ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12620000445976

Ethics application status

Approved

Date submitted

2/04/2020

Date registered

6/04/2020

Date last updated

15/05/2020

Date data sharing statement initially provided

6/04/2020

Type of registration

Prospectively registered

Titles & IDs

Public title

To compare the effectiveness of two drugs (hydroxychloroquine and lopinavir/ritonavir alone or combined in treating hospitalized patients with confirmed COVID-19 compared to standard of care

Scientific title

Australasian COVID-19 Trial (ASCOT). A multi-centre randomised clinical trial to assess clinical, virological and immunological outcomes in patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care

Secondary ID [1]

none

Universal Trial Number (UTN)

U1111-1250-5165

Trial acronym

ASCOT

Linked study record

Health condition

Health condition(s) or problem(s) studied:

COVID-19 (SARS-CoV-2)

Condition category

Condition code

Infection

Other infectious diseases

Respiratory

Other respiratory disorders / diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Intervention 1
Intervention Type: Drug
Intervention Administration: Oral
Intervention Name: Lopinavir/ritonavir
Intervention Description: Lopinavir (400mg)/ritonavir (100mg) twice daily for 10 days
Intervention Adherence: direct supervision while in hospital. Once home, adherence will be monitored through daily phone calls

Intervention 2
Intervention Type: Drug
Intervention Administration: Oral
Intervention Name: Hydroxychloroquine
Intervention Description: 800mg twice a day (4x200mg administered 12 hours apart) on Day 1, followed by 400mg twice a day for 6 days
Intervention Adherence: direct supervision while in hospital. Once home, adherence will be monitored through daily phone calls

Intervention 3
Intervention Type: Drug
Intervention Administration: Oral
Intervention Name: Lopinavir / ritonavir plus hydroxychloroquine
Intervention Description: Lopinavir (400mg)/ritonavir (100mg) twice daily for 10 days plus hydroxychloroquine 800mg twice a day (4x200mg administered 12 hours apart) on Day 1, followed by 400mg twice a day for 6 days
Intervention Adherence: direct supervision while in hospital. Once home, adherence will be monitored through daily phone calls

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

The control arm will receive usual routine medical care that all patients would receive if not part of this trial.

There is no specific medical care for patients diagnosed with COVID-19. Routine ususal medical care describes the care given by medical doctors to treat and control symptoms (i.e. medications for pain or oxygen therapy).

Control group

Active

Outcomes

Primary outcome [1]

Proportion of participants alive and not having required intensive respiratory support (invasive or non-invasive ventilation or humidified high flow nasal oxygen flow) at 15 days after enrolment.

This outcome is assessed by the number of patients who are not admitted into the intensive care unit (ICU)

Timepoint [1]

15 days after enrolment

Secondary outcome [1]

WHO 7-point outcome scale (clinician assessed)

Based on the following clinical improvement scale:
1. Not hospitalized, no limitations on activities;
2. Not hospitalized, limitations on activities;
3. Hospitalized, not requiring supplemental oxygen;
4. Hospitalized, requiring supplemental oxygen;
5. Hospitalized, on non-invasive ventilation or high flow oxygen devices;
6. Hospitalized, on invasive mechanical ventilation or ECMO
7. Death

Timepoint [1]

15 days post enrolment

Secondary outcome [2]

Mortality at 7, 15, 28, 90 days

Timepoint [2]

7, 15, 28, 90 days post enrolment

Secondary outcome [3]

Time to death

Assessed by reviewing hospital medical records

Timepoint [3]

Assessed up to 90 days post-enrolment

Secondary outcome [4]

Length of hospital stay.

Assessed by reviewing hospital medical records

Timepoint [4]

Discharge from hospital

Secondary outcome [5]

Receipt of invasive or non-invasive ventilation in first 28 days

Assessed by reviewing hospital medical records

Timepoint [5]

28 days post enrolment

Secondary outcome [6]

Length of receipt of invasive or non-invasive ventilation

Assessed by reviewing hospital medical records

Timepoint [6]

28 days post enrolment

Secondary outcome [7]

Length of ICU stay

Assessed by reviewing hospital medical records

Timepoint [7]

Release from ICU or death

Secondary outcome [8]

Presence of chest infiltrates on CXR or CT at day 3 and day 7

Assessed by reviewing hospital medical records

Timepoint [8]

3 and 7 days post enrolment

Secondary outcome [9]

Time to defervescence from randomisation

Assessed by reviewing hospital medical records

Timepoint [9]

Assessed up to 90 days post-enrolment

Secondary outcome [10]

Biomarker levels – C-reactive protein (CRP)

Assessed by serum assays

Timepoint [10]

