Remdesivir improves recovery time in early COVID-19 infection: first definitive results of benefit

1 June 2020. Related: COVID-19: investigational drugs, COVID-19.

Simon Collins, HIV i-Base

On 22 May 2020, the first clear results in favour of remdesivir being active against COVID-19, from the US NIAID ACTT study were published in the New England Journal of Medicine. [1]

Until now, even though recently approved in both the US and Japan, the data supporting remdesivir was contradictory, and top-line results had only been available by press release.

The preliminary results are sufficient to warrant widespread early access to remdesivir, including by compassionate access in Europe. They should also challenge other ongoing studies to look at adding remdesivir to current standard of care for all participants.

The international Adaptive Covid-19 Treatment Trial (ACTT-1) study is a phase 3, double-blind, placebo-controlled study that randomised 1063 participants to either intravenous remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The study was conducted in more than 60 sites in Denmark, Germany, Greece, Japan, Korea, Mexico, Singapore, Spain, the UK and the US.

The primary outcome was the time to recovery – although this had been changed during the study as more was learnt about COVID-19. This was defined by either discharge from hospital or remaining in hospital to reduce transmission (rather than for clinical reasons).

Baseline characteristics were well balanced between arms and included mean age 58.9 (±15.0); 64% male and 53% white, 23% Hispanic/Latino, 21% black or African American, 12% Asian. Median time from symptoms to randomisation was 9 days (IQR: 6 to 12). Just over 50% in each arm had two or more comorbidities, mainly hypertension (49%), obesity (37%) and type-2 diabetes (29%).

Randomisation was stratified by disease severity. Although baseline ordinal score (4 to 7) was generally balanced, more advanced oxygen support requiring invasive mechanical ventilation or ECMO (baseline score of 7) was 28% of placebo recipients (compared to 23% in the remdesivir group). Overall, 88% were classified as having severe stage disease (defined by one or more of: requiring invasive or non-invasive mechanical ventilation, requiring supplemental oxygen, an SpO2 ≤ 94% on room air, or respiratory rate ≥ 24 breaths per minute).

On 27 April 2020, the independent data and safety monitoring board (DSMB) for the study recommended early unblinding of the results due to significant differences in favour of remdesivir.

Preliminary results from 1049 participants (531 remdesivir vs 518 placebo) included a median recovery time of 11 days (95% CI: 9 to 12) vs 15 days (95% CI: 13 to 19) with a significant rate ratio of 1.32; 95% CI, 1.12 to 1.55; p<0.001).

Although there were numerically fewer deaths by day 14 in the remdesivir arm (n=32 vs 54; 7.1% vs 11.9%), the Kaplan-Meier estimates of mortality did not reach statistical significance (HR: 0.70; 95% CI: 0.47 to 1.04). All but two of the deaths (one in each arm) had severe stage disease at study entry.

Kaplan-Meier estimates of recovery only favoured remdesivir for participants with a baseline score of 5 (less severe illness) but not for participants with more advanced disease, see Table 1. However, an analysis adjusting for baseline ordinal score produced a similar treatment-effect estimate (RR 1.31; 95% CI, 1.12 to 1.54; 1017 patients).

Table 1: results by baseline ordinal score

* Key: 4 = not requiring oxygen; 5 = requiring supplemental oxygen; 6 = non-invasive ventilation or high-flow oxygen devices; 7 = mechanical ventilation or ECMO.

Serious adverse events occurred less frequently in the remdesivir arm 114/541 (21.1%) vs 141/522 patients (27.0%) in the placebo group. This included serious respiratory failure adverse events in 28 (5.2%) vs 42 (8.0%) of the remdesivir vs placebo participants respectively. No deaths were judged related to remdesivir/placebo. Grade 3 or 4 events also occurred less frequently in the remdesivir arm: 156 (28.8%) vs 172 (33.0%), respectively.

