Dataset Information

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

ABSTRACT:

Background

SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials.

Methods

ASCOT ADAPT is an international, investigator-initiated, adaptive platform, randomised controlled trial of therapeutics for non-critically ill patients hospitalised with COVID-19. The study design is open label and pragmatic. Potential participants are hospitalised adults with PCR confirmed, symptomatic, SARS-CoV-2 infection, within 14 days of symptom onset. Domains include antiviral, antibody and anticoagulant interventions, with a composite primary outcome of 28-day mortality or progression to intensive-care level respiratory or haemodynamic support. Initial interventions include intravenous nafamostat and variable dose anticoagulation. A range of secondary endpoints, and substudies for specific domains and interventions are outlined.

Discussion

This paper presents the trial protocol and management structure, including international governance, remote site monitoring and biobanking activities and provides commentary on ethical and pragmatic considerations in establishing the ASCOT ADAPT trial under pandemic conditions.

Trial registration

Australian and New Zealand Clinical Trials Registry (ACTRN12620000445976) and ClinicalTrials.gov (NCT04483960).

SUBMITTER: Denholm JT

PROVIDER: S-EPMC9747535 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Publications

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

Denholm Justin T JT Venkatesh Balasubramanian B Davis Joshua J Bowen Asha C AC Hammond Naomi E NE Jha Vivekanand V McPhee Grace G McQuilten Zoe Z O'Sullivan Matthew V N MVN Paterson David D Price David D Rees Megan M Roberts Jason J Jones Mark M Totterdell James J Snelling Thomas T Trask Nanette N Morpeth Susan S Tong Steven Yc SY

Trials 20221214 1

<h4>Background</h4>SARS-CoV-2 infection is associated with a significant risk of hospitalisation, death, and prolonged impact on quality of life. Evaluation of new treatment options and optimising therapeutic management of people hospitalised with SARS-CoV-2 infection remains essential, but rapid changes in pandemic conditions and potential therapies have limited the utility of traditional approaches to randomised controlled trials.<h4>Methods</h4>ASCOT ADAPT is an international, investigator-in ...[more]

PMID: 36514143

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Project description:IntroductionTo find effective and safe treatments for COVID-19, the WHO recommended to systemically evaluate experimental therapeutics in collaborative randomised clinical trials. As COVID-19 was spreading in Europe, the French national institute for Health and Medical Research (Inserm) established a transdisciplinary team to develop a multi-arm randomised controlled trial named DisCoVeRy. The objective of the trial is to evaluate the clinical efficacy and safety of different investigational re-purposed therapeutics relative to Standard of Care (SoC) in patients hospitalised with COVID-19.Methods and analysisDisCoVeRy is a phase III, open-label, adaptive, controlled, multicentre clinical trial in which hospitalised patients with COVID-19 in need of oxygen therapy are randomised between five arms: (1) a control group managed with SoC and four therapeutic arms with re-purposed antiviral agents: (2) remdesivir + SoC, (3) lopinavir/ritonavir + SoC, (4) lopinavir/ritonavir associated with interferon (IFN)-β-1a + SoC and (5) hydroxychloroquine + SoC. The primary endpoint is the clinical status at Day 15 on the 7-point ordinal scale of the WHO Master Protocol (V.3.0, 3 March 2020). This trial involves patients hospitalised in conventional departments or intensive care units both from academic or non-academic hospitals throughout Europe. A sample size of 3100 patients (620 patients per arm) is targeted. This trial has begun on 22 March 2020. Since 5 April 2020, DisCoVeRy has been an add-on trial of the Solidarity consortium of trials conducted by the WHO in Europe and worldwide. On 8 June 2020, 754 patients have been included.Ethics and disseminationInserm is the sponsor of DisCoVeRy. Ethical approval has been obtained from the institutional review board on 13 March 2020 (20.03.06.51744) and from the French National Agency for Medicines and Health Products (ANSM) on 9 March 2020. Results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT04315948 Eudra-CT 2020-000936-23.

