Background: Since the beginning of the pandemic, hundreds of trials have been performed looking at medications with the potential to be repurposed for use against COVID19. To date, no antiviral medications directed at SARS-CoV-2 have shown any convincing evidence of improvement. Treatments directed against the virus itself including ivermectin, hydroxychloroquine, and convalescent plasma have all fell well short of meaningful outcomes. Multiple previous trials (See discussion) have shown that remdesivir is associated with a shorter time to clinical improvement when the medication is started within 10 days of symptom onset. The largest trial on the topic [2] showed no benefit in mortality, initiation of ventilation or hospital length of stay. Due to the mixed previous results, there is no consensus on the use of remdesivir in COVID-19.
Paper: Ader F et al. Remdesivir Plus Standard of Care Versus Standard of Care Alone for the Treatment of Patients Admitted to Hospital with COVID-19 (DisCoVeRy): A Phase 3, Randomised, Controlled, Open-Label Trial. Lancet 2021. [Epub Ahead of Print]
Clinical Question: In hospitalized patients with ≤7 days of COVID-19 symptoms, does standard care plus remdesivir compared to standard care alone improve clinical status at day 15 as measured by the WHO seven-point ordinal scale?
What They Did:
- Phase 3, open-label, adaptive, multicenter, randomized, controlled trial
- Conducted in 48 sites in Europe (France, Belgium, Austria, Luxembourg)
- Patients randomized in a 1:1 fashion:
- Standard care alone
- Standard care + remdesivir 200mg IV infusion on day 1, followed by 100mg IV qD for 9d (10d total)
- Remdesivir could be stopped after 5d if patient was discharged
- Trial terminated on Jan 13th, 2021 on the basis of the evaluation of an interim report due to no chances of reaching a 5% significance, no evidence of efficacy, nor on mortality at day 29, and low recruitment over the last 6 weeks of the trial
Outcomes:
-
Primary: clinical status at day 15 measured by the WHO seven-point ordinal scale
- 1 = Not hospitalized, no limitation on activities
- 2 = Not hospitalized, limitation on activities
- 3 = Hospitalized, not requiring supplemental O2
- 4 = Hospitalized, requiring supplemental O2
- 5 = Hospitalized, on NIV or HFNC
- 6 = Hospitalized, on invasive mechanical ventilation, or ECMO
- 7 = Dead
-
Key Secondary:
- Clinical status and change from baseline of clinical status at days 3, 5, 8, 11, and 29
- Time to improvement of one and two categories or hospital discharge until day 29
- Change from baseline NEWS-2 at days 3, 5, 8, 11, 15, and 29
- Time to NEWS-2 of 2 or lower or hospital discharge until day 29
- Time to hospital discharge until day 29
- Duration of hospitalization
- Time to new mechanical ventilation, ECMO, or death until day 29
- In-hospital mortality and mortality at days 29 and 90
- Cumulative incidence of any grade 3 or 4 adverse events
- Any serious adverse events
Inclusion:
- Adult patients (Aged ≥18 years)
- Admitted to the hospital
- Laboratory-confirmed SARS-CoV-2 infection (Initially 72hrs prior to randomization, later changed to 9d prior to randomization)
- Illness of any duration (median was 9 days with a range of 7 to 12 days)
- Clinical evidence of hypoxemic pneumonia OR required oxygen supplementation
- Evidence of rales or crackles on examination and SpO2 ≤94% on RA
- Requirement of supplemental O2
- HFNC
- NIV
- Invasive mechanical ventilation
Exclusion:
- Elevated liver enzymes (>5x ULN)
- Severe chronic kidney disease (Stage 4 CKD or on HD)
- Any contraindication to one of the studied treatments or their use 29d prior to randomization
- Use of ribavirin
- Pregnancy or breastfeeding
Results:
- 847 patients enrolled
- Standard Care + Remdesivir = 429pts
- Standard Care Alone = 428pts
- Median time from symptom onset to randomization = 9d (Range 7 to 12 days)
- Severity of COVID-19 at randomization:
- Supplemental O2 with NC or face mask = 59%
- HFNC = 18%
- NIV = 4%
- Invasive mechanical ventilation = 18%
- At day 15, the distribution of the WHO ordinal scale was:
- Not Hospitalized, No Limitations on Activities
- Standard Care + Remdesivir: 15%
- Standard Care Alone: 17%
- Not Hospitalized, Limitation on Activities
- Standard Care + Remdesivir: 31%
- Standard Care Alone: 32%
- Hospitalized, Not Requiring Supplemental O2
- Standard Care + Remdesivir: 12%
- Standard Care Alone: 7%
- Hospitalized, Requiring Supplemental O2
- Standard Care + Remdesivir: 18%
- Standard Care Alone: 16%
- Hospitalized, On NIV or HFNO
- Standard Care + Remdesivir: 4%
- Standard Care Alone: 3%
- Hospitalized, On Invasive Mechanical Ventilation or ECMO
- Standard Care + Remdesivir: 15%
- Standard Care Alone: 19%
- Death
- Standard Care + Remdesivir: 5%
- Standard Care Alone: 6%
- The difference between groups was NOT statistically significant: OR 0.98; 95% CI 0.77 to 1.25; p = 0.85
- Not Hospitalized, No Limitations on Activities
- No difference in occurrence of serious adverse events between groups:
- Standard Care + Remdesivir: 33%
- Standard Care Alone: 31%
- P = 0.48
- No difference between groups observed for any secondary outcomes overall
- No difference in viral clearance between groups
- No difference in any of the outcomes regardless of severity of disease with one exception:
- New mechanical ventilation, ECMO or death within 29d (See discussion)
- Standard Care + Remdesivir: 29%
- Standard Care Alone: 51%