Days 1, 3 and 7 post enrolment

Secondary outcome [11]

Antibiotic use – number of days of use in first 10 days

Assessed by reviewing hospital medical records

Timepoint [11]

10 days post enrolment

Secondary outcome [12]

Safety. Any of the following adverse events in first 10 days.
- Diarrhoea – grade 2 or greater
- Nausea – grade 2 or greater
- Vomiting – grade 2 or greater
- Pancreatitis – grade 2 or greater
- QTc prolongation (>500ms) 24 hours following initial dose of study drugs

Assessed by reviewing hospital medical records

Timepoint [12]

10 days post enrolment

Secondary outcome [13]

Serious ventricular arrhythmia (including ventricular fibrillation) or sudden unexpected death in hospital

Assessed by reviewing hospital medical records

Timepoint [13]

Assessed up to 90 days post-enrolment

Secondary outcome [14]

Viral clearance. Proportion of patients with negative SARS-CoV-2 RT-PCR at day 3 and day 7 from upper or lower respiratory tract samples.

Assessed by throat swab assay

Timepoint [14]

3 and 7 days post enrolment

Secondary outcome [15]

Biomarker levels – Lactate dehydrogenase (LD or LDH)

Assessed by serum assays

Timepoint [15]

Days 1, 3 and 7 post enrolment

Secondary outcome [16]

Biomarker levels – D-Dimer

Assessed by serum assays

Timepoint [16]

Days 1, 3 and 7 post enrolment

Eligibility

Key inclusion criteria

1. Age 18 years and over
2. Confirmed SARS-CoV-2 by nucleic acid testing in the past 12 days
3. Able to be randomised within 12 days of symptom onset
4. Expected to be remain an inpatient for at least 48 hours from the time of randomisation

Minimum age

18 Years

Maximum age

No limit

Gender

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1. Currently admitted to an Intensive Care Unit (ICU)
2. Currently receiving intensive respiratory support (invasive or non-invasive ventilation or humidified high flow nasal oxygen)
3. Currently taking LPV/r OR hydroxychloroquine
4. Known allergy or hypersensitivity to LPV/r OR hydroxychloroquine
5. Use of medications that are contraindicated with LPV/r OR hydroxychloroquine that cannot be replaced or stopped during the study period. https://www.covid19-druginteractions.org/.
6. Currently on other investigational agents with targeted antiviral effects
7. Known cirrhosis or ALT or AST greater than 5x upper limit of normal
8. Previous participation in the trial
9. Known pregnancy
10. Known HIV infection not on antiretroviral therapy
11. QTc greater than or equal to 470 for males, QTc greater than or equal to 480 for females
12. Treating team deems enrolment in the study is not in the best interests of the patient
13. Unable to provide consent
14. Death is deemed to be imminent and inevitable within the next 24 hours

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Central randomisation by computer

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Participants will be randomised in a 1:1:1:1 ratio to the standard of care or treatment arms, where 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 as outlined in the data management SOP.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Factorial

Other design features

Phase

Phase 3

Type of endpoint(s)

Efficacy

Statistical methods / analysis

Data will be reported in accordance with the CONSORT guidelines for reporting of randomised trials. Proportions will be compared between treatment groups with Fisher’s exact or X2 tests, and the absolute difference in proportions reported with corresponding 95% confidence intervals. All-cause mortality will be presented in a Kaplan-Meier graph.
The primary analysis of both primary and secondary endpoints will be according to modified intention to treat principles (all participants with data available for the endpoint will be analysed according to the treatment allocation, regardless of what treatment they received). No assumptions will be made about those with missing data.
A secondary per-protocol analysis of all endpoints will be conducted. The per protocol population is defined as 1) for the control group: did not receive any LPV/r or hydroxychloroquine; 2) for the intervention group: received at least 80% of possible doses of LPV/r; 3) has available data.
We will perform the following subgroup analyses:
1. Age 65 and greater OR less than 65 years. Early experience with SARS-CoV-2 infection is that older age is associated with poorer outcomes.
2. Receipt of study drug within or after 96 hours of symptom onset. There is biological plausibility that early treatment to reduce viral replication will be more effective than later treatment when pulmonary pathology may already be evident.
3. Mild vs moderate severity at presentation. Initial severity at presentation may predict the later clinical course and there may be a differential effect of antiviral treatment. The absolute improvement in clinical outcomes may be more evident in the moderate severity group due to a higher event rate.
a. Mild severity at presentation is defined as: SaO2 equals 95% or more on room air AND not requiring supplemental oxygen AND not tachypnoeic (respiratory rate less than 24 breaths/min)
b. Moderate severity at presentation is defined as SaO2 equals 94% or less on room air OR requiring supplemental oxygen OR tachypnoeic (respiratory rate 24 or more breaths/min)
4. Baseline use of ACE inhibitors or ATIII blockers. These medications affect the renin angiotensin aldosterone system pathway, which may also be affected by SARS-CoV-2, which uses ACE2 as its cellular receptor. Use of these medications may result in differential susceptibility to SARS-CoV-2 infection, with the direction of effect uncertain.
5. Those with baseline immunosuppression vs those without. These are different patient groups with regards to underlying comorbidities and risk for severe sepsis. Patients will be considered immunosuppressed if in receipt of immunosuppressing medication considered by the site investigator to be equivalent to 20 mg or greater of prednisolone for 2 or more weeks, or with a known haematological malignancy.

