New England Journal of Medicine DECEMBER 02, 2020

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

WHO Solidarity Trial Consortium

Bottom Line

The WHO Solidarity trial found that four repurposed antiviral regimens—remdesivir, hydroxychloroquine, lopinavir/ritonavir, and interferon-beta-1a—provided no significant mortality or clinical benefit for hospitalized COVID-19 patients.

Key Findings

1. None of the four tested repurposed regimens (remdesivir, hydroxychloroquine, lopinavir, or interferon) significantly reduced in-hospital mortality compared with the standard of care.

2. The rate ratio for 28-day death was 0.95 (95% CI: 0.81-1.11) for remdesivir, 1.19 (95% CI: 0.89-1.59) for hydroxychloroquine, 1.00 (95% CI: 0.79-1.25) for lopinavir, and 1.16 (95% CI: 0.96-1.39) for interferon.

3. None of the investigated drugs substantially reduced the initiation of mechanical ventilation or the overall duration of hospital stay.

4. Subgroup analyses, including patients already receiving mechanical ventilation versus those who were not, consistently showed no significant mortality benefit across all treatment arms.

Study Design

Design

RCT

Open-Label

Sample

11,330

Patients

Duration

28 days

Median

Setting

Multicenter, 30 countries

Population Adults hospitalized with COVID-19

Intervention Local standard of care plus one of four regimens: remdesivir, hydroxychloroquine, lopinavir/ritonavir, or interferon-beta-1a

Comparator Local standard of care alone

Outcome In-hospital mortality

Study Limitations

• The study employed an open-label design, which may have introduced biases in clinical decision-making regarding discharge or escalation of care.

• The trial lacked a placebo control, relying instead on concurrent local standard-of-care comparisons.

• The broad, diverse international setting, while increasing generalizability, introduced heterogeneity in standard-of-care practices and disease severity across different healthcare systems.

• The trial design focused on hospitalized patients, leaving questions about the potential efficacy of these drugs when administered earlier in the disease course or as prophylaxis.

Clinical Significance

These findings provided high-quality evidence that discouraged the widespread use of several repurposed antivirals for hospitalized COVID-19 patients, directly impacting international clinical practice guidelines during the pandemic.

Historical Context

Launched in early 2020 in response to the COVID-19 pandemic, the Solidarity trial was a massive global effort to rapidly evaluate potential treatments. It was designed to provide quick, reliable evidence for repurposed drugs, counteracting the influx of inconclusive, small-scale, or non-randomized studies that emerged in the early months of the crisis.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

The Solidarity trial tested protease inhibitors like lopinavir/ritonavir. Based on your knowledge of viral replication, what specific stage of the viral life cycle do these drugs target, and why might inhibiting this stage late in a COVID-19 infection fail to improve mortality?

Key Response

Protease inhibitors prevent the cleavage of viral polyproteins into functional units, halting the assembly of new virions. In hospitalized COVID-19 patients, the disease often progresses from a viral replication phase to a hyper-inflammatory phase. By the time a patient is hospitalized, the peak viral load has often passed, meaning the primary driver of mortality is the host immune response rather than active viral replication.

Resident

A patient is admitted with COVID-19 pneumonia and is requesting hydroxychloroquine because they read about its in-vitro efficacy. How do the results of the WHO Solidarity trial inform your bedside counseling regarding the risk-benefit profile of this medication?

Key Response

The Solidarity trial demonstrated that hydroxychloroquine provided no significant reduction in mortality, initiation of ventilation, or duration of hospital stay among hospitalized patients. Clinical management should prioritize evidence-based interventions like corticosteroids (if oxygen is required) and avoid hydroxychloroquine, as its lack of benefit is coupled with potential risks like QTc prolongation and arrhythmias.

Fellow

The Solidarity trial reported a mortality rate ratio of 0.95 for remdesivir, which contrasts with the ACTT-1 trial's finding of a shortened time to recovery. How should a subspecialist integrate these seemingly discordant findings when determining the role of remdesivir in a resource-limited setting?

