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
Authors: Denholm Justin T. , Davis Joshua , Paterson David , Roberts Jason , Morpeth Susan , Snelling Thomas , Zentner Dominica , Rees Megan , O’Sullivan Matthew , Price David , Bowen Asha , Tong Steven Y. C. ,   for the ASCOT Investigator Group, Davis Joshua , Denholm Justin , Tong Steven , Rees Megan , Paterson David , Price David , Morpeth Susan , O’Sullivan Matthew , Roberts Jason , Snelling Thomas , Anderson Sue , McQuilton Zoe , Venkatesh Bala , Hammond Naomi , Jha Vivekanend , Burston Victoria John , McMahon James , Charles Patrick , Commons Robert , O’Brien Daniel , Mahoney Andrew , Sheffield David , Lim Lyn-Li , Gardiner Brad , Schulz Thomas , Torresi Joseph , Chean Roy , Sasadeusz Joseph , Rogers Ben , Aboltins Craig , Singh Kasha , Yong Michelle , Lister David , Visvanathan Kumar , Molton James , Tai Alex , Chalmers Rachel , Martinello Marianne , Wilson Paul , Gray Timothy , Coghill Sarah , Foo Hong , Sud Archana , Williams Jacob , Lwin Nilar , Post Jeffrey , van Haal Sebastian , Sullivan Richard , Matthews Gail , Kwan Benjamin Chi Hin , Slack Andrew , Shum Omar , Cochrane Belinda , Dotel Ravindra , Gray Timothy , Gilbey Timothy , Mina Michael , Su Yuen , Trethewy Chris , Hudson Bernie , Chatterji Arunavo , Mostert Christaan , New David , Raby Edward , Hui Sionh , Robinson Owen , Hart Julie , Tan Shu Jin , Arellano Astrid , Chambers Jonathan , Davis Jane , Rafiei Nastaran , Smith Simon , Sehu Marjoree , da Silva Janath , Griffin Paul , Henderson Andrew , Chaw Khin , Choong Keat , Burke Andrew , Heather Christopher , Senanayake Sanjaya , Boyd Mark , Rowe Emily , Anagnostou Mick , Trad Ali , Ratcliff Alison , Morpeth Susan , Dummer Jack , Bhally Hassan , Giola Massimo , Grimwade Kate , Chang Catharina Li-Lin , Verrall Ayesha , Hogg Stephen , Restropo Dalilah , Maze Michael , Ritchie Stephen , Gedye Craig , Chang Judy , Maze Michael , Pillai Priyanka , Flanagan Katie , Mora Jocelyn , Post Jenny , Lam Eileen , Littleford Roberta , Knoblauch Naomi , Slow Sandy 
Published: July 2020

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.