Recruitment

Recruitment status

Recruiting

Date of first participant enrolment

Anticipated

10/04/2020

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

2500

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

ACT,NSW,NT,QLD,SA,TAS,WA,VIC

Recruitment hospital [1]

The Canberra Hospital - Garran

Recruitment hospital [2]

Blacktown Hospital - Blacktown

Recruitment hospital [3]

Concord Repatriation Hospital - Concord

Recruitment hospital [4]

John Hunter Hospital - New Lambton

Recruitment hospital [5]

Lismore Base Hospital - Lismore

Recruitment hospital [6]

Liverpool Hospital - Liverpool

Recruitment hospital [7]

Calvary Mater Newcastle - Waratah

Recruitment hospital [8]

Nepean Hospital - Kingswood

Recruitment hospital [9]

Orange Health Service - Orange

Recruitment hospital [10]

Port Macquarie Base Hospital - Port Macquarie

Recruitment hospital [11]

Prince of Wales Hospital - Randwick

Recruitment hospital [12]

Royal Prince Alfred Hospital - Camperdown

Recruitment hospital [13]

St George Hospital - Kogarah

Recruitment hospital [14]

St Vincent's Hospital (Darlinghurst) - Darlinghurst

Recruitment hospital [15]

The Sutherland Hospital - Caringbah

Recruitment hospital [16]

The Tweed Hospital - Tweed Heads

Recruitment hospital [17]

Wollongong Hospital - Wollongong

Recruitment hospital [18]

Westmead Hospital - Westmead

Recruitment hospital [19]

Armidale Rural Referral Hospital - Armidale

Recruitment hospital [20]

Royal Darwin Hospital - Tiwi

Recruitment hospital [21]

Caboolture Hospital - Caboolture

Recruitment hospital [22]

Cairns Base Hospital - Cairns

Recruitment hospital [23]

Logan Hospital - Meadowbrook

Recruitment hospital [24]

Mackay Base Hospital - Mackay

Recruitment hospital [25]

Mater Sydney - North Sydney

Recruitment hospital [26]

Princess Alexandra Hospital - Woolloongabba

Recruitment hospital [27]

Redcliffe Hospital - Redcliffe

Recruitment hospital [28]

Royal Brisbane & Womens Hospital - Herston

Recruitment hospital [29]

Sunshine Coast University Hospital - Birtinya

Recruitment hospital [30]

The Prince Charles Hospital - Chermside

Recruitment hospital [31]

The Townsville Hospital - Douglas

Recruitment hospital [32]

Flinders Medical Centre - Bedford Park

Recruitment hospital [33]

Lyell McEwin Hospital - Elizabeth Vale

Recruitment hospital [34]

The Royal Adelaide Hospital - Adelaide

Recruitment hospital [35]

Launceston General Hospital - Launceston

Recruitment hospital [36]

Royal Hobart Hospital - Hobart

Recruitment hospital [37]

Armadale Kelmscott Memorial Hospital - Armadale

Recruitment hospital [38]

Fiona Stanley Hospital - Murdoch

Recruitment hospital [39]

Rockingham General Hospital - Cooloongup

Recruitment hospital [40]

Sir Charles Gairdner Hospital - Nedlands

Recruitment hospital [41]

St John of God Hospital, Midland - Midland

Recruitment hospital [42]

St John of God Hospital, Subiaco - Subiaco

Recruitment hospital [43]

Royal Perth Hospital - Perth

Recruitment hospital [44]

Albury Wodonga Health - Albury campus - Albury

Recruitment hospital [45]

Albury Wodonga Health - Wodonga campus - Wodonga

Recruitment hospital [46]

The Alfred - Melbourne

Recruitment hospital [47]

Austin Health - Austin Hospital - Heidelberg

Recruitment hospital [48]

Barwon Health - Geelong Hospital campus - Geelong

Recruitment hospital [49]

