key: cord-0990778-dieaqxmi
authors: Davies, M.; Osborne, V.; Lane, S.; Roy, D.; Dhanda, S.; Evans, A.; Shakir, S. A.
title: Remdesivir in treatment of COVID-19: A systematic benefit-risk assessment
date: 2020-05-12
journal: nan
DOI: 10.1101/2020.05.07.20093898
sha: b1e057d87220046279ea75579098f122712e055f
doc_id: 990778
cord_uid: dieaqxmi

Background: There is a need to identify effective, safe treatments for COVID-19 (coronavirus disease) rapidly, given the current, ongoing pandemic. A systematic benefit-risk assessment was designed and conducted to strengthen the ongoing understanding of the benefit-risk balance for remdesivir in COVID-19 treatment by using a structured method which uses all available data. Methods: The Benefit-Risk Action Team (BRAT) framework was used to assess the overall benefit-risk of the use of remdesivir as a treatment for COVID-19 compared to standard of care, placebo or other treatments. We searched PubMed,Google Scholar and government agency websites to identify literature reporting clinical outcomes in patients taking remdesivir for COVID-19. A value tree was constructed and key benefits and risks were ranked by two clinicians in order of considered importance. Results: Several key benefits and risks for use of remdesivir in COVID-19 compared to placebo have been identified. In one trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR=1.23, 95% CI: 0.87, 1.75), although the study was underpowered. In another trial, a shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days), with non-significant reduced mortality risk (8% vs 12%). Risk data were only available from one trial. This trial reported fewer serious adverse events in patients taking remdesivir (18%) comparted to the placebo group (26%), however more patients in the remdesivir group discontinued treatment as a result of an adverse event compared to those patients receiving placebo (12% vs 5%). Conclusions: Preliminary clinical trial results suggest a favourable benefit-risk profile for remdesivir compared to placebo, however there is limited safety data available at the current time. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.

Coronaviruses are a cause of respiratory tract infections in humans [1] . A novel coronavirus emerged in Wuhan, China in December 2019 [2] , subsequently called Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) [3] . Coronavirus disease (COVID-19) is caused by SARS-CoV-2 [3] and since March 2020 this outbreak has been declared a pandemic by the World Health Organisation (WHO) [4] . Fever, cough and shortness of breath are the main reported symptoms of COVID-19 [5] but it also has a concerning case mortality rate among certain populations, such as older adults and those with underlying health conditions.

Currently, there is a need to identify effective, safe treatments for COVID-19 as quickly as possible, due to the ongoing pandemic. One such proposed treatment is remdesivir, which is an investigational antiviral medicine with proven activity against RNA viruses [6, 7] .

Remdesivir was originally developed for treatment of Ebola Virus Disease and results from the phase 3 randomised clinical trial for this indication have been published [8] . It has been shown to have broad spectrum in-vitro activity against several coronaviruses, including SARS-CoV-2 [6, 9, 10] in-vivo activity against MERS-CoV in animal models [11, 12] , and has been made available for patients with COVID-19 through compassionate use programmes [13, 14] .

Several clinical trials are ongoing to examine the effectiveness and safety of remdesivir in COVID-19 in humans [15] [16] [17] [18] . Most recently, remdesivir was granted an Emergency Use Authorisation in COVID-19 by the US Food and Drug Administration. Whilst there is considerable interest in the use of Remdesivir for COVID-19, there has not been a systematic benefit-risk assessment on the use of remdesivir for COVID-19 treatment using a structured descriptive framework.

The ongoing monitoring of the benefit-risk balance for remdesivir in COVID-19 treatment is strengthened by use of a systematic assessment. The Benefit-Risk Action Team (BRAT) framework allows identification of the key benefits and risks of a product in a defined disease context within a structured descriptive framework; further quantitative assessments can then be applied and conducted according to the availability of relevant data at that time [19] . The BRAT framework was also specifically designed to assist communication with regulatory authorities [20] . The decision-making process is transparent due to the framework design, while any assumptions can be explored further by sensitivity analysis through a quantitative component [21] .

This benefit-risk assessment has been conducted based on publicly available publications to date (data-lock April 30th 2020). It is however acknowledged that there is extremely limited data available at this timepoint. The benefit-risk assessment has been designed to be . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint implemented regardless of the quantity of data available, but the intention is that the framework will subsequently be readily available to repeat the assessment as further data arise, e.g. results from new and ongoing clinical trials, allowing for rapid decision-making.

