12. Remdesivir Returns: The ACTT-1 Trial

They teased us with a press release weeks ago, and Faucci has been promoting it ever since – and now, we finally have the data from the ACTT-1 trial on remdesivir. Here we take a closer look to see if this really is the “very promising result” it was sold as.

 

Reminder: background on remdesivir

Antiviral with in-vitro promise Recent trial from Wang et al1 was negative for a difference in time to clinical improvement Trial was underpowered as it was stopped early due to slow recruitment They did note a trend towards faster improvement (18d vs 23d) in the subset of patients who received remdesivir within 10d of symptom onset

 

ACTT-1: Adaptive COVID-19 Treatment Trial2

Randomized, double-blind, placebo-controlled trial of remdesivir for COVID-19 Enrollment for 3 weeks in Feb/March at 60 sites in the US, Europe, and Asia Ended up being predominantly North American patients (about 80%) Methods Patients: adults with PCR-confirmed COVID infection with at least one of the following: radiographic infiltrates, SpO2 < 94% on RA, need for supplemental oxygen, or MV/ECMO Sub-stratified further into mild/moderate (SpO2 > 94% on RA, RR <24) vs severe disease; most patients (about 88%) had “severe” disease Key exclusion: transaminitis (AST/ALT > 5x ULN), renal dysfunction (GFR < 30), pregnancy/breastfeeding Intervention: remdesivir 200mg IV on day 1, then 100mg IV daily on days 2-10 Primary outcome: time to recovery, defined as the first day that the patient scored 1, 2, or 3 on an 8-point clinical scale 1 = totally well; 3 = still hospitalized but not requiring oxygen or ongoing medical treatments Primary outcome was actually changed near the start of the trial (previously designed as change in 8-point ordinal scale on day 15) Changed due to evolving knowledge of the potentially protracted course of COVID-19 Secondary outcomes: 14d and 28d mortality; as well as adverse events These results are actually an interim analysis: 1/3 of patients are still enrolled in the trial and have no documented final outcome yet Because of the nature of the results, the data safety monitoring committee recommended the results be released while the trial is still ongoing Results Patient population 1063 patients enrolled; though 301 are still continuing in the trial follow-up period (but their data to date was included in the analysis) Relatively sick; most people were hospitalized requiring at least supplemental oxygen; about 25% of patient were mechanically ventilated or on ECMO Most had at least one co-morbidity; most commonly hypertension (present in almost 50% of patients) Primary outcome Remdesivir group has faster time to clinical recovery: 11d vs 15d (rate ratio for recovery 1.32, CI 1.12-1.55) Note that the sickest subgroups – those on non-invasive or invasive ventilation, or ECMO – did not demonstrate any benefit Perhaps because in these groups there is a significant immune hyperactivation component? No change in the significance of the outcome when they adjusted for those randomized <10d after symptom onset vs >10d Secondary outcomes Mortality at 14d was numerically lower in the remdesivir group, but not (quite) statistically significant – HR for death 0.70 (CI 0.47-1.04) No significant difference in adverse events Caveats Change in primary outcome: we never like to see this in trials, but seems to have been done here for a fairly legitimate indication as our understanding of this disease evolved Notably, the analysis for their original primary endpoint still shows a statistically significant benefit to remdesivir Early unblinding and reporting of the trial: done when a planned interim analysis revealed a clinically significant benefit to remdesivir. The committee made the reasonable decision that in a pandemic situation, these were important results to be released as soon as possible. The authors themselves note that it is important that the full trial period (with follow-up and monitoring) be completed, and these full results will be reported separately It’s interesting that they chose to report mortality at 14 days, when their change in primary outcome acknowledges that COVID often has a more protracted course and requires a longer time frame of study. Although the reported difference sounds numerically impressive, the Kaplan-Meyer curves appear to be converging, suggesting that the benefit is only transient A lot of granular data is missing from this manuscript – hopefully will be included in the follow-up paper

 

Compared to the Wang trial

Overall these trials are fairly congruent (though one was technically negative, and one was positive) Both show a reduced in time to clinical improvement with remdesivir Statistical significance of the ACTT-1 trial (in contrast to Wang) likely primarily due to higher numbers, more statistical power, and perhaps the use of an 8-point vs 6-point ordinal scale Not convincing effect on mortality in either trial The ACTT-1 group reports that they measured viral load (as did Wang, who found no difference), but it’s not included in this paper

 

Where this leaves us

This is potentially promising! Remdesivir appears to hasten time to recovery - even without any effect on mortality, this could have very significant implications from a resource utilization perspective, especially in a pandemic BUT note that it is an IV drug - do we really need everyone hospitalized for 10 days to get the full treatment protocol? Mortality benefit is unclear; disappointingly, the curves seem to come together Remdesivir does appear safe We need the full data – stay tuned!

