hospitalised with COVID-19
In a randomized, double-blind, double placebo-controlled trial involving 1010 hospitalized COVID-19 patients requiring supplemental oxygen, the combination of baricitinib plus remdesivir was compared with dexamethasone plus remdesivir. The primary outcome, mechanical ventilation-free survival by day 29, was similar between both groups, with Kaplan-Meier estimates of 87.0% for the baricitinib group and 87.6% for the dexamethasone group (risk difference 0.6, p=0.91). However, the dexamethasone group experienced significantly more adverse events (37% vs. 30%), treatment-related adverse events (10% vs. 4%), and severe or life-threatening grade 3 or 4 adverse events (36% vs. 28%). The study suggests that while both treatments offer similar outcomes in preventing progression to mechanical ventilation, dexamethasone is associated with a higher incidence of adverse effects, highlighting the need for a more individualized approach to immunomodulation based on side-effect profiles, ease of administration, cost, and patient comorbidities.
(Source) - ATTACC Trial: Therapeutic Anticoagulation with Heparin in Critically Ill Patients with Covid-19
In a randomized clinical trial evaluating therapeutic-dose anticoagulation with heparin versus usual-care pharmacologic thromboprophylaxis in critically ill COVID-19 patients, the study was stopped early due to futility. The primary outcome, organ support–free days, showed a median of 1 day for the therapeutic-dose group and 4 days for the usual-care group, with an adjusted proportional odds ratio of 0.83, indicating no significant benefit. The survival rate to hospital discharge was similar between the groups (62.7% for therapeutic-dose and 64.5% for usual-care). Major bleeding was slightly higher in the therapeutic-dose group (3.8% vs. 2.3%). The findings suggest that therapeutic-dose anticoagulation did not improve survival or reduce the need for organ support in critically ill COVID-19 patients.
(Source) - BACC Bay Trial: Efficacy of Tocilizumab in Patients Hospitalized with Covid-19
In a randomized, double-blind, placebo-controlled trial involving 243 hospitalized COVID-19 patients not on mechanical ventilation, the efficacy of tocilizumab, an interleukin-6 receptor blocker, was evaluated. Patients were given either tocilizumab or placebo alongside standard care, with the primary outcome being intubation or death. The study found no significant difference between the tocilizumab and placebo groups in preventing intubation or death, nor in clinical worsening or the time to discontinuation of supplemental oxygen. Tocilizumab did not demonstrate efficacy in this patient population, though some benefit or harm could not be definitively excluded due to wide confidence intervals.
(Source) - BCN-PEP-Cov2 Trial: Hydroxychloroquine for Prevention of Covid-19
In an open-label, cluster-randomized trial conducted in Catalonia, Spain, involving 2314 asymptomatic contacts of COVID-19 patients, the efficacy of hydroxychloroquine as a postexposure therapy was assessed. Participants were either given hydroxychloroquine or received usual care, with the primary outcome being the development of PCR-confirmed, symptomatic COVID-19 within 14 days. The study found no significant difference in the incidence of symptomatic COVID-19 or SARS-CoV-2 transmission between the hydroxychloroquine and usual-care groups. However, adverse events were more frequent in the hydroxychloroquine group. The findings suggest that hydroxychloroquine did not prevent COVID-19 or SARS-CoV-2 infection in exposed individuals.
(Source) - BLAZE-1 Trial: Bamlanivimab plus Etesevimab in Mild or Moderate Covid-19
In a phase 3 trial involving high-risk ambulatory patients with mild or moderate COVID-19, the combination of neutralizing monoclonal antibodies bamlanivimab and etesevimab was tested against a placebo. The trial included 1035 patients, with the primary outcome being COVID-19-related hospitalization or death by day 29. Results showed that 2.1% of patients in the bamlanivimab–etesevimab group experienced hospitalization or death, compared to 7.0% in the placebo group, resulting in a significant reduction in risk. No deaths occurred in the treatment group, while 10 occurred in the placebo group. Additionally, a greater reduction in viral load was observed in the treatment group by day 7. The study concluded that bamlanivimab plus etesevimab significantly reduced COVID-19-related hospitalization and death and accelerated viral load reduction in high-risk patients.
(Source) - COMET-ICE: Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab
In a phase 3 trial involving high-risk, nonhospitalized patients with mild-to-moderate COVID-19, the efficacy of sotrovimab, a pan-sarbecovirus monoclonal antibody, was evaluated. The trial included 583 patients who were randomly assigned to receive either sotrovimab or a placebo within 5 days of symptom onset. The primary outcome was hospitalization or death within 29 days. The interim analysis showed that only 1% of patients in the sotrovimab group experienced disease progression leading to hospitalization or death, compared to 7% in the placebo group, resulting in an 85% relative risk reduction. Additionally, adverse events were less common with sotrovimab, and no significant safety concerns were identified. The study concluded that sotrovimab effectively reduced the risk of disease progression in high-risk COVID-19 patients.
