Clinical antiviral efficacy of remdesivir in COVID-19: an open label, randomized, controlled adaptive platform trial (PLATCOV)

Jittamala et al., The Journal of Infectious Diseases, doi:10.1093/infdis/jiad275, PLATCOV, NCT05041907

Jul 2023

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High conflict of interest RCT with very low risk patients with high existing immunity, showing faster viral clearance with remdesivir. The viral clearance half-life was very short in both arms. With rapid viral clearance and very low risk patients, the trial favors detecting an effect with intravenous treatments that have rapid onset of action.

Gérard, Zhou, Wu, Kamo, Choi, Kim show significantly increased risk of acute kidney injury with remdesivir.

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risk of hospitalization, 66.3% lower, RR 0.34, p = 1.00, treatment 0 of 67 (0.0%), control 1 of 69 (1.4%), NNT 69, relative risk is not 0 because of continuity correction due to zero events (with reciprocal of the contrasting arm).

relative clearance half-life, 28.9% better, RR 0.71, p < 0.001, treatment median 12.8 IQR 8.0 n=67, control median 18.0 IQR 10.5 n=69, primary outcome.

Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates

1. Gérard et al., Remdesivir and Acute Renal Failure: A Potential Safety Signal From Disproportionality Analysis of the WHO Safety Database, Clinical Pharmacology & Therapeutics, doi:10.1002/cpt.2145.wiley.com, doi.org.

2. Zhou et al., Acute Kidney Injury and Drugs Prescribed for COVID-19 in Diabetes Patients: A Real-World Disproportionality Analysis, Frontiers in Pharmacology, doi:10.3389/fphar.2022.833679.frontiersin.org, doi.org.

3. Wu et al., Acute Kidney Injury Associated With Remdesivir: A Comprehensive Pharmacovigilance Analysis of COVID-19 Reports in FAERS, Frontiers in Pharmacology, doi:10.3389/fphar.2022.692828.frontiersin.org, doi.org.

4. Kamo et al., Association of Antiviral Drugs for the Treatment of COVID-19 With Acute Renal Failure, In Vivo, doi:10.21873/invivo.13637.iiarjournals.org, doi.org.

5. Choi et al., Comparative effectiveness of combination therapy with nirmatrelvir–ritonavir and remdesivir versus monotherapy with remdesivir or nirmatrelvir–ritonavir in patients hospitalised with COVID-19: a target trial emulation study, The Lancet Infectious Diseases, doi:10.1016/S1473-3099(24)00353-0.sciencedirect.com, doi.org.

6. Kim et al., Investigating the Safety Profile of Fast‐Track COVID‐19 Drugs Using the FDA Adverse Event Reporting System Database: A Comparative Observational Study, Pharmacoepidemiology and Drug Safety, doi:10.1002/pds.70043.wiley.com, doi.org.

Jittamala et al., 20 Jul 2023, Randomized Controlled Trial, multiple countries, peer-reviewed, median age 30.1, 42 authors, study period 30 September, 2021 - 10 June, 2022, trial NCT05041907 (history) (PLATCOV). Contact: william@tropmedres.ac, nickw@tropmedres.ac.

This Paper Remdesivir All

Clinical Antiviral Efficacy of Remdesivir in Coronavirus Disease 2019: An Open-Label, Randomized Controlled Adaptive Platform Trial (PLATCOV)

Podjanee Jittamala, William H K Schilling, James A Watson, Viravarn Luvira, Tanaya Siripoon, Thundon Ngamprasertchai, Pedro J Almeida, Maneerat Ekkapongpisit, Cintia Cruz, James J Callery, Simon Boyd, Orawan Anunsittichai, Maliwan Hongsuwan, Yutatirat Singhaboot, Watcharee Pagornrat, Runch Tuntipaiboontana, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Srisuda Keayarsa, Wanassanan Madmanee, Renato S Aguiar, Franciele M Santos, Elizabeth M Batty, Pongtorn Hanboonkunupakarn, Borimas Hanboonkunupakarn, Sakol Sookprome, Kittiyod Poovorawan, Mallika Imwong, Walter R J Taylor, Vasin Chotivanich, Chunlanee Sangketchon, Wiroj Ruksakul, Kesinee Chotivanich, Sasithon Pukrittayakamee, Arjen M Dondorp, Nicholas P J Day, Mauro M Teixeira, Watcharapong Piyaphanee, Weerapong Phumratanaprapin, Nicholas J White, Nicholas J White, William Hk Schilling, Viravarn Luvira, James J Callery, Nicholas Pj Day, Sasithon Pukrittayakamee, Simon Boyd, Cintia Cruz, Arjen M Dondorp, Walter Rj Taylor, James A Watson, Watcharapong Piyaphanee, Kittiyod Poovorawan, Thundon Ngamprasertchai, Tanaya Siripoon, Borimas Hanboonkunupakarn, Kesinee Chotivanich, Podjanee Jittamala, Mallika Imwong, Maneerat Ekkapongpisit, Varaporn Kruabkontho, Thatsanun Ngernseng, Jaruwan Tubprasert, Mohammad Yazid Abdad, Srisuda Keayarsa, Orawan Anunsittichai, Maliwan Hongsuwan, Yutatirat Singhaboot, Wanassanan Madmanee, Elizabeth M Batty, Runch Tuntipaiboontana, Watcharee Pagornrat, Vasin Chotivanich, Wiroj Ruksakul, Chunlanee Sangketchon, Pongtorn Hanboonkunupakarn, Sakol Sookprome, Mauro M Teixeira, Pedro J Almeida, Renato S Aguiar, Franciele M Santos

The Journal of Infectious Diseases, doi:10.1093/infdis/jiad275

Background: Uncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Methods: In a multicenter open label, controlled, adaptive, pharmacometric platform trial, lowrisk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days) or no study drug. The primary outcome was the rate of viral clearance (estimated under a linear model fit to the daily log10 viral densities, days 0-7) in standardized duplicate oropharyngeal swab eluates, in a modified intention-to-treat population (mITT). This ongoing adaptive trial is registered at ClinicalTrials.gov (NCT05041907). Results: The two study arms enrolled 131 patients (remdesivir n=67, no study drug n=64) and estimated viral clearance rates from a median of 18 swab samples per patient (a total of 2356 qPCRs). Under the linear model, compared with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated SARS-CoV-2 viral clearance by 42% (95% credible interval [CI] 18 to 73). Interpretation: Parenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Pharmacometric assessment of therapeutics using the described method can rapidly and efficiently determine in vivo clinical efficacy.

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The primary outcome was the rate of severe acute respiratory syndrome ' 'coronavirus 2 (SARS-CoV-2) clearance (estimated under a linear model fit to the daily log10 ' 'viral densities, days 0–7) in standardized duplicate oropharyngeal swab eluates, in a ' 'modified intention-to-treat population. This ongoing adaptive trial is registered at ' 'ClinicalTrials.gov (NCT05041907).\n' ' \n' ' \n' ' Results\n' ' The 2 study arms enrolled 131 patients (remdesivir n = 67, no study ' 'drug n = 64) and estimated viral clearance rates from a median of 18 swab samples per patient ' '(a total of 2356 quantitative polymerase chain reactions). Under the linear model, compared ' 'with the contemporaneous control arm (no study drug), remdesivir accelerated mean estimated ' 'viral clearance by 42% (95% credible interval, 18%–73%).\n' ' \n' ' \n' ' Conclusions\n' ' Parenteral remdesivir accelerates viral clearance in early ' 'symptomatic COVID-19. 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