Evaluation of the Effects of Remdesivir and Hydroxychloroquine on Viral Clearance in COVID-19 : A Randomized Trial
Andreas Barratt-Due, Inge Christoffer Olsen, Katerina Nezvalova-Henriksen, Trine Kåsine, Fridtjof Lund-Johansen, Hedda Hoel, Aleksander Rygh Holten, Anders Tveita, Alexander Mathiessen, Mette Haugli, Ragnhild Eiken, Anders Benjamin Kildal, Åse Berg, Asgeir Johannessen, Lars Heggelund, Tuva Børresdatter Dahl, Karoline Hansen Skåra, Pawel Mielnik, Lan Ai Kieu Le, Lars Thoresen, Gernot Ernst, Dag Arne Lihaug Hoff, Hilde Skudal, Bård Reiakvam Kittang, Roy Bjørkholt Olsen, Birgitte Tholin, Carl Magnus Ystrøm, Nina Vibeche Skei, Trung Tran, Susanne Dudman, Jan Terje Andersen, Raisa Hannula, Olav Dalgard, Ane-Kristine Finbråten, Kristian Tonby, Bjorn Blomberg, Saad Aballi, Cathrine Fladeby, Anne Steffensen, Fredrik Müller, Anne Ma Dyrhol-Riise, Marius Trøseid, Pål Aukrust, NOR-Solidarity trial, Jorunn Brynhildsen, Waleed Ghanima, Lise Tuset Gustad, Anne Marie Halstensen, Liv Hesstvedt, Mona Holberg-Petersen, Synne Jenum, Simreen Kaur Johal, Anette Kolderup, Reidar Kvåle, Nina Langeland, Ravinea Manotheepan, Kristin Mohn, Richard Alexander Molvik, Karl Erik Müller, Lena Bugge Nordberg, Hans Schmidt Rasmussen, Dag Henrik Reikvam, Kjerstin Røstad, Lars Mølgaard Saxhaug, Vegard Skogen, Grethe-Elisabeth Stenvik, Birgitte Stiksrud, Ruth Foseide Thorkildsen, Leif Erik Vinge, Eline Brenno Vaage, Bjørn Åsheim-Hansen, Andreas Barratt-Due, Inge Christoffer Olsen, Katerina Nezvalova-Henriksen, Trine Kåsine, Fridtjof Lund-Johansen, Hedda Hoel, Aleksander Rygh Holten, Anders Tveita, Alexander Mathiessen, Mette Haugli, Ragnhild Eiken, Anders Benjamin Kildal, Åse Berg, Asgeir Johannessen, Lars Heggelund, Tuva Børresdatter Dahl, Karoline Hansen Skåra, Pawel Mielnik, Lan Ai Kieu Le, Lars Thoresen, Gernot Ernst, Dag Arne Lihaug Hoff, Hilde Skudal, Bård Reiakvam Kittang, Roy Bjørkholt Olsen, Birgitte Tholin, Carl Magnus Ystrøm, Nina Vibeche Skei, Trung Tran, Susanne Dudman, Jan Terje Andersen, Raisa Hannula, Olav Dalgard, Ane-Kristine Finbråten, Kristian Tonby, Bjorn Blomberg, Saad Aballi, Cathrine Fladeby, Anne Steffensen, Fredrik Müller, Anne Ma Dyrhol-Riise, Marius Trøseid, Pål Aukrust, Andreas Barratt-Due, Inge Christoffer Olsen, Katerina Nezvalova-Henriksen, Trine Kåsine, Fridtjof Lund-Johansen, Hedda Hoel, Aleksander Rygh Holten, Anders Tveita, Alexander Mathiessen, Mette Haugli, Ragnhild Eiken, Anders Benjamin Kildal, Åse Berg, Asgeir Johannessen, Lars Heggelund, Tuva Børresdatter Dahl, Karoline Hansen Skåra, Pawel Mielnik, Lan Ai Kieu Le, Lars Thoresen, Gernot Ernst, Dag Arne Lihaug Hoff, Hilde Skudal, Bård Reiakvam Kittang, Roy Bjørkholt Olsen, Birgitte Tholin, Carl Magnus Ystrøm, Nina Vibeche Skei, Trung Tran, Susanne Dudman, Jan Terje Andersen, Raisa Hannula, Olav Dalgard, Ane-Kristine Finbråten, Kristian Tonby, Bjorn Blomberg, Saad Aballi, Cathrine Fladeby, Anne Steffensen, Fredrik Müller, Anne Ma Dyrhol-Riise, Marius Trøseid, Pål Aukrust, NOR-Solidarity trial, Jorunn Brynhildsen, Waleed Ghanima, Lise Tuset Gustad, Anne Marie Halstensen, Liv Hesstvedt, Mona Holberg-Petersen, Synne Jenum, Simreen Kaur Johal, Anette Kolderup, Reidar Kvåle, Nina Langeland, Ravinea Manotheepan, Kristin Mohn, Richard Alexander Molvik, Karl Erik Müller, Lena Bugge Nordberg, Hans Schmidt Rasmussen, Dag Henrik Reikvam, Kjerstin Røstad, Lars Mølgaard Saxhaug, Vegard Skogen, Grethe-Elisabeth