Remdesivir (1) – Veklury®

• Clinical trials
  • The ACTT-1 trial is a placebo-controlled, double-blind, multicentre, multinational, randomised parallel-group trial of remdesivir, which was conducted at 60 centres in 10 countries.
  • The CAP-2 trial was a placebo-controlled, double-blind, randomised, parallel-group trial of remdesivir, conducted exclusively at 10 centres in Wuhan (China).
  • The GS5774-A study is a three-arm, open-label, multicentre, randomised parallel-group study in which patients were treated with remdesivir for either 5 days or 10 days, or received standard COVID-19 treatment alone.

a) Adults with COVID-19 and pneumonia requiring supplemental oxygen, who were receiving low-flow oxygen at the start of treatment

• Hint for a minor additional benefit
• In general, it can be assumed that the treatment of hospitalised patients with COVID-19 has improved since the start of the pandemic. Consequently, the treatment of COVID-19 described in the included studies, which were conducted at the start of the pandemic, can only be applied to the current care situation to a limited extent.
• Given the limitations of the available evidence, and despite the existence of several RCTs, there is a hint of a minor additional benefit in terms of the certainty of the findings.
• mortality
  • For the LFO patient population, the meta-analysis of studies with high certainty of evidence (ACTT-1 and GS5774-A) shows a statistically significant advantage for remdesivir plus standard therapy for the endpoint of all-cause mortality.
  • In the CAP-2 trial, however, no advantages of remdesivir on overall survival were observed that would provide a hint of additional benefit.
  • The inclusion of the CAP-2 study therefore results in a heterogeneous data set which, given the uncertainties regarding the implementation of the appropriate comparator therapy in the individual study populations, cannot be assessed.
  • The mortality data cannot therefore be used for the benefit assessment.
• Morbidity – Recovery
  • For the LFO patient population, the meta-analysis of studies with high certainty of evidence shows a statistically significant advantage in favour of remdesivir plus standard therapy for the endpoint of recovery at day 14/15.
  • The inclusion of the CAP-2 study, with moderate certainty of evidence, yields a statistically non-significant result given the homogeneous data set.
  • For the LFO patient population, the meta-analysis of studies with high certainty of evidence shows a statistically significant advantage in favour of remdesivir plus standard therapy for the endpoint of recovery at the end of the study.
  • The inclusion of the CAP-2 trial in the meta-analysis of all three trials also yields a statistically significant advantage for remdesivir plus standard therapy, with homogeneous data, albeit with a wider confidence interval (RR 1.17; 95% CI 1.01–1.36).
  • In summary, taking into account the uncertainties regarding the implementation of the appropriate comparator therapy in the individual study populations, an advantage for remdesivir is inferred.
• quality of life
  • Endpoints relating to health-related quality of life were not assessed in the included studies.
• Side effects
  • When recording adverse events (AEs) and discontinuations due to AEs, a wide range of disease-related events were also recorded in the studies.
  • Accordingly, the results for individual common adverse events (e.g. respiratory failure) show comparable advantages for remdesivir compared to those for morbidity.
  • Consequently, the overall rates of SUEs and discontinuations due to AEs cannot be used to assess the side effects of remdesivir.
  • However, based on the results for common SUEs and discontinuations due to AEs, no adverse effects of remdesivir are expected to such an extent that they could call into question the additional benefit of remdesivir.
• Overall assessment
  • For the assessment of the additional benefit of remdesivir compared with standard of care in adults with COVID-19 who had LFO at the start of treatment, the meta-analytical summary of the ACTT-1, GS5774-A and CAP-2.
  • In the mortality endpoint category, the available results for the overall survival endpoint show a statistically significant advantage for remdesivir compared with the appropriate comparator therapy.
  • However, the inclusion of the CAP-2 study results in a heterogeneous data set, meaning that no conclusions can be drawn regarding the benefit assessment.
  • For the morbidity endpoint category, there are also advantages for remdesivir with regard to the recovery endpoint.
  • However, the inclusion of the CAP-2 study in the analysis at day 14/15 results in a statistically non-significant outcome.
  • When the CAP-2 study is included in the analysis of recovery at the end of the study, the advantage for remdesivir remains statistically significant, albeit with a wider confidence interval.
  • No data are available regarding health-related quality of life, as this was not assessed in the studies.
  • The overall rates of serious adverse events (SAEs) and discontinuations due to adverse events (AEs) for assessing the side effects of remdesivir are not usable due to the extensive recording of disease-related events.
  • Uncertainties relate to the implementation of the appropriate comparator therapy in the included studies.
  • Although the standard treatment for COVID-19 used in the studies also included corticosteroids, these were used to a very varying extent across the studies.
  • According to the S3 guideline – Recommendations for the inpatient management of patients with COVID-19 – treatment with dexamethasone should be administered to patients with severe (SpO₂ < 90 %, respiratory rate > 30/min) or critical (ARDS, sepsis, mechanical ventilation, vasopressor use) COVID-19.
  • It is unclear to what extent this recommendation also applies to patients with moderate COVID-19 who are being treated with LFO.
  • According to the clinical experts, during the treatment phase of COVID-19 with LFO, the concurrent use of remdesivir and dexamethasone is only appropriate during a brief transitional phase from the viral replication phase to the hyperinflammatory phase of the disease.
  • It is also unclear whether dexamethasone was used to a sufficient extent during this transitional phase in the studies.
  • Overall, remdesivir shows positive effects compared with standard therapy with regard to the endpoint of recovery.
  • Uncertainties arise regarding the implementation of the appropriate comparator therapy and due to the heterogeneous study population in the mortality endpoint category.
  • Overall, a minor additional benefit for remdesivir compared with the appropriate comparator therapy is observed.

