ACTT-1

Published

Beigel JH, et al. "Remdesivir for the Treatment of Covid-19 - Preliminary Report". The New England Journal of Medicine. 2020. (e-pub 2020-05-22):1-12.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

Among patients hospitalized for Covid-19 with lower respiratory tract involvement, does remdesivir reduce the time to recovery?

Bottom Line

Among patients with Covid-19 hospitalized with lower respiratory tract involvement, remdesivir reduced the median time to recovery by approximately four days. There was no difference in 14-day survival between remdesivir and placebo groups. The report of 28-day mortality is pending.

Major Points

Originally developed as a treatment for the Ebola virus, remdesivir is a prodrug adenosine analogue that inhibits RNA-dependent RNA polymerases of several RNA viruses. Remdesivir was identified as a potentially promising therapeutic agent for the treatment of Covid-19 after preclinical investigations discovered in vitro inhibitory activity against SARS-CoV-2 as well as related coronaviruses SARS-CoV and MERS-CoV.

The Adaptive Covid-19 Treatment Trial (ACTT-1) was carried out in during the height to the Covid-19 pandemic in the United States and Europe and is the first study to demonstrate a clinical benefit for a pharmacologic agent in the treatment of Covid-19. This study follows an earlier but smaller double-blind placebo-controlled randomized control trial of remdesivir conducted in the Chinese province of Hubei, which found a numerical reduction in time to clinical improvement but otherwise no statistically significant clinical benefits.

The preliminary report of the ACTT-1 trial demonstrates that a 10-day course of remdesivir in hospitalized patients with severe Covid-19 is superior to placebo in reducing the the time to recovery, with a medial time to recovery of 11 days in the remdesivir group compared to 15 days in the placebo group. However, although there is a trend to overall reduced mortality with remdesivir (7.1% in the remdesivir group compared to 11.9%) at 14 days, this difference was not statistically significant. Subgroup analyses demonstrated that the reduction in time to recovery is driven by patients requiring supplemental oxygen. This subgroup has a statistically significant reduction in mortality at 14 days (HR 0.22, 95% CI 0.08-0.58).

The preliminary report of the ACTT-1 trial was published after the data and safety monitoring board recommended to unblind the results of the trial despite the fact the trial was ongoing. The findings were subsequently made public. These decisions were made as the findings of this trial may affect the care of patients who remain participants in the trial and for patients outside the trial who may benefit from remdesivir treatment.

In an accompanying editorial, Dolin and Hirsch note the preliminary nature of this study's findings, and that further follow-up is needed. A subsequent and final report of mortality at 28 days is pending.

A concurrent study investigated 5- versus 10-day remdesivir in patients with severe Covid-19 indicated similar outcomes in both treatment arms. Given the limited supply of remdesivir, limiting use to a 5-day course would seem reasonable among patients in whom remdesivir is being used.

Guidelines

As a result of the preliminary data presented in the ACTT-1 trial, the NIH Covid-19 Treatment Guidelines recommends the use of remdesivir for the treatment of hospitalized Covid-19 patients with severe disease (defined as SpO2 ≤94% on ambient air or requiring supplemental oxygen, mechanical ventilation, or ECMO). This guideline does not recommend remdesivir for the treatment of mild or moderate Covid-19 outside the setting of a clinical trial.

Design

• International, multicenter, double-blind, placebo-controlled, randomized control trial
• N=1,063 patients with Covid-19
  • Remdesivir (n=541)
  • Placebo (n=522)
• Setting: 60 trial sites and 13 subsites in the United States, Denmark, the United Kingdom, Greece, Germany, Korea, Mexico, Spain, Japan, and Singapore
• Enrollment: 21 Feb 2020 to 19 Apr 2020
• Analysis: Intention-to-treat
• Primary outcome: Time to recovery

Population

Eligibility criteria are included in the Supplemental Appendix.

Inclusion Criteria

• Age ≥18 years
• Laboratory-confirmed SARS-CoV-2 infection (as determined by a PCR)
• Evidence of lower respiratory tract infection at the time of enrollment based on one of the following:
  • Radiographic infiltrates by imaging study
  • SpO2 ≤94% on room air
  • Requiring supplemental oxygen, mechanical ventilation, or ECMO
• No limit to the duration of symptoms prior to enrollment

Exclusion Criteria

• ALT or AST >5x ULN
• Impaired renal function by eGFR or need for hemodialysis or hemofiltration
• Allergy to study product
• Pregnancy or breast-feeding
• Anticipated discharge from the hospital or transfer to another hospital within 72 hours of enrollment
• Other treatments for Covid-19 may be given if a hospital had a written policy or guideline. However, if a hospital did not have a written policy or guideline, other experimental treatment or off-label use of marketed medications intended as specific treatment for Covid-19 were prohibited from day 1 through day 29 (such medications may be given prior to enrollment).

Baseline Characteristics

• Mean age: 59 years
• Female sex: 36%
• Number of co-existing conditions: none 21%, one 27%, two or more 52.1%
• Important co-existing conditions: hypertension 50%, obesity 37%, type 2 diabetes 30%
• Median time from symptom onset to randomization: 9 days
• Ordinal score of disease severity: (4) 11.9%, (5) 39.6%, (6) 18.5%, (7) 25.6%, (missing score) 4.3%

Interventions

• 1:1 randomization to remdesivir or placebo

  • Remdesivir: 200-mg loading dose on day 1, followed by 100 mg/d on days 2 through 10 or until hospital discharge or death
  • Placebo: matching placebo administered according to the same schedule and in the same volume as remdesivir; some sites made use of normal saline when a matching placebo was not available due to shortages

Outcomes

Comparisons are remdesivir vs. placebo.

Primary Outcomes

Time to recovery

11 vs. 15 days (RR 1.32, 95% CI 1.12–1.55; P<0.001)

Secondary Outcomes

14-day mortality

7.1% vs. 11.9% (HR 0.70, 95% CI 0.47–1.04)

Subgroup Analysis

Subgroup analyses were conducted on the basis of geographic region, race, ethnic group, age, sex, symptom duration, and disease category at study entry (not receiving supplemental oxygen, receiving supplemental oxygen, receiving mechanical ventilation, etc.). The benefit of remdesivir was most pronounced for younger patients (age 18 to <40 years) and those receiving supplemental oxygen. There was no significant difference between outcome according to symptom duration or sex.

Adverse Events

Serious adverse events

21.1% vs 27%

Respiratory failure

5.2% vs 8.0%

Grade 3-4 adverse events

28.8% vs. 33.0%

Criticisms

• Prior to the start of the trial, the primary outcome was defined as the difference in clinical status at day 15, based on baseline disease category. This initial primary outcome was changed to a key secondary outcome upon the recommendation of trial statisticians, who were blinded to treatment assignments, to make time to recovery the primary outcome. At the time of this proposal, 72 patients had been enrolled in the trial. The authors write that this change in the primary outcome was made in response to developing information that Covid-19 had a more protracted course than previously thought. Ultimately, both statistically significant differences were observed in both the original and new primary outcomes.
• A shortage of matching placebos occurred at some sites such that normal saline was used in its place. This situation may have compromised blinding.

Funding

• The trial was primarily funded by the National Institute of Allergy and Infectious Diseases (NIAID) of the NIH. Gilead Sciences, which is the manufacturer of remdesivir, provided the drug but did not provide any financial support.