Clinical trial NCT04483960: Australasian COVID-19 Trial (ASCOT) ADAptive Platform Trial
Official title: A Multi-centre Randomised Adaptive Platform Clinical Trial to Assess Clinical, Virological and Immunological Outcomes in Patients With SARS-CoV-2 Infection (COVID-19)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: SARS-CoV-2 Infection (COVID-19)
Lead sponsor: University of Melbourne
Sponsor class: OTHER
Collaborators: name: The Peter Doherty Institute for Infection and Immunity
name: Australasian Society for Infectious Diseases
name: Hunter Medical Research Institute
name: Aotearoa Clinical Trials
name: Australian and New Zealand Intensive Care Research Centre
First posted: 2020-07-23
Enrollment: 2200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Intervention model description: Participants enrolled into the study have the option of deciding whether to be randomised in one or more (if available) treatment domains concurrently, if they meet the eligibility criteria.
Primary purpose: TREATMENT

Brief summary: An International Multi-Centre Randomised Adaptive Platform Clinical Trial to Assess the Clinical, Virological and Immunological Outcomes in Patients with SARS-CoV-2 Infection (COVID-19).

Detailed description: ASCOT is an investigator-initiated, multi-centre, open-label, randomised controlled, Bayesian, adaptive platform trial. The objective of ASCOT is to identify the regimen (combination of interventions) associated with the highest chance of improving clinical outcomes in adults hospitalised with COVID-19.

Platform trials allow multiple questions to be evaluated simultaneously and sequentially within the platform, and evaluate interaction between different treatment options, to achieve the goal of determining the optimal combination of treatments for the disease as rapidly as possible. Study treatments are categorised into different treatment domains.

The adaptive nature of the trial means treatments within a domain or an entire domain can be removed or added based on accruing data analysed at frequent intervals or based on external evidence.

\[Domain Closed\] Intervention domain A (antiviral): Participants will be randomised to receive either i) standard of care without nafamostat; or ii) standard of care with nafamostat

\[Never Opened\] Intervention domain B (antibody): Participants will be randomised to receive either i) standard of care without hyperimmune globulin; or ii) standard of care with hyperimmune globulin

\[Domain Closed\] Intervention domain C (anticoagulation): Participants will be randomised to receive either i) standard dose thromboprophylaxis; or ii) intermediate dose thromboprophylaxis; or iii) therapeutic anticoagulation

Intervention domain Q (Antiviral II):

Participants will be randomised to receive either i) no antiviral agents; or ii) oral nirmatrelvir-ritonavir; or iii) intravenous remdesivir iiii) oral nirmatrelvir-ritonavir + Intravenous remdesivir

Eligibility criteria: Inclusion Criteria:

A.Core Platform (all participants must meet the following):

1. Adult (as defined by local jurisdiction) patient admitted to hospital with acute illness and suspected or proven SARS-CoV-2 infection.

B. Antiviral II Domain (all participants in the Antiviral II domain must meet the following):

1. SARS-CoV-2 infection has been confirmed by positive rapid antigen test OR polymerase chain reaction test within the last 7 days

Exclusion Criteria:

A. Core platform exclusions (all participants must not meet the following):

1. Death is deemed to be imminent and inevitable during the next 24 hours AND one or more of the patient, substitute decision maker or attending physician are not committed to full active treatment
2. Patient is expected to be discharged from hospital today or tomorrow
3. More than 14 days have elapsed while admitted to hospital with symptoms of an acute illness due to proven SARS-CoV-2 infection
4. Previous participation in this trial, or another trial that is analysed within the same statistical model as this trial, within the last 90 days

B. Antiviral II Domain exclusions (patients at sites participating in the Antiviral II Domain must not meet the following):

1. Severe renal impairment, defined as eGFR\<30ml/min or receipt of renal replacement therapy
2. Severe hepatic impairment, defined as proven or suspected cirrhosis with Child Pugh class of C, OR acute hepatitis, defined as AST or ALT\>5 times the upper limit of normal in the testing laboratory.
3. The patient has received, at the time of eligibility assessment, \>24h of an antiviral agent intended to have activity against SARS-CoV-2, within the past 7 days
4. The patient is known to be pregnant or breastfeeding
5. The treating clinician believes that participation in the domain would not be in the best interests of the patient

B.1. Antiviral II Domain Non-Immune Suppressed Stratum-specific Exclusion Criteria (all non-immune suppressed patients at sites participating in the Antiviral II Domain must not meet the following):