To examine the benefit-risk profile of remdesivir in COVID-19 patients compared to standard of care, placebo or other treatments.

The BRAT framework was used to assess the overall benefit-risk of using remdesivir as a treatment for COVID-19 compared to standard of care, placebo or other treatments. BRAT uses a six step iterative process to support the decision and communication of a Benefit-Risk Assessment: define decision context, identify outcomes, identify data sources, customise framework, assess outcome importance, and display and interpret key Benefit-Risk metrics [20, 21] . We identified three settings of interest for use of COVID-19 treatments; treatment for severe disease, treatment of milder disease in the community, and prevention in health care professionals exposed to the virus. We have focused on the use of remdesivir for the treatment of severe COVID-19 disease within this benefit-risk assessment. For the purposes of this study, we considered severe COVID-19 to include any patient who was hospitalised as a result of the infection.

The population of interest were patients with severe COVID-19, while the exposure of interest was remdesivir. The comparators of interest were standard of care, placebo or other treatments for COVID-19.

Regardless of importance, all potential benefits and risks related to remdesivir were initially identified. Key benefits and risks were then selected by clinician judgement, which were those considered to drive the benefit-risk balance of remdesivir. The key benefits and risks were used to construct a value tree, ranking benefits and risks in order of considered importance.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint

We searched PubMed, Google Scholar and government agency websites to identify suitable data for inclusion. The search strategy used was: remdesivir AND (coronavirus OR covid* OR "SARS-CoV-2" OR "2019-NCov") Papers were included if they reported quantitative data on effectiveness and/or safety of remdesivir in patients with severe COVID-19. Case reports were excluded. Results were restricted to English language only (abstracts in English language were acceptable where sufficient data was provided) and peer-reviewed publications (for PubMed and Google Scholar) since 2019 to 30th April 2020. Where a control group was included, data were extracted for each benefit and risk, for both remdesivir and the comparator (standard of care, placebo or other treatments).

A summary benefit-risk table was created to allow visualisation of the magnitude of each benefit and risk. Risk differences and corresponding 95% confidence intervals (CI) were calculated for each outcome where both numerator (number of events) and denominator (number of patients at risk) were available for both the treatment group (remdesivir) and comparator group.

Due to paucity of data, a fully quantitative assessment was not undertaken. However, the risks and risk difference per 1000 patients were calculated for each benefit and risk. The outcomes identified in the value tree were ranked so that swing weighting can be applied in future assessments. The weighted net clinical benefit (wNCB) can subsequently be calculated using these weights [21] [22] [23] . We would propose using the Sutton et al method, where benefits have a positive contribution to the wNCB and risks have a negative contribution [23] ; the overall wNCB would be considered positive (benefit outweighs the risk) where wNCB >0. A sensitivity analysis can also be used to examine the robustness of the assigned weights and whether significant changes would alter the benefit-risk profile [19] . Analysis using wNCB was not undertaken at this time due to the limited release of clinical trial data. Figure 1 displays the value tree of the key benefits and risks related to remdesivir treatment in COVID-19. The benefits included in the value tree include key endpoints included in clinical trial protocols for studies assessing the efficacy of remdesivir in severe COVID-19 disease. As . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint remdesivir is currently not approved for use in any condition, it is acknowledged that its safety profile has not been completely characterised. For the purposes of identifying potentials risks associated with the use of remdesivir in COVID-19 disease, safety data has been identified from currently available sources. These include studies reporting its use in the treatment of Ebola Virus Disease [8] , cases series documenting the use of remdesivir in COVID-19 disease [24] , and safety data included in the study by Wang et al [25] . Both the efficacy and safety outcomes have been presented in ranked numerical order according to perceived clinical significance.

The . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint

As remdesivir is an unapproved medicine in most countries, its safety profile has not yet been fully characterised. Known key risks at the current time have been included in the value tree, identified from a variety of sources, including recently published clinical trial data in the context of COVID-19 [25] . These have also been ranked according to perceived seriousness. Cardiovascular outcomes including hypotension and arrhythmias have been documented following the use of remdesivir [8, 27, 24] , however the risk of cardiovascular outcomes with remdesivir remains largely unknown [28] . Hypotension was reported in one patient in the phase 3 study investigating remdesivir in the context of Ebola Virus Disease; this patient subsequently suffered a cardiac arrest, although the author states that this death could not readily be distinguishable from underlying fulminant Ebola Virus Disease itself [8] . Cardiac arrest was also reported in a further patient in the remdesivir group reported in the COVID-19 study by Wang et al [25] . Multiple organ dysfunction, septic shock, acute kidney injury and hypotension have also been reported as adverse events amongst patients provided with remdesivir either on a compassionate-use basis, or in a clinical trial [24, 25] . Respiratory failure or acute respiratory distress syndrome has been cited as an adverse event in patients taking remdesivir [25, 29] , and as such has been included here, although it is acknowledged that this may be related to underlying disease (COVID-19), rather than to remdesivir.

Elevations in liver transaminases and gastrointestinal events, including diarrhoea, have also been reported with the use of remdesivir [13, 8, 24, 30] , in addition to reports of haemorrhage of the lower gastrointestinal (GI) tract [25, 31] .

Where available, clinical trial data relating to any efficacy or safety outcomes included in the value tree for both remdesivir and a comparator group were extracted and included in Table   1 . Based on this data, summary metrics including risks per 1000 patient years, and risk differences have been presented in Table 2 . We identified 68 papers through literature searching from PubMed and 384 papers from Google Scholar. We also identified results from one clinical trial on the NIAID website. After initial review, one paper and results from one clinical trial on the NIAID website were included in the final benefit-risk assessment.

In the Wang et al trial, the benefit of time to clinical improvement was not statistically significant (21 vs 23 days, HR=1.23, 95% CI: 0.87, 1.75). In the NIAID trial, a statistically significant shorter time to recovery in patients treated with remdesivir was observed (11 vs 15 days; p<0.001), with non-significant reduced mortality risk (8% vs 12%; p=0.059). Other . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint non-significant benefit data were identified from the Wang et al trial including invasive ventilation and oxygen use at day 28 (1% vs 4% and 12% vs 17%, respectively).

Risk data were only available from the Wang et al trial, which reported fewer serious adverse events in patients taking remdesivir (18%) comparted to the placebo group (26%), however more patients in the remdesivir group discontinued treatment as a result of an adverse event compared to those patients receiving placebo (12% vs 5%).

This benefit-risk assessment presented the currently known key benefits and risks for the use of remdesivir for severe COVID-19 disease. The value tree provides a visual summary of these key benefits and risks, which have been ranked according to perceived clinical importance. As remdesivir is currently unlicensed in most countries, these include endpoints used in remdesivir clinical trials, and risks identified from available data sources. A literature search (including grey literature from government agency websites) identified relevant numerical data for these outcomes for both remdesivir, and comparator groups. Recently, the first results from a randomised, double-blind, placebo-controlled clinical trial studying remdesivir in the context of COVID-19 have been published [25] . The primary outcome suggested a reduction in the median time to clinical improvement, although this difference was non-significant (21 vs 23 days, HR=1.23, 95% CI: 0.87, 1.75). However, the planned sample size of 453 patients (151 on placebo and 302 on remdesivir) was not reached due to difficulties in enrolment, and therefore this study may have been underpowered to detect significant differences.

Nevertheless, multiple additional endpoints were included in this study, and these data have been presented in Table 1 . Whilst no statistically significant differences were observed between the remdesivir and placebo group [25] , the study reported generally improved outcomes in the remdesivir group compared to placebo, including reductions in mortality, risk of invasive and non-invasive ventilation, and need for supportive oxygen at day 28.

Data has also been presented for remdesivir and the placebo group included in the Adaptive COVID-19 treatment trial [26] . As of 29 th April 2020, limited data has been made available on the NIH website [26] and suggested a statistically significant reduction in time to recovery from a median 15 days (placebo group) to 11 days (remdesivir group) (p<0.001). Further study results provided suggested a non-significant reduced mortality risk amongst remdesivir patients (8.0%) vs. patients given placebo (11.6%), p=0.059, which equates to 40 fewer deaths per 1000 patients treated with remdesivir.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint Key risks have been identified and included based on currently available evidence, however it is acknowledged that the safety profile of remdesivir has not been fully characterized. From risk data currently available, key risks were identified and ranked according to seriousness.