Stenvik, Birgitte Stiksrud, Ruth Foseide Thorkildsen, Leif Erik Vinge, Eline Brenno Vaage, Bjørn Åsheim-Hansen, Andreas Barratt-Due, Inge Christoffer Olsen, Katerina Nezvalova-Henriksen, Trine Kåsine, Fridtjof Lund-Johansen, Hedda Hoel, Aleksander Rygh Holten, Anders Tveita, Alexander Mathiessen, Mette Haugli, Ragnhild Eiken, Anders Benjamin Kildal, Åse Berg, Asgeir Johannessen, Lars Heggelund, Tuva Børresdatter Dahl, Karoline Hansen Skåra, Pawel Mielnik, Lan Ai Kieu Le, Lars Thoresen, Gernot Ernst, Dag Arne Lihaug Hoff, Hilde Skudal, Bård Reiakvam Kittang, Roy Bjørkholt Olsen, Birgitte Tholin, Carl Magnus Ystrøm, Nina Vibeche Skei, Trung Tran, Susanne Dudman, Jan Terje Andersen, Raisa Hannula, Olav Dalgard, Ane-Kristine Finbråten, Kristian Tonby, Bjorn Blomberg, Saad Aballi, Cathrine Fladeby, Anne Steffensen, Fredrik Müller, Anne Ma Dyrhol-Riise, Marius Trøseid, Pål Aukrust
Abstract
Background: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known.
Objective: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx.
Design: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616).
Setting: 23 hospitals in Norway.
Patients: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection.
Intervention: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87).
Measurements: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables.
Results: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance.
Limitation: The trial had no placebo group.
Conclusion: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19.
Primary funding source: National Clinical Therapy Research in the Specialist Health Services, Norway.
Conflict of interest statement
Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M21-0653.
Figures
![Visual Abstract.. Remdesivir and Hydroxychloroquine: Effects on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-AIME202109210-M210653_visual-abstract.jpg)
![Figure 1.. Study flow diagram.](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ff1.jpg)
![Appendix Figure 1.. Cumulative probability plots for…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa1.jpg)
![Figure 2.. Efficacy of viral clearance by…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ff2.jpg)
![Appendix Figure 2.. Box plots of change…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa2.jpg)
![Figure 3.. Effect of remdesivir and HCQ…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ff3.jpg)
![Appendix Figure 3.. Effect of remdesivir on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa3.jpg)
![Appendix Figure 4.. Effect of HCQ on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa4.jpg)
![Appendix Figure 5.. Efficacy of remdesivir on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa5.jpg)
![Appendix Figure 6.. Efficacy of HCQ on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa6.jpg)
![Appendix Figure 7.. Effect of remdesivir on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa7.jpg)
Appendix Figure 8.. Effect of HCQ on…
Appendix Figure 8.. Effect of HCQ on inflammatory markers, lymphocytes, and neutrophils.
In subgroup analyses…
- Remdesivir for the treatment of COVID-19.Ansems K, Grundeis F, Dahms K, Mikolajewska A, Thieme V, Piechotta V, Metzendorf MI, Stegemann M, Benstoem C, Fichtner F. Ansems K, et al. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD014962. doi: 10.1002/14651858.CD014962. Cochrane Database Syst Rev. 2021. PMID: 34350582 Free PMC article. Updated.