1. Onset of COVID-related symptoms was more than 7 days (i.e., 168 hours) ago

B2. Antiviral II domain Intervention-specific Exclusion Criteria (All patients at sites participating in the Antiviral II Domain will be excluded from the below interventions if they meet the following):

Will be excluded from receiving Remdesivir if:

1. No venous access is available and none can be created
2. Known hypersensitivity to remdesivir or its excipients

Will be excluded from receiving Nirmatrelvir/ritonavir if:

1. The patient is unable to take, tolerate or absorb oral or enteral medications
2. Known hypersensitivity to any of nirmatrelvir, ritonavir or its excipients
3. Receipt of a concomitant drug with a high-risk interaction with nirmatrelvir-ritonavir which cannot be ceased or substituted.

Will be excluded from receiving no antiviral agent if:

1. The patient is in the Immune Suppressed Stratum
2. The patient is receiving or has received supplemental oxygen on the calendar day of eligibility assessment.
3. The patient is considered by the treating clinician to be at very high risk for progression to severe COVID-19

Primary outcomes:
measure: A hierarchical ordinal scale that is a composite of mortality during the acute hospital admission and the duration of organ failure support while admitted to an ICU up until the end of study day 21.
timeFrame: Day 21
Secondary outcomes:
measure: Core Secondary Outcome: WHO 8-point ordinal outcome scale
timeFrame: Day 14
measure: Core Secondary Outcome: All-cause mortality
timeFrame: Day 28, 90 and 180
measure: Core Secondary Outcome: Days alive and free of hospital
timeFrame: Day 28
measure: Core Secondary Outcome: Days alive and free of supplemental oxygen, invasive or non-invasive ventilation
timeFrame: Day 28
measure: Core Secondary Outcome: Days alive and free of invasive or non-invasive ventilation or high flow oxygen
timeFrame: Day 28
measure: Core Secondary Outcome: Days alive and free of invasive mechanical ventilation
timeFrame: Day 28
measure: Core Secondary Outcome: Shortness of breath
timeFrame: Day 180
measure: Core Secondary Outcome: Quality of life
timeFrame: Day 180
measure: Core Secondary Outcome: Destination at time of hospital discharge
timeFrame: Up to day 90
measure: Core Secondary Outcome: Admission (or re-admission) to ICU
timeFrame: During the participant's index hospitalisation. Up to day 90.
measure: Core secondary outcome measures for participants admitted to ICU: ICU mortality
timeFrame: Up to day 90
measure: Core secondary outcome measures for participants admitted to ICU: ICU length of stay
timeFrame: Up to day 90
measure: Core secondary outcome measures for participants admitted to ICU: Ventilator-free days
timeFrame: Up to day 28
measure: Core secondary outcome measures for participants admitted to ICU: Organ failure free days
timeFrame: Up to day 28
measure: Antiviral II Domain Secondary Outcome: Length of hospital stay (in days)
timeFrame: During the participant's index hospitalisation. Censored 90 days after enrolment.
measure: Antiviral II Domain Secondary Outcome: Proportion of participants with baseline respiratory symptoms in whom all acute respiratory symptoms have resolved at study day 7
timeFrame: Day 7
Other outcomes:
Locations:
city: Blacktown
country: Australia
facility: Blacktown Hospital
state: New South Wales
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Hospital
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Wagga Wagga
country: Australia
facility: Wagga Wagga Base Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Wollongong
country: Australia
facility: Wollongong Hospital
state: New South Wales
city: Tiwi
country: Australia
facility: Royal Darwin Hospital
state: Northern Territory
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Ballarat Central
country: Australia
facility: Ballarat Health Services
state: Victoria
city: Box Hill
country: Australia
facility: Eastern Health (Box Hill Hospital)
state: Victoria
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Epping
country: Australia
facility: Northern Health
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: St Albans
country: Australia
facility: Western Health
state: Victoria
city: Warragul
country: Australia
facility: West Gippsland Hospital
state: Victoria
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
Study officials:
affiliation: Melbourne Health
name: Steven Tong, Prof
role: STUDY_CHAIR
References:
citation: Bassi A, Arfin S, Joshi R, Bathla N, Hammond NE, Rajbhandari D, Tirupakuzhi Vijayaraghavan BK, Venkatesh B, Jha V. Challenges in operationalising clinical trials in India during the COVID-19 pandemic. Lancet Glob Health. 2022 Mar;10(3):e317-e319. doi: 10.1016/S2214-109X(21)00546-5. Epub 2021 Dec 22. No abstract available.