Evaluation of the effectiveness of remdesivir in treating severe COVID-19 using data from the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, national cohort study

Arch et al., medRxiv, doi:10.1101/2021.06.18.21259072, Jun 2021
Mortality, day 28 20% improvement lower risk ← → higher risk Mortality, day 14 18% Ventilation -68% Liver dysfunction -47% Remdesivir  Arch et al.  LATE TREATMENT Is late treatment with remdesivir beneficial for COVID-19? PSM prospective study of 6,230 patients in the United Kingdom Lower mortality (p=0.034) and higher ventilation (p=0.003) c19early.org Arch et al., medRxiv, June 2021 0 0.5 1 1.5 2+ RR
PSM analysis of remdesivir use in the UK showing no significant reduction in mortality at 14 days, and significantly higher mechanical ventilation/ECMO and liver dysfunction.
Authors appear to have abandoned this preprint, with no journal publication as of April 2026.
Version 2 of the preprint reframes the results toward a more favorable interpretation of remdesivir - removing the negative conclusion from v1 and emphasizing 28-day results. Version 2 also removed several paragraphs from v1's discussion about propensity score limitations and the omission of variables like oxygen saturation, respiratory rate, GCS, urea, and CRP from the matching model - a section that was self-critical about study weaknesses with authors stating "with hindsight these may have been important to consider..." The acknowledgment that "73% of patients given remdesivir were excluded" was changed to "43% were excluded" in v2 - this reflects a different denominator (v1 counted all remdesivir patients in the database; v2 counts only those eligible after other criteria were applied).
Contradiction regarding equivalent standard of care assumption: in the methods section, authors state regarding corticosteroids that 'remdesivir patients will have received these in the same way as non-remdesivir patients.' However, the results demonstrate a large discrepancy, with 94% of remdesivir patients receiving dexamethasone post-baseline compared to only 62% of matched controls, directly invalidating their methodology assumption.
Adjustment for post-baseline treatment (collider bias): the primary logistic regression model adjusts for 'dexamethasone use during hospitalisation'. Adjusting for a post-baseline variable that may be influenced by patient deterioration or unmeasured disease severity introduces collider bias and distorts the true treatment effect.
Severe imbalance in post-baseline therapies indicating unmeasured severity bias: despite propensity score matching on baseline characteristics, post-baseline non-invasive ventilation (28.8% vs 10.2%) and mechanical ventilation (6.8% vs 3.3%) were much higher in the remdesivir group. This strongly indicates residual confounding, where the remdesivir group either had higher unmeasured baseline severity or was subject to a significantly more aggressive care pathway.
Contradictory sample sizes for the primary outcome across sections: the CONSORT flowchart (Figure 1) and the main text state that 1,507 remdesivir and 4,734 control patients were included in the primary outcome analysis. However, Table 2 lists the incidence denominators as 1,502 for remdesivir and 4,728 for control.
Mismatch in the number of patients included in the logistic regression model: page 8 states '6,202 patients were included in a logistic regression model (Table 2)'. However, Table 2 reports counts summing to 6,192 patients.
Manufacturer involvement in Statistical Analysis Plan: authors note that the manufacturer (Gilead) was given the opportunity to review and comment on the SAP.
Inconsistent control group mortality percentage: the abstract and text report the 14-day mortality for the control group as 11.9% (565/4,734). Table 2 reports it as 12.0%.
Author financial ties to the manufacturer: several authors disclose that they are coordinating or serving as lead statistician for trials fully or partially funded by Gilead, the manufacturer of remdesivir. This is properly disclosed but represents a substantial financial conflict of interest.
Mismatch in categorical sum for comorbidities: in Table 1, under 'Number of key comorbidities' for the matched remdesivir group, the total N is reported as 1,542, but the sum of the constituent categories (0: 470, 1: 470, 2+: 603) mathematically equals 1,543.
Gérard, Zhou, Wu, Kamo, Choi, Kim show increased risk of acute kidney injury, Leo, Briciu, Muntean, Petrov, Arch show increased risk of liver injury, and Negru, Cheng, Mohammed, Kwok, Zhu show increased risk of cardiac disorders with remdesivir.
Remdesivir efficacy disappears with longer followup. Mixed-effects meta-regression of efficacy as a function of followup duration across all remdesivir studies shows decreasing efficacy with longer followup17. This may reflect antiviral efficacy being offset by serious adverse effects of treatment.
Follow-up duration (days) Mortality efficacy Remdesivir benefit disappears with longer follow-up - side effects may offset antiviral action 0 15 30 45 60 75 90 105 120 -25% 0% 25% 50% c19early.org April 2026 mixed-effects meta-regression slope -0.54 [95% CI -0.9 to -0.18] p=0.0032
Standard of Care (SOC) for COVID-19 in the study country, the United Kingdom, is very poor with very low average efficacy for approved treatments18. The United Kingdom focused on expensive high-profit treatments, approving only one low-cost early treatment, which required a prescription and had limited adoption. The high-cost prescription treatment strategy reduces the probability of early treatment due to access and cost barriers, and eliminates complementary and synergistic benefits seen with many low-cost treatments.