Bendigo Health Care Group - Bendigo Hospital - Bendigo

Recruitment hospital [50]

Cabrini Hospital - Malvern - Malvern

Recruitment hospital [51]

Box Hill Hospital - Box Hill

Recruitment hospital [52]

Epworth Freemasons (Clarendon Street) - East Melbourne

Recruitment hospital [53]

Goulburn Valley Health - Shepparton campus - Shepparton

Recruitment hospital [54]

Knox Private Hospital - Wantirna

Recruitment hospital [55]

Latrobe Regional Hospital - Traralgon

Recruitment hospital [56]

Royal Melbourne Hospital - Royal Park campus - Parkville

Recruitment hospital [57]

Monash Medical Centre - Clayton campus - Clayton

Recruitment hospital [58]

Dandenong Hospital - Dandenong

Recruitment hospital [59]

Casey Hospital - Berwick

Recruitment hospital [60]

The Northern Hospital - Epping

Recruitment hospital [61]

Broadmeadows Health Service - Broadmeadows

Recruitment hospital [62]

Bundoora Extended Care Centre - Bundoora

Recruitment hospital [63]

Frankston Hospital - Frankston

Recruitment hospital [64]

Peter MacCallum Cancer Centre - Melbourne

Recruitment hospital [65]

St John of God Hospital, Ballarat - Ballarat

Recruitment hospital [66]

St Vincent's Hospital (Melbourne) Ltd - Fitzroy

Recruitment hospital [67]

Footscray Hospital - Footscray

Recruitment hospital [68]

Sunshine Hospital - St Albans

Recruitment hospital [69]

West Gippsland Healthcare Group - Warragul

Recruitment postcode(s) [1]

2605 - Garran

Recruitment postcode(s) [2]

2148 - Blacktown

Recruitment postcode(s) [3]

2139 - Concord

Recruitment postcode(s) [4]

2305 - New Lambton

Recruitment postcode(s) [5]

2480 - Lismore

Recruitment postcode(s) [6]

2170 - Liverpool

Recruitment postcode(s) [7]

2298 - Waratah

Recruitment postcode(s) [8]

2747 - Kingswood

Recruitment postcode(s) [9]

2800 - Orange

Recruitment postcode(s) [10]

2444 - Port Macquarie

Recruitment postcode(s) [11]

2031 - Randwick

Recruitment postcode(s) [12]

2050 - Camperdown

Recruitment postcode(s) [13]

2217 - Kogarah

Recruitment postcode(s) [14]

2010 - Darlinghurst

Recruitment postcode(s) [15]

2229 - Caringbah

Recruitment postcode(s) [16]

2485 - Tweed Heads

Recruitment postcode(s) [17]

2500 - Wollongong

Recruitment postcode(s) [18]

2145 - Westmead

Recruitment postcode(s) [19]

2350 - Armidale

Recruitment postcode(s) [20]

0810 - Tiwi

Recruitment postcode(s) [21]

4510 - Caboolture

Recruitment postcode(s) [22]

4870 - Cairns

Recruitment postcode(s) [23]

4131 - Meadowbrook

Recruitment postcode(s) [24]

4740 - Mackay

Recruitment postcode(s) [25]

2060 - North Sydney

Recruitment postcode(s) [26]

4102 - Woolloongabba

Recruitment postcode(s) [27]

4020 - Redcliffe

Recruitment postcode(s) [28]

4029 - Herston

Recruitment postcode(s) [29]

4575 - Birtinya

Recruitment postcode(s) [30]

4032 - Chermside

Recruitment postcode(s) [31]

4814 - Douglas

Recruitment postcode(s) [32]

5042 - Bedford Park

Recruitment postcode(s) [33]

5112 - Elizabeth Vale

Recruitment postcode(s) [34]

5000 - Adelaide

Recruitment postcode(s) [35]

7250 - Launceston

Recruitment postcode(s) [36]

7000 - Hobart

Recruitment postcode(s) [37]

6112 - Armadale

Recruitment postcode(s) [38]

6150 - Murdoch

Recruitment postcode(s) [39]

6168 - Cooloongup

Recruitment postcode(s) [40]

6009 - Nedlands

Recruitment postcode(s) [41]

6056 - Midland

Recruitment postcode(s) [42]

6008 - Subiaco

Recruitment postcode(s) [43]

6000 - Perth

Recruitment postcode(s) [44]

2640 - Albury

Recruitment postcode(s) [45]

3690 - Wodonga

Recruitment postcode(s) [46]

3004 - Melbourne

Recruitment postcode(s) [47]

3084 - Heidelberg

Recruitment postcode(s) [48]