Project description:AimTo inform the oversight of future clinical trials during a pandemic, we summarise the experiences of the Data Monitoring Committee (DMC) for the Randomised Evaluation of COVID therapy trial (RECOVERY), a large-scale randomised adaptive platform clinical trial of treatments for hospitalised patients with COVID-19.Methods and findingsDuring the first 24 months of the trial (March 2020 to February 2022), the DMC oversaw accumulating data for 14 treatments in adults (plus 10 in children) involving > 45,000 randomised patients. Five trial aspects key for the DMC in performing its role were: a large committee of members, including some with extensive DMC experience and others who had broad clinical expertise; clear strategic planning, communication, and responsiveness by the trial principal investigators; data collection and analysis systems able to cope with phases of very rapid recruitment and link to electronic health records; an ability to work constructively with regulators (and other DMCs) to address emerging concerns without the need to release unblinded mortality results; and the use of videoconferencing systems that enabled national and international members to meet at short notice and from home during the pandemic when physical meetings were impossible. Challenges included that the first four treatments introduced were effectively 'competing' for patients (increasing pressure to make rapid decisions on each one); balancing the global health imperative to report on findings with the need to maintain confidentiality until the results were sufficiently certain to appropriately inform treatment decisions; and reliably assessing safety, especially for newer agents introduced after the initial wave and in the small numbers of pregnant women and children included. We present a series of case vignettes to illustrate some of the issues and the DMC decision-making related to hydroxychloroquine, dexamethasone, casirivimab + imdevimab, and tocilizumab.ConclusionsRECOVERY's streamlined adaptive platform design, linked to hospital-level and population-level health data, enabled the rapid and reliable assessment of multiple treatments for hospitalised patients with COVID-19. The later introduction of factorial assessments increased the trial's efficiency, without compromising the DMC's ability to assess safety and efficacy. Requests for the release of unblinded primary outcome data to regulators at points when data were not mature required significant efforts in communication with the regulators by the DMC to avoid inappropriate early trial termination.

Project description:BackgroundLong-term-specific sequelae or persistent symptoms (SPS) after hospitalisation due to COVID-19 are not known. The aim of this study was to explore the presence of SPS 12 months after discharge in survivors hospitalised due to COVID-19 and compare it with survivors hospitalised due to other causes.MethodsProspective cohort study, the Andalusian Cohort of Hospitalised patients for COVID-19 (ANCOHVID study), conducted in 4 hospitals and 29 primary care centres in Andalusia, Spain. The sample was composed of 906 adult patients; 453 patients hospitalised due to COVID-19 (exposed) and 453 hospitalised due to other causes (non-exposed) from March 1 to April 15, 2020, and discharged alive. The main outcomes were (1) the prevalence of SPS at 12 months after discharge and (2) the incidence of SPS after discharge. Outcome data at 12 months were compared between the exposed and non-exposed cohorts. Risk ratios were calculated, and bivariate analyses were performed.ResultsA total of 163 (36.1%) and 160 (35.3%) patients of the exposed and non-exposed cohorts, respectively, showed at least one SPS at 12 months after discharge. The SPS with higher prevalence in the subgroup of patients hospitalised due to COVID-19 12 months after discharge were persistent pharyngeal symptoms (p<0.001), neurological SPS (p=0.049), confusion or memory loss (p=0.043), thrombotic events (p=0.025) and anxiety (p=0.046). The incidence of SPS was higher for the exposed cohort regarding pharyngeal symptoms (risk ratio, 8.00; 95% CI, 1.85 to 36.12), confusion or memory loss (risk ratio, 3.50; 95% CI, 1.16 to 10.55) and anxiety symptoms (risk ratio, 2.36; 95% CI, 1.28 to 4.34).ConclusionsThere was a similar frequency of long-term SPS after discharge at 12 months, regardless of the cause of admission (COVID-19 or other causes). Nevertheless, some symptoms that were found to be more associated with COVID-19, such as memory loss or anxiety, merit further investigation. These results should guide future follow-up of COVID-19 patients after hospital discharge.

Dataset Information

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

Background

Methods

Discussion

Trial registration

Publications

ASCOT ADAPT study of COVID-19 therapeutics in hospitalised patients: an international multicentre adaptive platform trial.

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