The study also concludes that the high mortality even with remdesivir suggests that treatment with an antiviral drug alone is unlikely to be sufficient and that combination therapy should still be investigated. However, no viral load results have been presented for this study and this is not listed as a secondary endpoint in the information on clinicaltrials.gov registry for other phase 3 studies.

comment

These results provide the first evidence that remdesivir can significantly improve outcomes, although early access and use seems important. This should increase demand for compassionate access in the UK, at earlier stages of infection. [2]

Although the initial primary endpoint was difference in clinical status, defined by 8-point ordinal scale at day 15, this was changed a priori to time to recovery (ordinal scale score 1, 2 or 3) during the 28 days after enrolment.

There was an overall difference between the arms with regard to median recovery time, but no statistically significant benefit in terms of overall mortality. This suggests that optimal benefit is for patients hospitalised, requiring oxygen or non-invasive ventilation.  However, less of an effect for patients requiring mechanical ventilation or ECMO.

The Gilead 5774 Simple study in moderate infection will provide data on the impact of remdesivir 5 days vs 10 days vs standard of care in a larger number of hospitalised patients not needing oxygen supplementation or with O2 >94% on air.  This should be reporting soon.

The DISCOVERY Trial (the European arm of the adaptive-platform Solidarity study) should provide data on SARS-CoV-2 RNA, at least in terms of time to undetectability.  This includes remdesivir as one of the treatment arms.

Additional remdesivir studies in the UK are comparing 5-day vs 10-day remdesivir treatment.

Even though not yet approved in Europe, other ongoing studies that currently use standard of care control arms should also consider remdesivir to current standard of care.

Remdesivir was approved by the FDA on 1 May 2020. [3, 4] The EMA has already announced that remdesivir will be evaluated using a rolling review process to accelerate this decision in Europe. 

Gilead has signed non-exclusive licensing agreements with five generic drug makers to manufacture remdesivir for distribution in 127 countries and to expand the supply of remdesivir for COVID-19. [6]

The agreements are with Cipla, Ferozsons, Hetero, Jubilant Lifesciences and Mylan and the countries include nearly all low-income and lower-middle income countries, as well as several upper-middle- and high-income countries that face significant obstacles to healthcare access.

On 26 May 2020, the UK MHRA agreed expanded access to remdesivir. [7]

STOP PRESS: As this issue of HIV and COVID-19 was being finalised for distribution, Gilead issued a press release on the SIMPLE-Moderate study. Top-line results showed that in moderate COVID-19 disease – those with pneumonia who do not require supplemental oxygen – a 5-day course of remdesivir led to greater clinical improvement than standard of care alone. [8]

This article was first posted online on 23 May 2020.

References

1. Beigel JH et al. Remdesivir for the treatment of covid-19 – preliminary report. NEJM
   DOI: 10.1056/NEJMoa2007764. (22 May 2020).
   https://www.nejm.org/doi/full/10.1056/NEJMoa2007764
2. European Medicine’s Agency press statement. EMA provides recommendations on compassionate use of remdesivir for COVID-19. (3 April 2020).
   https://www.ema.europa.eu/en/news/ema-provides-recommendations-compassionate-use-remdesivir-covid-19
3. FDA news release. Coronavirus (COVID-19) Update: FDA issues emergency use authorization for potential COVID-19 treatment. (1 May 2020).
   https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment
4. Remdesivir Safety information.
   https://www.fda.gov/media/137566/download
5. European Medicine’s Agency press statement. EMA starts rolling review of remdesivir for COVID-19. (30 April 2020).
   https://www.ema.europa.eu/en/news/ema-starts-rolling-review-remdesivir-covid-19
6. Gilead press statement. Voluntary licensing agreements for remdesivir.
   https://www.gilead.com/purpose/advancing-global-health/covid-19/voluntary-licensing-agreements-for-remdesivir
7. UK access to remdesivir approved: but MHRA criteria exclude some who could benefit. HTB. (28 May 2020).
   https://i-base.info/htb/38051
8. Gilead press statement. Gilead announces results from phase 3 trial of remdesivir in patients with moderate COVID-19. (1 June 2020).
   https://www.gilead.com/news-and-press/press-room/press-releases/2020/6/gilead-announces-results-from-phase-3-trial-of-remdesivir-in-patients-with-moderate-covid-19