- Repurposed Antiviral Drugs for Covid-19 - Interim WHO Solidarity Trial Results.WHO Solidarity Trial Consortium; Pan H, Peto R, Henao-Restrepo AM, Preziosi MP, Sathiyamoorthy V, Abdool Karim Q, Alejandria MM, Hernández García C, Kieny MP, Malekzadeh R, Murthy S, Reddy KS, Roses Periago M, Abi Hanna P, Ader F, Al-Bader AM, Alhasawi A, Allum E, Alotaibi A, Alvarez-Moreno CA, Appadoo S, Asiri A, Aukrust P, Barratt-Due A, Bellani S, Branca M, Cappel-Porter HBC, Cerrato N, Chow TS, Como N, Eustace J, García PJ, Godbole S, Gotuzzo E, Griskevicius L, Hamra R, Hassan M, Hassany M, Hutton D, Irmansyah I, Jancoriene L, Kirwan J, Kumar S, Lennon P, Lopardo G, Lydon P, Magrini N, Maguire T, Manevska S, Manuel O, McGinty S, Medina MT, Mesa Rubio ML, Miranda-Montoya MC, Nel J, Nunes EP, Perola M, Portolés A, Rasmin MR, Raza A, Rees H, Reges PPS, Rogers CA, Salami K, Salvadori MI, Sinani N, Sterne JAC, Stevanovikj M, Tacconelli E, Tikkinen KAO, Trelle S, Zaid H, Røttingen JA, Swaminathan S. WHO Solidarity Trial Consortium, et al. N Engl J Med. 2021 Feb 11;384(6):497-511. doi: 10.1056/NEJMoa2023184. Epub 2020 Dec 2. N Engl J Med. 2021. PMID: 33264556 Free PMC article. Clinical Trial.
- Remdesivir and three other drugs for hospitalised patients with COVID-19: final results of the WHO Solidarity randomised trial and updated meta-analyses.WHO Solidarity Trial Consortium. WHO Solidarity Trial Consortium. Lancet. 2022 May 21;399(10339):1941-1953. doi: 10.1016/S0140-6736(22)00519-0. Epub 2022 May 2. Lancet. 2022. PMID: 35512728 Free PMC article.
- Chloroquine or hydroxychloroquine for prevention and treatment of COVID-19.Singh B, Ryan H, Kredo T, Chaplin M, Fletcher T. Singh B, et al. Cochrane Database Syst Rev. 2021 Feb 12;2(2):CD013587. doi: 10.1002/14651858.CD013587.pub2. Cochrane Database Syst Rev. 2021. PMID: 33624299 Free PMC article.
- Remdesivir plus standard of care versus standard of care alone for the treatment of patients admitted to hospital with COVID-19 (DisCoVeRy): a phase 3, randomised, controlled, open-label trial.Ader F, Bouscambert-Duchamp M, Hites M, Peiffer-Smadja N, Poissy J, Belhadi D, Diallo A, Lê MP, Peytavin G, Staub T, Greil R, Guedj J, Paiva JA, Costagliola D, Yazdanpanah Y, Burdet C, Mentré F; DisCoVeRy Study Group. Ader F, et al. Lancet Infect Dis. 2022 Feb;22(2):209-221. doi: 10.1016/S1473-3099(21)00485-0. Epub 2021 Sep 14. Lancet Infect Dis. 2022. PMID: 34534511 Free PMC article. Clinical Trial.
- Peginterferon lambda for the treatment of hospitalized patients with mild COVID-19: A pilot phase 2 randomized placebo-controlled trial.Kim MH, Elbaz J, Jilg N, Gustafson JL, Xu M, Hatipoglu D, Nohelty E, Kim AY, Chung RT. Kim MH, et al. Front Med (Lausanne). 2023 Feb 24;10:1095828. doi: 10.3389/fmed.2023.1095828. eCollection 2023. Front Med (Lausanne). 2023. PMID: 36910479 Free PMC article.
- Plitidepsin in adult patients with COVID-19 requiring hospital admission: A long-term follow-up analysis.Varona JF, Landete P, Paredes R, Vates R, Torralba M, Guisado-Vasco P, Porras L, Muñoz P, Gijon P, Ancochea J, Saiz E, Meira F, Jimeno JM, Lopez-Martin JA, Estrada V. Varona JF, et al. Front Cell Infect Microbiol. 2023 Feb 22;13:1097809. doi: 10.3389/fcimb.2023.1097809. eCollection 2023. Front Cell Infect Microbiol. 2023. PMID: 36909731 Free PMC article.