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risk of death, 19.9% lower, RR 0.80, p = 0.03, treatment 203 of 1,491 (13.6%), control 777 of 4,676 (16.6%), NNT 33, odds ratio converted to relative risk, PSM, day 28.
risk of death, 18.0% lower, RR 0.82, p = 0.12, treatment 140 of 1,502 (9.3%), control 565 of 4,728 (12.0%), NNT 38, odds ratio converted to relative risk, PSM, day 14.
risk of mechanical ventilation, 68.0% higher, RR 1.68, p = 0.003, treatment 106 of 1,498 (7.1%), control 153 of 4,602 (3.3%), odds ratio converted to relative risk, PSM, day 28.
Liver dysfunction, 47.0% higher, RR 1.47, p < 0.001, treatment 124 of 1,443 (8.6%), control 241 of 4,483 (5.4%), odds ratio converted to relative risk, PSM, day 28.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Arch et al., 21 Jun 2021, prospective, propensity score matching, United Kingdom, preprint, 10 authors, average treatment delay 6.0 days.
$0 $500 $1,000+ Efficacy vs. cost for COVID-19 treatment protocols c19early.org April 2026 United Kingdom Russia Sudan Angola Colombia Kenya Mozambique Peru Philippines Vietnam France Italy Japan Canada China Uzbekistan Iran Nepal Bangladesh Ethiopia Ghana Germany Mexico South Korea Saudi Arabia Algeria Morocco Yemen Poland Venezuela India DR Congo Madagascar Thailand Uganda Egypt Nigeria Bolivia Zambia Austria Croatia Fiji Bosnia-Herzegovina Ukraine Côte d'Ivoire Bulgaria Greece Slovakia Singapore Iceland New Zealand Trinidad and Tobago Mongolia Czechia Israel Belarus North Macedonia Hong Kong Qatar Panama Serbia CAR The United Kingdom favored high-profit treatments.The average efficacy of treatments was very low.High-cost protocols reduce early treatment, andforgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
$0 $500 $1,000+ Efficacy vs. cost for COVID-19treatment protocols worldwide c19early.org April 2026 United Kingdom Russia Sudan Angola Colombia Kenya Mozambique Peru Vietnam Brazil France Italy Japan Canada China Uzbekistan Iran Nepal Bangladesh Ethiopia Ghana Germany Mexico South Korea Saudi Arabia Algeria Morocco Yemen Poland Venezuela India DR Congo Madagascar Thailand Uganda Egypt Nigeria Bolivia Austria Fiji Georgia Ukraine Côte d'Ivoire Eritrea Bulgaria Greece Slovakia Singapore Iceland New Zealand Mongolia Czechia Israel Belarus North Macedonia Hong Kong Qatar Panama Serbia CAR The UK favored high-profit treatments.The average efficacy was very low.High-cost protocols reduce early treatment,and forgo complementary/synergistic benefits. More effective More expensive 75% 50% 25% ≤0%
Abstract: medRxiv preprint doi: https://doi.org/10.1101/2021.06.18.21259072; this version posted June 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Evaluation of the effectiveness of remdesivir in treating severe COVID-19 using data from the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, national cohort study. Short Running title: ISARIC4C Remdesivir effectiveness study Authors Arch BN1, Kovacs D2*, Scott JT3*, Jones AP1, Harrison EM4, Rosala-Hallas A1, Gamble CG1, Openshaw PJM 5, Baillie JK6, Semple MG7,8 on behalf of ISARIC4C Investigators *Joint 2nd authors Affiliations 1. Liverpool Clinical Trials Centre, Clinical Directorate, Faculty of Health and Life Sciences, University of Liverpool, UK. 2. Institute of Biodiversity, Animal health and Comparative Medicine, University of Glasgow, Glasgow, UK 3. MRC-University of Glasgow Centre for Virus Research, Glasgow, UK 4. Centre for Medical Informatics, The Usher Institute, University of Edinburgh, Edinburgh, UK 5. National Heart and Lung Institute, Imperial College London, London, UK 6. Roslin Institute, University of Edinburgh, Edinburgh, UK 7. Health Protection Research Unit in Emerging and Zoonotic Infections, Institute of Infection, Veterinary and Ecological Sciences, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK. 8. Department of Respiratory Medicine, Alder Hey Children’s Hospital, Liverpool, UK. Corresponding author Barbara Arch. Liverpool Clinical Trials Centre, University of Liverpool, Institute in the Park, Alder Hey Childrens Hospital, Eaton Road, Liverpool, L12 2AP. Email: barbara.arch@liverpool.ac.uk, Tel: +44(0)151 795 8751 Word Count Abstract 267/300 Manuscript (excluding Research in Context Panel) 3,579/3,500 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. Page 1 of 22 medRxiv preprint doi: https://doi.org/10.1101/2021.06.18.21259072; this version posted June 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Abstract Background Remdesivir was given UK early-access approval for use in COVID-19 in people aged 12 years and older on 26th May 2020 on the basis of unmet clinical need. Evidence on the side effects, complications of therapy and effectiveness of this therapy is lacking or conflicting. Methods Adults with severe COVID-19 treated with remdesivir were compared with propensity-score matched controls, identified from the ISARIC WHO Clinical Characterisation Protocol study of UK hospitalised patients with COVID-19. Remdesivir patients were matched to controls according to baseline underlying 14-day mortality risk. The effect of remdesivir on short-term outcomes was investigated (primary outcome: 14-day mortality). Effect sizes were estimated and adjusted for potential confounders using multivariable modelling. Results 1,549 patients given remdesivir and 4,964 matched controls were identified satisfying inclusion and exclusion criteria. The balance diagnostic threshold was achieved. Patients had symptoms for a median of 6 days prior to..