3220 - Geelong

Recruitment postcode(s) [49]

3550 - Bendigo

Recruitment postcode(s) [50]

3144 - Malvern

Recruitment postcode(s) [51]

3128 - Box Hill

Recruitment postcode(s) [52]

3002 - East Melbourne

Recruitment postcode(s) [53]

3630 - Shepparton

Recruitment postcode(s) [54]

3152 - Wantirna

Recruitment postcode(s) [55]

3844 - Traralgon

Recruitment postcode(s) [56]

3052 - Parkville

Recruitment postcode(s) [57]

3168 - Clayton

Recruitment postcode(s) [58]

3175 - Dandenong

Recruitment postcode(s) [59]

3806 - Berwick

Recruitment postcode(s) [60]

3076 - Epping

Recruitment postcode(s) [61]

3047 - Broadmeadows

Recruitment postcode(s) [62]

3083 - Bundoora

Recruitment postcode(s) [63]

3199 - Frankston

Recruitment postcode(s) [64]

3350 - Ballarat

Recruitment postcode(s) [65]

3065 - Fitzroy

Recruitment postcode(s) [66]

3011 - Footscray

Recruitment postcode(s) [67]

3021 - St Albans

Recruitment postcode(s) [68]

3820 - Warragul

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

Funding & Sponsors

Funding source category [1]

University

Name [1]

University of Melbourne

Address [1]

Parkville, VIC 3010

Country [1]

Australia

Funding source category [2]

University

Name [2]

University of Queensland

Address [2]

Centre for Clinical Research
Building 71/918, Royal Brisbane Women's Campus
Herston, QLD 4029

Country [2]

Australia

Funding source category [3]

Other

Name [3]

Hunter Medical Research Institute: a partnership between the University of Newcastle, Hunter New England Local Health District

Address [3]

Lot 1, Kookaburra Cct
New Lambton Heights NSW 2305

Country [3]

Australia

Funding source category [4]

Charities/Societies/Foundations

Name [4]

The Pratt Foundation

Address [4]

Level 11, 2 Southbank Bvd
Southbank VIC 3006

Country [4]

Australia

Funding source category [5]

Charities/Societies/Foundations

Name [5]

Royal Brisbane Women's Hospital Foundation

Address [5]

Block 20, Royal Brisbane Women's Hospital
Butterfield St, Herston, QLD 4029

Country [5]

Australia

Funding source category [6]

Charities/Societies/Foundations

Name [6]

Hospital Research Foundation

Address [6]

60 Woodville Rd,
Woodville SA 5011

Country [6]

Australia

Primary sponsor type

University

Name

University of Melbourne

Address

Parkville, VIC, 3050

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Other collaborator category [1]

Other Collaborative groups

Name [1]

The Australasian Society for Infectious Diseases Clinical Research Network (ASID CRN)

Address [1]

Suite 302, Level 3, 478 George Street
Sydney NSW 2000
Australia

Country [1]

Australia

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Melbourne Health Human Research Ethics Committee

Ethics committee address [1]

Royal Melbourne Hospital Office for Research
CITY CAMPUS
Level 2
South West
300 Grattan Street
Parkville Victoria 3050

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

20/03/2020

Approval date [1]

03/04/2020

Ethics approval number [1]

HREC/62646/MH-2020

Summary

Brief summary

The study aims to assess clinical, virological and immunological outcomes in patients with SARS-CoV-2 infection (COVID-19) treated with lopinavir/ritonavir and/or hydroxychloroquine compared to standard of care

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

A/Prof Steven Tong

Address

The Peter Doherty Institute for Infection and Immunity
792 Elizabeth Street
Melbourne, Victoria 3000

Country

Australia

Phone

+61 03 9342 9406

Fax

steven.tong@unimelb.edu.au

Contact person for public queries

Name

A/Prof Steven Tong

Address

The Peter Doherty Institute for Infection and Immunity
792 Elizabeth Street
Melbourne, Victoria 3000

Country

Australia

Phone

+61 03 9342 9406

Fax

ascot-team@unimelb.edu.au

Contact person for scientific queries

Name

A/Prof Steven Tong

Address

The Peter Doherty Institute for Infection and Immunity
792 Elizabeth Street
Melbourne, Victoria 3000

Country

Australia

Phone

+61 03 9342 9406

Fax

steven.tong@unimelb.edu.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

The trial steering committee will be the custodians of the final trial dataset. No-one outside the trial steering committee will be given access to the data without the permission of the trial steering committee. No identifying data will be given to any third parties at any stage.

What supporting documents are/will be available?

No other documents available

Summary results

No Results

Trial Review