- Remdesivir Influence on SARS-CoV-2 RNA Viral Load Kinetics in Nasopharyngeal Swab Specimens of COVID-19 Hospitalized Patients: A Real-Life Experience.Campogiani L, Iannetta M, Di Lorenzo A, Zordan M, Pace PG, Coppola L, Compagno M, Malagnino V, Teti E, Andreoni M, Sarmati L. Campogiani L, et al. Microorganisms. 2023 Jan 25;11(2):312. doi: 10.3390/microorganisms11020312. Microorganisms. 2023. PMID: 36838277 Free PMC article.
- Remdesivir for the treatment of COVID-19.Grundeis F, Ansems K, Dahms K, Thieme V, Metzendorf MI, Skoetz N, Benstoem C, Mikolajewska A, Griesel M, Fichtner F, Stegemann M. Grundeis F, et al. Cochrane Database Syst Rev. 2023 Jan 25;1(1):CD014962. doi: 10.1002/14651858.CD014962.pub2. Cochrane Database Syst Rev. 2023. PMID: 36695483 Review.
- Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID-19 (Bari-SolidAct): a randomised, double-blind, placebo-controlled phase 3 trial.Trøseid M, Arribas JR, Assoumou L, Holten AR, Poissy J, Terzić V, Mazzaferri F, Baño JR, Eustace J, Hites M, Joannidis M, Paiva JA, Reuter J, Püntmann I, Patrick-Brown TDJH, Westerheim E, Nezvalova-Henriksen K, Beniguel L, Dahl TB, Bouscambert M, Halanova M, Péterfi Z, Tsiodras S, Rezek M, Briel M, Ünal S, Schlegel M, Ader F, Lacombe K, Amdal CD, Rodrigues S, Tonby K, Gaudet A, Heggelund L, Mootien J, Johannessen A, Møller JH, Pollan BD, Tveita AA, Kildal AB, Richard JC, Dalgard O, Simensen VC, Baldé A, de Gastines L, Del Álamo M, Aydin B, Lund-Johansen F, Trabaud MA, Diallo A, Halvorsen B, Røttingen JA, Tacconelli E, Yazdanpanah Y, Olsen IC, Costagliola D; EU SolidAct study group. Trøseid M, et al. Crit Care. 2023 Jan 10;27(1):9. doi: 10.1186/s13054-022-04205-8. Crit Care. 2023. PMID: 36627655 Free PMC article. Clinical Trial.
- Multicenter Study
- Pragmatic Clinical Trial
- Randomized Controlled Trial
- Adenosine Monophosphate / analogs & derivatives*
- Adenosine Monophosphate / therapeutic use
- Alanine / analogs & derivatives*
- Alanine / therapeutic use
- Antibodies, Viral / blood
- Antiviral Agents / therapeutic use*
- Biomarkers / blood
- COVID-19 / complications
- COVID-19 / mortality
- COVID-19 / virology*
- COVID-19 Drug Treatment*
- Cause of Death
- Female
- Hospital Mortality
- Humans
- Hydroxychloroquine / therapeutic use*
- Inflammation / virology
- Male
- Middle Aged
- Norway / epidemiology
- Oropharynx / virology
- Respiratory Insufficiency / virology
- SARS-CoV-2 / immunology
- Severity of Illness Index
- Standard of Care
- Treatment Outcome
- Viral Load / drug effects*
- Antibodies, Viral
- Antiviral Agents
- Biomarkers
- remdesivir
- Adenosine Monophosphate
- Hydroxychloroquine
- Alanine
- ClinicalTrials.gov/NCT04321616
- Full Text Sources
- Other Literature Sources
- Medical
- Miscellaneous
![Appendix Figure 8.. Effect of HCQ on…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8279143/bin/aim-olf-M210653-M210653ffa8.jpg)
References
- Pan H , Peto R , Henao-Restrepo AM , et al; WHO Solidarity Trial Consortium. Repurposed antiviral drugs for Covid-19 — interim WHO Solidarity trial results. N Engl J Med. 2021;384:497-511. [PMID: ] doi:10.1056/NEJMoa2023184
- Horby P , Mafham M , Linsell L , et al; RECOVERY Collaborative Group. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383:2030-2040. [PMID: ] doi:10.1056/NEJMoa2022926
- Beigel JH , Tomashek KM , Dodd LE , et al; ACTT-1 Study Group Members. Remdesivir for the treatment of Covid-19 — final report. N Engl J Med. 2020;383:1813-1826. [PMID: ] doi:10.1056/NEJMoa2007764
- Gordon PA , Winer JB , Hoogendijk JE , et al. Immunosuppressant and immunomodulatory treatment for dermatomyositis and polymyositis. Cochrane Database Syst Rev. 2012:CD003643. [PMID: ] doi:10.1002/14651858.CD003643.pub4
- Wang M , Cao R , Zhang L , et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro [Letter]. Cell Res. 2020;30:269-271. [PMID: ] doi:10.1038/s41422-020-0282-0
- Rochwerg B , Siemieniuk RA , Agoritsas T , et al. A living WHO guideline on drugs for covid-19. BMJ. 2020;370:m3379. [PMID: ] doi:10.1136/bmj.m3379
- Chief Investigators of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) Trial on hydroxychloroquine. No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19. Nuffield Department of Population Health. 5 June 2020. Accessed at on 5 June 2020.