 

 

Sources

Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020;395: 1569-78. doi:10.1016/S0140-6736(20)31022-9 Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. New Eng J Med, May 2020. doi:10.1056/NEJMoa2007764

They teased us with a press release weeks ago, and Faucci has been promoting it ever since – and now, we finally have the data from the ACTT-1 trial on remdesivir. Here we take a closer look to see if this really is the “very promising result” it was sold as.

 

Reminder: background on remdesivir

Antiviral with in-vitro promise Recent trial from Wang et al1 was negative for a difference in time to clinical improvement Trial was underpowered as it was stopped early due to slow recruitment They did note a trend towards faster improvement (18d vs 23d) in the subset of patients who received remdesivir within 10d of symptom onset

 

ACTT-1: Adaptive COVID-19 Treatment Trial2

Randomized, double-blind, placebo-controlled trial of remdesivir for COVID-19 Enrollment for 3 weeks in Feb/March at 60 sites in the US, Europe, and Asia Ended up being predominantly North American patients (about 80%) Methods Patients: adults with PCR-confirmed COVID infection with at least one of the following: radiographic infiltrates, SpO2 < 94% on RA, need for supplemental oxygen, or MV/ECMO Sub-stratified further into mild/moderate (SpO2 > 94% on RA, RR 5x ULN), renal dysfunction (GFR < 30), pregnancy/breastfeeding Intervention: remdesivir 200mg IV on day 1, then 100mg IV daily on days 2-10 Primary outcome: time to recovery, defined as the first day that the patient scored 1, 2, or 3 on an 8-point clinical scale 1 = totally well; 3 = still hospitalized but not requiring oxygen or ongoing medical treatments Primary outcome was actually changed near the start of the trial (previously designed as change in 8-point ordinal scale on day 15) Changed due to evolving knowledge of the potentially protracted course of COVID-19 Secondary outcomes: 14d and 28d mortality; as well as adverse events These results are actually an interim analysis: 1/3 of patients are still enrolled in the trial and have no documented final outcome yet Because of the nature of the results, the data safety monitoring committee recommended the results be released while the trial is still ongoing Results Patient population 1063 patients enrolled; though 301 are still continuing in the trial follow-up period (but their data to date was included in the analysis) Relatively sick; most people were hospitalized requiring at least supplemental oxygen; about 25% of patient were mechanically ventilated or on ECMO Most had at least one co-morbidity; most commonly hypertension (present in almost 50% of patients) Primary outcome Remdesivir group has faster time to clinical recovery: 11d vs 15d (rate ratio for recovery 1.32, CI 1.12-1.55) Note that the sickest subgroups – those on non-invasive or invasive ventilation, or ECMO – did not demonstrate any benefit Perhaps because in these groups there is a significant immune hyperactivation component? No change in the significance of the outcome when they adjusted for those randomized 10d Secondary outcomes Mortality at 14d was numerically lower in the remdesivir group, but not (quite) statistically significant – HR for death 0.70 (CI 0.47-1.04) No significant difference in adverse events Caveats Change in primary outcome: we never like to see this in trials, but seems to have been done here for a fairly legitimate indication as our understanding of this disease evolved Notably, the analysis for their original primary endpoint still shows a statistically significant benefit to remdesivir Early unblinding and reporting of the trial: done when a planned interim analysis revealed a clinically significant benefit to remdesivir. The committee made the reasonable decision that in a pandemic situation, these were important results to be released as soon as possible. The authors themselves note that it is important that the full trial period (with follow-up and monitoring) be completed, and these full results will be reported separately It’s interesting that they chose to report mortality at 14 days, when their change in primary outcome acknowledges that COVID often has a more protracted course and requires a longer time frame of study. Although the reported difference sounds numerically impressive, the Kaplan-Meyer curves appear to be converging, suggesting that the benefit is only transient A lot of granular data is missing from this manuscript – hopefully will be included in the follow-up paper

 

Compared to the Wang trial

Overall these trials are fairly congruent (though one was technically negative, and one was positive) Both show a reduced in time to clinical improvement with remdesivir Statistical significance of the ACTT-1 trial (in contrast to Wang) likely primarily due to higher numbers, more statistical power, and perhaps the use of an 8-point vs 6-point ordinal scale Not convincing effect on mortality in either trial The ACTT-1 group reports that they measured viral load (as did Wang, who found no difference), but it’s not included in this paper

 

Where this leaves us

This is potentially promising! Remdesivir appears to hasten time to recovery - even without any effect on mortality, this could have very significant implications from a resource utilization perspective, especially in a pandemic BUT note that it is an IV drug - do we really need everyone hospitalized for 10 days to get the full treatment protocol? Mortality benefit is unclear; disappointingly, the curves seem to come together Remdesivir does appear safe We need the full data – stay tuned!

 

 

Sources

Wang Y, Zhang D, Du G et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 2020;395: 1569-78. doi:10.1016/S0140-6736(20)31022-9 Beigel JH, Tomashek KM, Dodd LE et al. Remdesivir for the Treatment of Covid-19 — Preliminary Report. New Eng J Med, May 2020. doi:10.1056/NEJMoa2007764