DOI record: { "DOI": "10.1101/2021.06.18.21259072", "URL": "http://dx.doi.org/10.1101/2021.06.18.21259072", "abstract": "<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Remdesivir has been evaluated in clinical trial populations, but there is a sparsity of evidence evaluating effectiveness in general populations.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Adults eligible to be treated with remdesivir, requiring oxygen but not ventilated, were identified from UK patients hospitalised with COVID-19. Patients treated with remdesivir within 24h of hospitalisation were compared with propensity-score matched controls; estimates of effectiveness were calculated for short-term outcomes (14-day mortality, 28-day mortality, time-to-recovery among others) using multivariable modelling.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>9,278 out of 39,330 patients satisfied eligibility criteria. 1,549 patients were identified as ‘treated’ and matched with 4,964 controls. Patients were 62% male, mean (SD) age 63.1 (15.6) years, 80% ‘White’ ethnicity, and symptomatic for a median of 6 days prior to baseline. There was no statistically significant benefit of remdesivir at 14 days in terms of mortality or clinical status; there were signals of effectiveness in time-to-recovery after day 9, and a reduction in 28-day mortality.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>In a real-world setting, initiation of remdesivir within 24h of hospitalisation in conjunction with standard of care was not associated with a benefit at 14 days but supports clinical trial evidence of a potential reduction in 28-day mortality.</jats:p></jats:sec>", "accepted": { "date-parts": [ [ 2022, 3, 9 ] ] }, "author": [ { "ORCID": "http://orcid.org/0000-0001-6060-8091", "affiliation": [], "authenticated-orcid": false, "family": "Arch", "given": "B N", "sequence": "first" }, { "ORCID": "http://orcid.org/0000-0002-2187-743X", "affiliation": [], "authenticated-orcid": false, "family": "Kovacs", "given": "D", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-8030-5223", "affiliation": [], "authenticated-orcid": false, "family": "Scott", "given": "J T", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-5253-730X", "affiliation": [], "authenticated-orcid": false, "family": "Jones", "given": "A P", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-5018-3066", "affiliation": [], "authenticated-orcid": false, "family": "Harrison", "given": "E M", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-8012-9995", "affiliation": [], "authenticated-orcid": false, "family": "Rosala-Hallas", "given": "A", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-3021-1955", "affiliation": [], "authenticated-orcid": false, "family": "Gamble", "given": "C G", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0002-7220-2555", "affiliation": [], "authenticated-orcid": false, "family": "Openshaw", "given": "P J M", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-5258-793X", "affiliation": [], "authenticated-orcid": false, "family": "Baillie", "given": "J K", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0001-9700-0418", "affiliation": [], "authenticated-orcid": false, "family": "Semple", "given": "M G", "sequence": "additional" } ], "container-title": [], "content-domain": { "crossmark-restriction": false, "domain": [] }, "created": { "date-parts": [ [ 2021, 6, 21 ] ], "date-time": "2021-06-21T13:50:14Z", "timestamp": 1624283414000 }, "deposited": { "date-parts": [ [ 2022, 3, 11 ] ], "date-time": "2022-03-11T16:15:21Z", "timestamp": 1647015321000 }, "group-title": "Infectious Diseases (except HIV/AIDS)", "indexed": { "date-parts": [ [ 2024, 3, 19 ] ], "date-time": "2024-03-19T20:16:30Z", "timestamp": 1710879390079 }, "institution": [ { "name": "medRxiv" } ], "is-referenced-by-count": 8, "issued": { "date-parts": [ [ 2021, 6, 21 ] ] }, "link": [ { "URL": "https://syndication.highwire.org/content/doi/10.1101/2021.06.18.21259072", "content-type": "unspecified", "content-version": "vor", "intended-application": "similarity-checking" } ], "member": "246", "original-title": [], "posted": { "date-parts": [ [ 2021, 6, 21 ] ] }, "prefix": "10.1101", "published": { "date-parts": [ [ 2021, 6, 21 ] ] }, "publisher": "Cold Spring Harbor Laboratory", "reference": [ { "key": "2022031108150491000_2021.06.18.21259072v2.1", "unstructured": "NICE. 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Late treatment
is less effective
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