(Source) - COV-BARRIER Trial: baricitinib for the treatment of hospitalised adults with COVID-19
In a phase 3, double-blind, randomized, placebo-controlled trial conducted across 101 centers in 12 countries, the efficacy and safety of baricitinib, an oral Janus kinase 1/2 inhibitor, were evaluated in hospitalized adults with COVID-19 receiving standard care, including corticosteroids and antivirals like remdesivir. Among 1,525 participants, 27.8% of those receiving baricitinib and 30.5% of those receiving placebo progressed to severe disease, a difference that was not statistically significant. However, baricitinib significantly reduced 28-day all-cause mortality by 38.2% compared to placebo (8% vs. 13%) and also reduced 60-day all-cause mortality (10% vs. 15%). The safety profile of baricitinib was similar to that of standard care, with no significant differences in serious adverse events, infections, or thromboembolic events. Despite no significant impact on disease progression, baricitinib combined with standard care was associated with reduced mortality in hospitalized COVID-19 patients.
(Source) - COVACTA Trial: Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia
In this phase 3 trial, 452 patients hospitalized with severe COVID-19 pneumonia were randomly assigned in a 2:1 ratio to receive either tocilizumab, a monoclonal antibody against the interleukin-6 receptor, or a placebo. The study aimed to evaluate the efficacy of tocilizumab in improving clinical status at day 28, measured on an ordinal scale from 1 (discharged) to 7 (death). Results showed no significant difference between the two groups, with a median clinical status score of 1.0 in the tocilizumab group and 2.0 in the placebo group. Serious adverse events were similar between groups, occurring in 34.9% of patients in the tocilizumab group and 38.5% in the placebo group. Mortality at day 28 was nearly identical between the two groups (19.7% vs. 19.4%). The study concluded that tocilizumab did not significantly improve clinical outcomes or reduce mortality in patients with severe COVID-19 pneumonia.
(Source) - COVE Trial: Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine
This phase 3 trial evaluated the mRNA-1273 vaccine, designed to prevent COVID-19, in 30,420 high-risk participants across the United States. Participants were randomly assigned to receive two doses of the vaccine or a placebo. The vaccine showed 94.1% efficacy in preventing COVID-19 illness, including severe cases, with all severe cases and one fatality occurring in the placebo group. The vaccine was generally well-tolerated, with no significant safety concerns beyond transient local and systemic reactions.
(Source) - COVI-HIGH Trial: High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia
This multicenter, open-label trial assessed whether high-flow nasal oxygen (HFNO) compared to conventional oxygen therapy (COT) could prevent the need for more intensive respiratory support in patients with COVID-19 pneumonia and mild hypoxemia. Among 364 patients, there was no significant difference between the HFNO and COT groups in the escalation of respiratory support, clinical recovery, ICU admission rates, or hospital length of stay. The study concluded that HFNO did not significantly reduce the likelihood of requiring more advanced respiratory interventions in this patient population.
(Source) - COVI-PRONE Trial: Effect of Awake Prone Positioning on Endotracheal Intubation in Patients With COVID-19 and Acute Respiratory Failure
This randomized clinical trial investigated whether prone positioning could reduce the need for endotracheal intubation in adults who were awake and had hypoxemic respiratory failure due to COVID-19. Among 400 participants, prone positioning resulted in a 34.1% intubation rate compared to 40.5% with usual care. Although the hazard ratio was 0.81, the difference was not statistically significant. The findings suggest that while prone positioning did not significantly reduce intubation rates, the effect size was imprecise and may still indicate a clinically important benefit.
(Source) - COVID-19 PEP Trial: Hydroxychloroquine as Postexposure Prophylaxis for Covid-19
This randomized, double-blind, placebo-controlled trial evaluated the effectiveness of hydroxychloroquine as postexposure prophylaxis for COVID-19. Conducted across the U.S. and parts of Canada, it involved 821 asymptomatic adults who had been exposed to COVID-19. Participants were randomly assigned to receive either hydroxychloroquine or placebo within 4 days after exposure. The study found no significant difference in the incidence of COVID-19 between the hydroxychloroquine group (11.8%) and the placebo group (14.3%). Although side effects were more common with hydroxychloroquine, there were no serious adverse reactions. The results suggest that hydroxychloroquine does not prevent COVID-19 when used as postexposure prophylaxis.
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