Brian Locke

Trial Appraisals

ACTT-1: Remesevir for COVID-19

RECOVERY: Dexamethasone for COVID-19

##ACTT-1 Background/Context: Compassionate use paper maybe positive? but obviously not the right methodology to determine efficacy.

RDV: known to have in vitro activity against other coronaviruses, but previously no FDA indication (drug in need of a disease).

1st RCT: Chinese Academy of Medical Science trial in Lancet - no difference, n=237 patients of RDV vs placebo, underpowered due to control of epidemic.

####Funding NIAID, Gilead provided the drug but no funding or study design.

####Study Design

  • Double blind RCT 1:1 remdesevir vs placebo
  • designed to achieve 85% power for detecting a recovery rate ratio of 1.35 with a two-sided type-I error rate of 5%

####Population

  • 60 trial sites and 13 subsites in the United States (45 sites), Denmark (8), the United Kingdom (5), Greece (4), Germany (3), Korea (2), Mexico (2), Spain (2), Japan (1), and Singapore (1).
  • 541 randomized to remdesevir, 522 to placebo group
  • age 58.9, 64% male, 53% white/20.6%black/12.6%Asian/23.4Hispanic or Latinx. -HTN present in 49.6%, obesity 37.0%, DM 29.7%
  • avg 9 days since randomization [6,12 IQR]

####Intervention

  • Remdesivir was administered intravenously as a 200-mg loading dose on day 1, followed by a 100-mg maintenance dose administered daily on days 2 through 10 or until hospital discharge or death

####Control

  • supportive care, other experimental interventions allowed.
  • note: they ran out of placebos at some sites, which may have compromised blinding.

####Study procedures

  • Randomization was stratified by study site and disease severity at enrollment
  • Patients assessed daily during hospitalization on an ordinal scale:
  • 1, not hospitalized, no limitations of activities;
  • 2, not hospitalized, limitation of activities, home oxygen requirement, or both;
  • 3, hospitalized, not requiring supplemental oxygen and no longer requiring ongoing medical care (used if hospitalization was extended for infection-control reasons);
  • 4, hospitalized, not requiring supplemental oxygen but requiring ongoing medical care (Covid-19–related or other medical conditions);
  • 5, hospitalized, requiring any supplemental oxygen;
  • 6, hospitalized, requiring noninvasive ventilation or use of high-flow oxygen devices;
  • 7, hospitalized, receiving invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO);
  • 8, death

####Inclusion Criteria 18+ y/o hospitalized patients w COVID positive by RTPCR less than 72h before hospitalization and 1 of:

  • radiographic infiltrates by imaging study
  • sp02 <94%
  • requiring supplemental oxygen, mechanical ventilation, or ECMO

No requirement in relation to time of onset of symptoms.

Exclusion: AST/ALT more than 5x ULN, eGFR <30, Pregnancy/Breast feeding, allergy

####Primary Outcome -stratified log-rank test of time to recovery (defined as the first day, during the 28 days after enrollment, on which a patient satisfied categories 1, 2, or 3 on the eight-category ordinal scale) with stratification by disease severity -akin to the hazard ratio in survival analysis but for the beneficial outcome of recovery

####Secondary Outcomes mortality at 14 and 28 days after enrollment and grade 3 and 4 adverse events and serious adverse events that occurred during the trial. Prespecified subgroups in these analyses were defined according to sex, disease severity (as defined for stratification and by ordinal scale at enrollment), age (18 to 39 years, 40 to 64 years, or 65 years of age or older), and duration of symptoms before randomization (≤10 days or >10 days).

####Followup

  • a total of 391 patients in the remdesivir group and 340 in the placebo group had completed the trial through day 29, recovered, or died. (less than enrolled due to many having been
  • Participants discharged from the hospital had study visits at Days 15 and 29. -99.2% assigned to placebo got placebo. 98.1% assigned to RDV got RDV

####Results

  • Remdesevir had shorter time to recovery than placebo group (median 11 days vs 15 days).
  • Stratification by enrollment severity: Receiving oxygen = large benefit. No benefit if on HFNC/NIPV, Ventilation, or ECMO at enrollment.
  • <10d since symptoms and >10d symptoms both had statistically significant improvement (rate ratio).

alt

Secondary:

  • Mortality: hazard ratio for death at 14d, 0.70; 95% CI, 0.47 to 1.04; 1059 patients. (5.9% in remdesevir, 10.4% in placebo)
  • 28d not done due to too many patient's not 28d in to study period.

####Adverse Events

  • No categories (including AKI) were more common in RDV group.

####Conclusion -RDV decreases time to recovery by ~4 days (in an otherwise 2 week course) in patients requiring oxygen at admission. -It may also decrease mortality. It is possible that the 28d mortality analysis will look less promising than the 14d if RDV only delays morality but does not actually change clinical course. This is the price for only getting the interim analysis (presumably, final analysis to come - though it was unblinded and crossover was allowed after so this may not be as useful) -No benefit was seen in critically ill patients. -Most secondary outcomes were not reported. -Blinding is potentially important as primary outcome is behavior related. -subsequent trial did not find a difference between 5 and 10 day courses so that has been adopted (though this was not a non-inferiority trial)

##RECOVERY

critique: incomplete outcome followup in control group?