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The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial.
Trials. 2020 Jul 14; 21(1):646.T

Abstract

OBJECTIVES

To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection.

TRIAL DESIGN

ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management.

PARTICIPANTS

Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently.

INTERVENTION AND COMPARATOR

Participants will be randomised 1:1:1:1 to: Group 1: standard of care; Group 2: lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form; Group 3: hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days; Group 4: lopinavir /ritonavir plus hydroxychloroquine.

MAIN OUTCOMES

Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated.

RANDOMISATION

The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have individual participant allocation provided through a web-based trial enrolment platform.

BLINDING (MASKING)

This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required.

NUMBERS TO BE RANDOMISED (SAMPLE SIZE)

We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required sample size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 2440.

TRIAL STATUS

ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021.

TRIAL REGISTRATION

Australian New Zealand Clinical Trials Registry (ACTRN12620000445976). Prospectively registered April 6, 2020.

FULL PROTOCOL

The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Authors+Show Affiliations

Victorian Infectious Diseases Service, The Royal Melbourne Hospital, and Doherty Department University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, Victoria, Australia. justin.denholm@mh.org.au.Menzies School of Health Research, Charles Darwin University, Darwin, Australia. Department of Infectious Diseases, John Hunter Hospital, Newcastle, NSW, Australia.University of Queensland Centre for Clinical Research, Faculty of Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia. Department of Infectious Diseases, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.University of Queensland Centre for Clinical Research, Faculty of Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia. Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia. Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes, France.Middlemore Hospital, Counties Manukau District Health Board, Auckland, New Zealand.School of Public Health, University of Sydney, Sydney, New South Wales, Australia.Department of Cardiology, The Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.Department of Respiratory Medicine, The Royal Melbourne Hospital and Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia. University of Sydney, Sydney, New South Wales, Australia.Centre for Epidemiology & Biostatistics, Melbourne School of Population & Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Victorian Infectious Diseases Reference Laboratory Epidemiology Unit at the Peter Doherty Institute for Infection & Immunity, Royal Melbourne Hospital and The University of Melbourne, Melbourne, Victoria, Australia.Telehealth Kids Institute, Perth, West Australia, Australia.Victorian Infectious Diseases Service, The Royal Melbourne Hospital, and Doherty Department University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, 792 Elizabeth Street, Melbourne, Victoria, Australia. Menzies School of Health Research, Charles Darwin University, Darwin, Australia.No affiliation info available

Pub Type(s)

