ACTT-1 – Remdesivir

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“Remdesivir for the Treatment of Covid-19 — Preliminary Report”

J.H. Beigel, et al. and the ACTT-1 Study Group Members

N Engl J Med. 2020 May 22:NEJMoa2007764. doi: 10.1056/NEJMoa2007764 [Full text]

Several therapeutic agents have been and are being evaluated treatment of COVID-19, but Remdesivir is the probably the only anti-viral targeted therapy under consideration. Remdesivir inhibits the viral RNA polymerase, has activity against SARS-CoV and MERS-CoV, as well as SARS-CoV-2 in vitro.

The NIH sponsored Adaptive Covid-19 Treatment Trial (ACTT-1) evaluated treatment with remdesivir (200 mg day 1 and then 100 mg daily for up to 9 more days) compared with placebo. It should be noted the quality of this study is a somewhat rarity in the era of COVID-19. Many are observational, and those that have been randomized have been open label. This double-blinded, international, multicenter, placebo controlled trial trial is one of the few rigorous trials that would have met pre-COVID19 standards for changing clinical practice.

Patient Population 

Adults that were enrolled were those with confirmed COVID-19 and evidence of lower respiratory tract (LRT) involvement, as evidenced by any of the following: (1) infiltrates on imaging, (2) SpO2 ≤94% on RA, or (3) requiring supplemental O2, mechanical ventilation, or ECMO. There was no limit to the duration of symptoms prior to enrollment. Pregnant patients or those with an ALT/AST >5x ULN , impaired renal function, or needing HD/hemofiltration were excluded. A total of 1,063 patients were enrolled, 541 in the remdesivir group and 541 placebo.

The patients groups were equivalent at baseline and were roughly 64% male, 53% white, 50% had HTN and 29% had DM. Most (~89%) had “severe” disease or worse at enrollment, meaning they had an SpO2 ≤ 94% or RR > 24.

Results

The primary outcome was time to recovery, meaning the patient was discharged or no longer requiring hospital care (i.e., improved but awaiting rehab). Remdesivir showed an improved time to recovery of 11d when compared to 15 days for placebo (RR 1.32 95% CI 1.12-1.55).

In subgroup analysis the benefit was mostly seen in the group that required some oxygen support but not HFNC or MV (7 vs. 9d, RR 1.47 95% CI 1.17-1.84). The subgroups that were hospitalized without oxygen requirement or needing HFNC or MV had no benefit. Similarly there was a mortality benefit at 14 days in the group requiring some oxygen (2% vs. 10% HR 0.22 85% CI 0.08–0.58). While these are both interesting and promising, recall they are secondary outcomes.There were no differences in rate of adverse events.

Discussion 

The results were unblinded early even though the study was ongoing because the results were thought too important to not release to the public in the midst of the pandemic. A decision such as this is not taken lightly and relates to the magnitiude of the difference in the primary outcome. Though the impact is moderate [1], it should again be emphasized this is one of the few double-blind, randomized trials completed during the pandemic. Additionally there is promise that earlier adminuistration of Remdesivir could be more impactful [1].

A potential red flag with this study was that the primary outcome was changed after enrollment had commenced. The authors explain the change (originally the primary outcome was at only day 15) noting the original choice was made before a true understanding of the disease course and how protracted it could be. We can be reassured that the changes were proposed by statisticians who were unaware of treatment assignment and had no knowledge of outcome data.

A separate trial by Goldman et al. looked at 5 day vs. 10 day regimen and found that 5 days was equivalent [2]. Given the limited supply of Remdesivir, a 5 day course is recommended instead of the 10 day course used in ACTT-1. Additionally, NIH guidelines recommend prioritizing Remdesivir to those on oxygen but not HFNC/MV/ECMO, the subgroup that had the most benefit in ACTT-1. The same guidelines are unable to recommend for or against using Remdesivir in those requiring HFNC/MV/ECMO given the uncertainty in those subgroups [3].

  1. Dolin R, Hirsch MS. Remdesivir – An Important First Step. N Engl J Med. 2020 May 27:NEJMe2018715. doi: 10.1056/NEJMe2018715. Epub ahead of print. PMID: 32459913; PMCID: PMC7269011.
  2. Goldman JD, Lye DCB, Hui DS, Marks KM, Bruno R, Montejano R, Spinner CD, Galli M, Ahn MY, Nahass RG, Chen YS, SenGupta D, Hyland RH, Osinusi AO, Cao H, Blair C, Wei X, Gaggar A, Brainard DM, Towner WJ, Muñoz J, Mullane KM, Marty FM, Tashima KT, Diaz G, Subramanian A; GS-US-540-5773 Investigators. Remdesivir for 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020 May 27:NEJMoa2015301. doi: 10.1056/NEJMoa2015301. Epub ahead of print. PMID: 32459919; PMCID: PMC7377062.
  3. NIH COVID19 Treatment Guidelines.