b) Adults with COVID-19 and pneumonia requiring supplementary oxygen who are receiving high-flow oxygen or non-invasive ventilation at the start of treatment

• The additional benefit is not proven.
• mortality
  • For the HFO/NIV patient population, the meta-analysis of studies with high certainty of evidence shows no statistically significant difference between the treatment groups for the endpoint of overall mortality.
• Morbidity – Recovery
  • For the HFO/NIV patient population, the meta-analysis of studies with high certainty of evidence showed no statistically significant difference between the treatment groups for the endpoint of recovery, either at day 14/15 or at the end of the study.
• quality of life
  • Endpoints relating to health-related quality of life were not assessed in the included studies.
• Side effects
  • When recording adverse events (AEs) and discontinuations due to AEs, a wide range of disease-related events were also recorded in the studies.
  • Accordingly, the results for individual common adverse events (e.g. respiratory failure) show comparable advantages for remdesivir compared to those for morbidity.
  • Consequently, the overall rates of SUEs and discontinuations due to AEs cannot be used to assess the side effects of remdesivir.
• Overall assessment
  • For the assessment of the additional benefit of remdesivir compared with standard of care in adults with COVID-19 with HF / NIV at the start of treatment, results on mortality (overall survival) and morbidity (recovery) are available from the meta-analytical summary of the ACTT-1 and GS5774-A studies.
  • Across the studies, there are major uncertainties regarding the implementation of the appropriate comparator therapy in patients receiving HFO / NIV at the start of treatment.
  • The study results are nevertheless presented but are not used for the benefit assessment.
  • For the endpoint of overall mortality, there is no statistically significant difference between the treatment groups.
  • Similarly, for the morbidity endpoint of recovery, there was no statistically significant difference between the treatment groups either at day 14/15 or at the end of the study.
  • Endpoints relating to health-related quality of life were not assessed in the included studies.
  • The overall rates of SUEs and discontinuations due to AEs for the assessment of remdesivir’s side effects are not usable due to the extensive co-recording of disease-related events.
  • Notwithstanding the uncertainties regarding the extent to which the appropriate comparator therapy can be regarded as having been fully implemented, even a substantive assessment would reveal neither positive nor negative effects for remdesivir in adults receiving HFO/NIV at the start of treatment.
  • In summary, for adults with COVID-19 and pneumonia who require HFO or NIV at the start of treatment, there is no hint of additional benefit from remdesivir compared with the appropriate comparator therapy; an additional benefit is therefore not proven.

c) Adolescents with COVID-19 and pneumonia requiring additional oxygen support who are receiving low- or high-flow oxygen or non-invasive ventilation at the start of treatment

• An additional benefit is not proven.
• No adolescents were included in the studies within the patient populations relevant to the benefit assessment.
• Furthermore, the pharmaceutical manufacturer has not provided any data on the extrapolation of the results to adolescents.
• As the risk of mortality from COVID-19 varies significantly depending on age, the results of the benefit assessment observed in adults cannot be extrapolated to adolescents.
• There are therefore no usable data available for adolescents, and the additional benefit is not proven for this patient population either.

Courtesy translation only, please refer to the German original.