Clinical Trial Protocol
Comparative Study
Letter
Multicenter Study

Language

eng

PubMed ID

32665040

Citation

Denholm, Justin T., et al. "The Australasian COVID-19 Trial (ASCOT) to Assess Clinical Outcomes in Hospitalised Patients With SARS-CoV-2 Infection (COVID-19) Treated With Lopinavir/ritonavir And/or Hydroxychloroquine Compared to Standard of Care: a Structured Summary of a Study Protocol for a Randomised Controlled Trial." Trials, vol. 21, no. 1, 2020, p. 646.
Denholm JT, Davis J, Paterson D, et al. The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):646.
Denholm, J. T., Davis, J., Paterson, D., Roberts, J., Morpeth, S., Snelling, T., Zentner, D., Rees, M., O'Sullivan, M., Price, D., Bowen, A., & Tong, S. Y. C. (2020). The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial. Trials, 21(1), 646. https://doi.org/10.1186/s13063-020-04576-9
Denholm JT, et al. The Australasian COVID-19 Trial (ASCOT) to Assess Clinical Outcomes in Hospitalised Patients With SARS-CoV-2 Infection (COVID-19) Treated With Lopinavir/ritonavir And/or Hydroxychloroquine Compared to Standard of Care: a Structured Summary of a Study Protocol for a Randomised Controlled Trial. Trials. 2020 Jul 14;21(1):646. PubMed PMID: 32665040.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The Australasian COVID-19 Trial (ASCOT) to assess clinical outcomes in hospitalised patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care: A structured summary of a study protocol for a randomised controlled trial. AU - Denholm,Justin T, AU - Davis,Joshua, AU - Paterson,David, AU - Roberts,Jason, AU - Morpeth,Susan, AU - Snelling,Thomas, AU - Zentner,Dominica, AU - Rees,Megan, AU - O'Sullivan,Matthew, AU - Price,David, AU - Bowen,Asha, AU - Tong,Steven Y C, AU - ,, Y1 - 2020/07/14/ PY - 2020/06/28/received PY - 2020/07/02/accepted PY - 2020/7/16/entrez PY - 2020/7/16/pubmed PY - 2020/8/19/medline KW - COVID-19 KW - Randomised controlled trial KW - hydroxychloroquine KW - lopinavir KW - protocol KW - ritonavir SP - 646 EP - 646 JF - Trials JO - Trials VL - 21 IS - 1 N2 - OBJECTIVES: To determine if lopinavir/ritonavir +/- hydroxychloroquine will reduce the proportion of participants who survive without requiring ventilatory support, 15 days after enrolment, in adult participants with non-critically ill SARS-CoV-2 infection. TRIAL DESIGN: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled trial. Participants will have been hospitalised with confirmed COVID-19, and will be randomised 1:1:1:1 to receive lopinavir /ritonavir, hydroxychloroquine, both or neither drug in addition to standard of care management. PARTICIPANTS: Participants will be recruited from >80 hospitals across Australia and New Zealand, representing metropolitan and regional centres in both public and private sectors. Admitted patients will be eligible if aged ≥ 18 years, have confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days and are expected to remain an inpatient for at least 48 hours from the time of randomisation. Potentially eligible participants will be excluded if admitted to intensive care or requiring high level respiratory support, are currently receiving study drugs or their use is contraindicated due to allergy, drug interaction or comorbidities (including baseline QTc prolongation of 470ms for women or 480ms for men), or death is anticipated imminently. INTERVENTION AND COMPARATOR: Participants will be randomised 1:1:1:1 to: Group 1: standard of care; Group 2: lopinavir (400mg) / ritonavir (100mg) twice daily for 10 days in tablet form; Group 3: hydroxychloroquine (800mg) 4x200mg administered 12 hours apart on Day 1, followed by 400mg twice a day for 6 days; Group 4: lopinavir /ritonavir plus hydroxychloroquine. MAIN OUTCOMES: Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation) at 15 days after enrolment. A range of clinical and virological secondary outcomes will also be evaluated. RANDOMISATION: The randomisation schedule will be generated by an independent statistician. Randomisation will be stratified by site and will be in permuted blocks of variable block size. The randomised sequence allocation will only be accessible to the data management group, and site investigators will have individual participant allocation provided through a web-based trial enrolment platform. BLINDING (MASKING): This is an open-label study, with researchers assessing the laboratory outcomes blinded to treatment allocation. No unblinding procedures relating to potential adverse effects are therefore required. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We assumed that 5% of participants receiving standard of care would meet the primary outcome, aimed to evaluate whether interventions could lead to a relative risk of 0.5, assuming no interaction between intervention arms. This corresponds to a required sample size of 610 per arm, with a 5% two-sided significance level (alpha) and 80% power. The total sample size therefore is planned to be 2440. TRIAL STATUS: ASCOT protocol version 3, May 5, 2020. Recruitment opened April 4, 2020 and is ongoing, with planned completion of enrolment July 31, 2021. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12620000445976). Prospectively registered April 6, 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. SN - 1745-6215 UR - https://www.unboundmedicine.com/medline/citation/32665040/The_Australasian_COVID_19_Trial__ASCOT__to_assess_clinical_outcomes_in_hospitalised_patients_with_SARS_CoV_2_infection__COVID_19__treated_with_lopinavir/ritonavir_and/or_hydroxychloroquine_compared_to_standard_of_care:_A_structured_summary_of_a_study_protocol_for_a_randomised_controlled_trial_ L2 - https://trialsjournal.biomedcentral.com/articles/10.1186/s13063-020-04576-9 DB - PRIME DP - Unbound Medicine ER -