The cardiovascular side effects of remdesivir are largely unknown; one patient in the study by Wang et al was noted to have had a cardiac arrest. Individual cases of multiple organ dysfunction syndrome and septic shock were also reported in this study [25] , whilst reports were also identified in patients receiving remdesivir on a compassion ate use basis [24] . In the latter case, reports of these events occurred in patients who were on invasive ventilation.

Whilst there were multiple reports of liver enzyme abnormalities in patients who received remdesivir in the study by Wang et al [25] , three patients discontinued treatment as a result of liver enzyme elevation (two reports of raised alanine aminotransferase, one report of increased total bilirubin). Reports of acute respiratory distress syndrome have also been reported as adverse events in patients taking remdesivir [25, 29] . Sixteen patients experienced this outcome during treatment in the study by Wang et al, [25] , which led to discontinuation in seven patients. Finally, whilst fewer patients experienced an adverse event classified as serious in the remdesivir group (18%) compared to the placebo group (26%), a higher number of patients discontinued remdesivir as a result of an adverse event (12% vs. 5%) [25] .

Currently there would appear to be favourable efficacy results from patients treated with remdesivir in the context of severe COVID-19 disease from these preliminary data available.

The data in the study by Wang et al [25] did not include any statistically significant results, although it is acknowledged that the study was underpowered. Primary endpoint data available from the Adaptive COVID 19 trial [26] have also suggested a shorter time to recovery in patients treated with remdesivir, with non-significant reduced mortality risk. There is limited safety data available at the current time, although it is expected that this will increase as more clinical trial safety data becomes available. From the limited clinical trial safety data , it is unclear whether reports of serious adverse events are a function of the underlying severe COVID-19 disease, or attributable to treatment with remdesivir. It is anticipated that both the efficacy, and the safety profile will be further strengthened in the coming months with the availability of additional clinical trial data.

Sample sizes for each outcome were limited to those available in the original studies and may not have adequate power to detect differences in risk between groups, especially where the outcomes examined were not the primary outcome of interest. The benefit-risk assessment is . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 12, 2020. . https://doi.org/10.1101/2020.05.07.20093898 doi: medRxiv preprint limited by the availability of data in the published literature. However, this assessment can be subsequently updated once further data from clinical trials are available. In addition, given the public health urgency of the COVID-19 pandemic, it is important to provide a systematic assessment of the benefits and risks of remdesivir treatment with evidence available to date and establish a framework which can be used to rapidly update the assessment once further data become available.

Data quality is not reflected in this benefit-risk assessment, though all data was extracted from peer-reviewed manuscripts, with the exception of data included from the Adaptive COVID-19 treatment trial. These data were obtained from the NIAID website, and included time to recovery and mortality data. Since the full results of this clinical trial were not made available at the time of datalock (April 30 th 2020), a wNCB analysis was not undertaken because there was a concern that only including efficacy outcomes from the Adaptive COVID-19 treatment trial may bias the wNCB results. It is anticipated that such an analysis can be undertaken in the future when results are made available, to provide further evidence on the benefit-risk profile.

Confirmation of causality was not a requirement for inclusion of data in the BRAT assessment.

Patients may have been on other concomitant medications or had other medical conditions at the time of remdesivir treatment. Finally, we considered hospitalisation of patients to reflect severe COVID-19, but we acknowledge that severity of disease may vary regardless of hospitalisation.

Preliminary clinical trial results suggest a favourable benefit-risk profile for remdesivir compared to placebo, however there is limited safety data available at the current time. The current framework summarises the key anticipated benefits and risks for which further data are needed. Ongoing clinical trial data can be incorporated into the framework when available to provide an updated benefit-risk assessment.

. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted May 12, 2020. 

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Death All-cause mortality -Risk and time to death

ICU admission -invasive mechanical ventilation and/or ECMO, duration, time to ICU Clinical endpoints 5. Other clinical outcomes -time to improvement or recovery, duration of hospitalisation 7. Liver -elevations of transaminases

Renal -Acute Kidney Injury, impaired renal function Clinical endpoints 2. Multiple Organ Dysfunction Syndrome / Septic shock

Viral load parameters -Clearance rate (throat, sputum, nasopharyngeal swabs) 4. Oxygen -Number of patients requiring supplemental oxygen

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