Key Response

Solidarity was powered for mortality and showed no benefit, whereas ACTT-1 focused on recovery time. This suggests that while remdesivir may have a modest effect on viral clearance or symptom duration in specific subsets (e.g., those on low-flow oxygen), it does not significantly alter the hard endpoint of death in a broad hospitalized population. In resource-limited settings, the high cost and lack of mortality benefit may prioritize other interventions like oxygen and dexamethasone.

Attending

The Solidarity trial used a 'pragmatic' design with minimal data collection. From a leadership perspective, how does this trial design influence our ability to implement 'Medical Reversal' for widely used but unproven therapies during a pandemic?

Key Response

Solidarity exemplifies how large-scale, simple RCTs can rapidly debunk treatments adopted via 'biological plausibility' or observational data. It teaches that in a crisis, enrolling patients in a platform trial is more ethical and clinically impactful than 'compassionate use,' as it provides the statistical power necessary to officially retire ineffective treatments from standard protocols.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the implications of using an 'unblinded, open-label' design in the Solidarity trial. While mortality is a robust endpoint, how might the lack of a placebo control have introduced 'performance bias' regarding the secondary endpoints of discharge and ventilation?

Key Response

In an open-label trial, clinicians' knowledge of the treatment assignment can influence subjective decisions, such as when to initiate mechanical ventilation or when a patient is 'stable enough' for discharge. This bias could potentially mask or exaggerate differences between groups. However, for the primary endpoint of all-cause mortality, the lack of blinding is less likely to distort the results, supporting the trial's core conclusions.

Journal Editor

As a peer reviewer, how would you evaluate the 'interim' nature of this report? Specifically, does the lack of granular data on symptom onset duration (time from first symptoms to randomization) represent a fatal flaw in the study's ability to assess antiviral efficacy?

Key Response

A tough reviewer would flag that antivirals are highly time-dependent. Without knowing if patients received the drugs within the first 5-7 days of symptoms, the study might be underestimating the benefit of the drugs if they were mostly given late. However, given the massive sample size and the pragmatic objective of the trial—to see if these drugs work in the real-world context of hospitalization—the editor would likely weigh the public health importance over the lack of precise viral kinetics.

Guideline Committee

The WHO Solidarity trial results led to a 'Strong Recommendation Against' the use of hydroxychloroquine and lopinavir/ritonavir. How does the 'Certainty of Evidence' provided by this trial compare to the evidence used in earlier, smaller guidelines that supported these drugs?

Key Response

Earlier guidelines relied on low-certainty evidence from in-vitro studies and small observational cohorts (e.g., Gautret et al.). The Solidarity trial provided 'High Certainty' evidence due to its large-scale randomization and multi-country reach, which minimized selection bias and increased precision. This allowed organizations like the WHO and IDSA to issue definitive 'Strong' recommendations against these drugs, superseding earlier 'Conditional' or 'Emergency Use' authorizations.

Clinical Landscape

Noteworthy Related Trials

2020

RECOVERY Trial

n = 11,500 · NEJM

Tested

Dexamethasone

Population

Hospitalized COVID-19 patients

Comparator

Standard of care

Endpoint

28-day mortality

Key result: Dexamethasone reduced deaths by one-third in ventilated patients and by one-fifth in those receiving oxygen alone.

2020

ACTT-1 Trial

n = 1,063 · NEJM

Tested

Remdesivir

Population

Hospitalized adults with COVID-19

Comparator

Placebo

Endpoint

Time to recovery

Key result: Remdesivir was associated with a shorter time to recovery compared to placebo in hospitalized patients.

2021

TOGETHER Trial

n = 3,515 · Lancet Glob Health

Tested

Fluvoxamine

Population

High-risk outpatients with early COVID-19

Comparator

Placebo

Endpoint

Retention in an emergency setting or hospitalization due to COVID-19

Key result: Treatment with fluvoxamine reduced the need for prolonged emergency department observation or hospitalization.

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