- World Health Organization. WHO discontinues hydroxychloroquine and lopinavir/ritonavir treatment arms for COVID-19. 4 July 2020. Accessed at on 4 July 2020.
- National Intensive Care and Pandemic Registry. Accessed at on 4 May 2021.
- Laake JH , Buanes EA , Småstuen MC , et al. Characteristics, management and survival of ICU patients with coronavirus disease-19 in Norway, March-June 2020. A prospective observational study. Acta Anaesthesiol Scand. 2021;65:618-628. [PMID: ] doi:10.1111/aas.13785
- Bimonte S , Crispo A , Amore A , et al. Potential antiviral drugs for SARS-cov-2 treatment: preclinical findings and ongoing clinical research. In Vivo. 2020;34:1597-1602. [PMID: ] doi:10.21873/invivo.11949
- Wang Y , Zhang D , Du G , et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395:1569-1578. [PMID: ] doi:10.1016/S0140-6736(20)31022-9
- Lyngbakken MN , Berdal JE , Eskesen A , et al. A pragmatic randomized controlled trial reports lack of efficacy of hydroxychloroquine on coronavirus disease 2019 viral kinetics. Nat Commun. 2020;11:5284. [PMID: ] doi:10.1038/s41467-020-19056-6
- Dolin R , Hirsch MS . Remdesivir — an important first step [Editorial]. N Engl J Med. 2020;383:1886-1887. [PMID: ] doi:10.1056/NEJMe2018715
- Maciorowski D , Idrissi SZE , Gupta Y , et al. A review of the preclinical and clinical efficacy of remdesivir, hydroxychloroquine, and lopinavir-ritonavir treatments against COVID-19. SLAS Discov. 2020;25:1108-1122. [PMID: ] doi:10.1177/2472555220958385
- White NJ , Watson JA , Hoglund RM , et al. COVID-19 prevention and treatment: a critical analysis of chloroquine and hydroxychloroquine clinical pharmacology. PLoS Med. 2020;17:e1003252. [PMID: ] doi:10.1371/journal.pmed.1003252
- Spinner CD , Gottlieb RL , Criner GJ , et al; GS-US-540-5774 Investigators. Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial. JAMA. 2020;324:1048-1057. [PMID: ] doi:10.1001/jama.2020.16349
- Corman VM , Landt O , Kaiser M , et al. Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR. Euro Surveill. 2020;25. [PMID: ] doi:10.2807/1560-7917.ES.2020.25.3.2000045
- Dreier J , Störmer M , Kleesiek K . Use of bacteriophage MS2 as an internal control in viral reverse transcription-PCR assays. J Clin Microbiol. 2005;43:4551-7. [PMID: ]
- Holter JC , Pischke SE , de Boer E , et al. Systemic complement activation is associated with respiratory failure in COVID-19 hospitalized patients. Proc Natl Acad Sci U S A. 2020;117:25018-25025. [PMID: ] doi:10.1073/pnas.2010540117
- Amanat F , Stadlbauer D , Strohmeier S , et al. A serological assay to detect SARS-CoV-2 seroconversion in humans. Nat Med. 2020;26:1033-1036. [PMID: ] doi:10.1038/s41591-020-0913-5
Source: PubMed