- HR 0.66; 95% CI 0.47 to 0.91; p = 0.010
- New mechanical ventilation, ECMO or death within 29d (See discussion)
Strengths:
- Asks a clinically important question where there is uncertainty
- Multicenter randomized clinical trial
- Independent data safety and monitoring board externally reviewed the trial data at regular intervals for efficacy, safety, and futility
- Funders of the study had no role in study design, data collection, data analysis, data interpretation, or manuscript writing
- Groups balanced at baseline in regard to age, coexisting conditions, symptom onset, severity of COVID-19 and oxygen support
Limitations:
- Open-label study can cause bias in results. Allocated treatment was not masked to participants or study investigators.This can influence subjective outcomes, such as the decision to begin corticosteroids or initiation of invasive mechanical ventilation
- Viral load assessment wasn’t available for 18% of patients enrolled and ≈50% of patients had no viral load available at baseline.But the proportions of tested viral loads were equal between groups
- Plasma concentrations of the prodrug remdesivir were only tested in 10% of patients while the intracellular active metabolite was not measured
- Unclear if remdesivir given earlier in disease course (i.e. ≤6d) would show any difference in clinical outcomes
Discussion:
- Putting all the evidence together:
- Multiple previous RCTs (3 trials) reported a faster time to recovery in patients treated with remdesivir, but no difference in mortality. However, two trials on the topic found no benefit
- ACTT-1: ≈1000pts [Link is HERE] – Shorter time to clinical improvement
- Goldman et al: ≈400pts [Link is HERE] – 10d course no benefit; 5d course shorter time to clinical improvement
- Spinner et al: ≈600pts [Link is HERE] – 10d course no benefit; 5d course shorter time to clinical improvement (This is confusing)
- Solidarity: ≈2800pts [Link is HERE] – Negative trial
- Wang et al: ≈200pts [Link is HERE] – Negative trial
- The weight of evidence before DiSCoVeRy seems to point to no benefit of remdesivir in COVID-19
- DiSCoVeRy (≈850pts) found no significant difference in the clinical status at days 15 and 29, time to hospital discharge, or 28-day all-cause mortality
- Multiple previous RCTs (3 trials) reported a faster time to recovery in patients treated with remdesivir, but no difference in mortality. However, two trials on the topic found no benefit
- ACTT-1 vs DisCoVeRy:
- Oxygen Support at Baseline:
- ACTT-1: 87%
- DisCoVeRy: 99%
- Use of Corticosteroids:
- ACTT-1: 23%
- DisCoVeRy: 40%
- DisCoVeRy showed that remdesivir significantly delayed the need for new mechanical ventilation or ECMO, or death (consistent with ACTT-1) BUT…
- Decision to intubate a patient or put on ECMO is subjective and can vary
- Additionally, any signal of benefit was not seen in any of the secondary outcomes of respiratory status, NEWS-2 score, and DID NOT translate into a reduced mortality at day 28 (consistent with Solidarity trial)
- The outcome of new mechanical ventilation, ECMO or death within 29d in the severe group is simply strange because there was no difference in the moderate disease group.At face value one would think that an antiviral would have its best effect earlier in disease rather than in severe disease for the simple fact that severe disease is out of the viral phase of replication where antivirals should have almost no effect
- This was a secondary outcome, which makes it hypothesis generating at best
- Prespecified subgroup analysis was done across duration of symptoms: ≤7d, 8 – 14d, and >14d and disease severity.There was no observed difference in viral kinetics or viral loads.
- Oxygen Support at Baseline:
Author Conclusion: “No clinical benefit was observed from the use of remdesivir in patients who were admitted to hospital for COVID-19, were symptomatic for more than 7 days, and required oxygen support.”
Clinical Take Home Point: Although earlier trials showed a signal of benefit for remdesivir improving time to recovery, no trials have shown an improvement in mortality, a more important clinical outcome. Additionally, this is now the third trial showing no clinical benefit of remdesivir. The current evidence does not support the use of remdesivir in hospitalized patients with symptoms for more than 7 days and requiring oxygen support. This story sounds much like another antiviral medication used for another viral illness (i.e. Tamiflu for influenza), except this medication is much more expensive ($3k – 5k for a 5 day course).
References:
- Ader F et al. Remdesivir Plus Standard of Care Versus Standard of Care Alone for the Treatment of Patients Admitted to Hospital with COVID-19 (DisCoVeRy): A Phase 3, Randomised, Controlled, Open-Label Trial. Lancet 2021. [Epub Ahead of Print]
- Pan H et al. Repurposed Antiviral Drugs for COVID-19 – Interim WHO Solidarity Trial Results. NEJM 2021. PMID: 33264556
For More Thoughts on This Topic Checkout:
- REBEL EM: Remdesivir ACTT-1 – Adaptive COVID-19 Treatment Trial Part 1
- REBEL EM: Remdesivir in Moderate COVID-19
- REBEL EM: COVID-19 – Remdesivir RCT #3 (5d vs 10d)
- REBEL EM: Two More Trials Just Published on Remdesivir
Post Peer Reviewed By: Anand Swaminathan, MD (Twitter: @EMSwami)
The post The DisCoVeRy Trial: Remdesivir in COVID-19 – An Expensive Version of Tamiflu? appeared first on REBEL EM - Emergency Medicine Blog.