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Posted On: 08/21/2020 12:55:16 PM
Posted By: reallypeople?
Jama beat down of Remdesivir
In this clinical trial of patients with moderate COVID-19 pneumonia, those who were randomized to remdesivir treatment for up to 5 days had significantly higher odds of having a better clinical status distribution on day 11 than those receiving standard care, but with an effect size of uncertain clinical importance. The difference in the distribution of clinical status on day 11 between the 10-day remdesivir and standard care groups was not significant.
Several factors may account for the lack of difference in clinical status observed in the 10-day remdesivir group, although the median length of treatment was 6 days in this group. Given the open-label design of the study and the requirement for intravenous dosing of remdesivir, discharge decisions may have been influenced by the assigned duration of remdesivir therapy. Rates of discharge peaked on the day after the end of dosing in both groups: on day 6 for the 5-day group and on day 11 for the 10-day group (eFigure 1 in Supplement 3). However, when outcomes at days 14 and 28 were evaluated, similar distributions of clinical status were observed between patients in the remdesivir groups, possibly pointing to differences compared with standard care. Patients were not stratified by site at enrollment, which may have led to imbalances in patient care and discharge practices. In addition, the possibility that additional days of hospitalization and remdesivir treatment for patients in the 10-day group had a negative effect on outcomes cannot be excluded, although the rates of grade 3 or higher adverse events and serious adverse events were not higher in the 10-day remdesivir group than in the 5-day remdesivir and standard care groups.
There was no a priori knowledge of the trajectories of patients hospitalized with moderate COVID-19 disease—those with confirmed infiltrates by radiology, but with room-air oxygen saturations greater than 94% at rest. The majority of these patients were enrolled within 2 days of hospitalization, yet 15% received supplemental oxygen on day 1. This is a relevant observation for future trials as the ordinal clinical status scales used to date do not take into account oxygen saturation values or oxygen supplies and patterns of use in different health systems.17 In the ACTT-1 and RECOVERY trials, mortality and treatment effects were strongly influenced by clinical status at randomization, confirming a spectrum of severity among hospitalized patients with COVID-19.11,17 Future trials should consider studying individual severity strata incorporating further clarification and refinements in their definitions. Factors that contribute to patients progressing to severe and critical COVID-19 remain to be elucidated. The risk of rapid disease progression described to date points to the potential benefit of earlier intervention with an effective antiviral.6,18
Limitations
This study has several limitations. First, the original protocol was written when COVID-19 cases were largely confined to Asia and the clinical understanding of disease was limited to case series.19,20 This led to a change in the primary end point on the first day of study enrollment as it became clear that hospital discharge rates varied greatly across regions and the ordinal scale had become standard for interventional COVID-19 studies.11,21 Second, the study used an open-label design, which potentially led to biases in patient care and reporting of data. Third, because of the urgent circumstances in which the study was conducted, virologic outcomes such as effect of remdesivir on SARS-CoV-2 viral load were not assessed. Fourth, other laboratory parameters that may have aided in identifying additional predictors of outcomes were not routinely collected. Fifth, the ordinal scale used to evaluate outcomes was not ideal for detecting differences in patients with moderate COVID-19, especially for a clinical situation in which discharge decisions may be driven by factors other than clinical improvement.
Conclusions
Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
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Article Information
Corresponding Author: Diana M. Brainard, MD, Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404 (diana.brainard@gilead.com).
Accepted for Publication: August 12, 2020.
Read More: https://investorshangout.com/post/viewremoved...z6Vm0h1rxy
Posted On: 08/21/2020 12:55:16 PM
Posted By: reallypeople?
Jama beat down of Remdesivir
In this clinical trial of patients with moderate COVID-19 pneumonia, those who were randomized to remdesivir treatment for up to 5 days had significantly higher odds of having a better clinical status distribution on day 11 than those receiving standard care, but with an effect size of uncertain clinical importance. The difference in the distribution of clinical status on day 11 between the 10-day remdesivir and standard care groups was not significant.
Several factors may account for the lack of difference in clinical status observed in the 10-day remdesivir group, although the median length of treatment was 6 days in this group. Given the open-label design of the study and the requirement for intravenous dosing of remdesivir, discharge decisions may have been influenced by the assigned duration of remdesivir therapy. Rates of discharge peaked on the day after the end of dosing in both groups: on day 6 for the 5-day group and on day 11 for the 10-day group (eFigure 1 in Supplement 3). However, when outcomes at days 14 and 28 were evaluated, similar distributions of clinical status were observed between patients in the remdesivir groups, possibly pointing to differences compared with standard care. Patients were not stratified by site at enrollment, which may have led to imbalances in patient care and discharge practices. In addition, the possibility that additional days of hospitalization and remdesivir treatment for patients in the 10-day group had a negative effect on outcomes cannot be excluded, although the rates of grade 3 or higher adverse events and serious adverse events were not higher in the 10-day remdesivir group than in the 5-day remdesivir and standard care groups.
There was no a priori knowledge of the trajectories of patients hospitalized with moderate COVID-19 disease—those with confirmed infiltrates by radiology, but with room-air oxygen saturations greater than 94% at rest. The majority of these patients were enrolled within 2 days of hospitalization, yet 15% received supplemental oxygen on day 1. This is a relevant observation for future trials as the ordinal clinical status scales used to date do not take into account oxygen saturation values or oxygen supplies and patterns of use in different health systems.17 In the ACTT-1 and RECOVERY trials, mortality and treatment effects were strongly influenced by clinical status at randomization, confirming a spectrum of severity among hospitalized patients with COVID-19.11,17 Future trials should consider studying individual severity strata incorporating further clarification and refinements in their definitions. Factors that contribute to patients progressing to severe and critical COVID-19 remain to be elucidated. The risk of rapid disease progression described to date points to the potential benefit of earlier intervention with an effective antiviral.6,18
Limitations
This study has several limitations. First, the original protocol was written when COVID-19 cases were largely confined to Asia and the clinical understanding of disease was limited to case series.19,20 This led to a change in the primary end point on the first day of study enrollment as it became clear that hospital discharge rates varied greatly across regions and the ordinal scale had become standard for interventional COVID-19 studies.11,21 Second, the study used an open-label design, which potentially led to biases in patient care and reporting of data. Third, because of the urgent circumstances in which the study was conducted, virologic outcomes such as effect of remdesivir on SARS-CoV-2 viral load were not assessed. Fourth, other laboratory parameters that may have aided in identifying additional predictors of outcomes were not routinely collected. Fifth, the ordinal scale used to evaluate outcomes was not ideal for detecting differences in patients with moderate COVID-19, especially for a clinical situation in which discharge decisions may be driven by factors other than clinical improvement.
Conclusions
Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
Back to top
Article Information
Corresponding Author: Diana M. Brainard, MD, Gilead Sciences, 333 Lakeside Dr, Foster City, CA 94404 (diana.brainard@gilead.com).
Accepted for Publication: August 12, 2020.
Read More: https://investorshangout.com/post/viewremoved...z6Vm0h1rxy
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