COVID-19: multi-arm, multi stage adaptive clinical trial (CoV-MAMS)
Lead Research Organisation:
University of Oxford
Department Name: UNLISTED
Abstract
The coronavirus epidemic is a global health emergency. The infection can, in a minority of cases, cause serious lung disease requiring hospital-care and even death. Whilst general hospital care can improve patients’ recovery, there are currently no specific medicines for this infection. The best way to prove that medicines are effective and safe is through clinical trials which compare the new medicine against normal care.
Clinical trials of two of the most promising medicines have already enrolled patients in China. There are, however, many other medicines that have been proposed for the treatment of patients with the novel coronavirus.
We will start a new trial in the UK to test up to four additional medicines. Patients hospitalised with confirmed coronavirus infection will be invited to join the trial and we will assess whether the new medicines are safe and can improve patients’ recovery.
We will use a flexible design that allows us to add new medicines as they become available. The trial will start by testing two medicine, a drug that may slow down the replication of the virus and a drug that may reduce the inflammation associated with the infection. Other medicines will be added when they become available.
Clinical trials of two of the most promising medicines have already enrolled patients in China. There are, however, many other medicines that have been proposed for the treatment of patients with the novel coronavirus.
We will start a new trial in the UK to test up to four additional medicines. Patients hospitalised with confirmed coronavirus infection will be invited to join the trial and we will assess whether the new medicines are safe and can improve patients’ recovery.
We will use a flexible design that allows us to add new medicines as they become available. The trial will start by testing two medicine, a drug that may slow down the replication of the virus and a drug that may reduce the inflammation associated with the infection. Other medicines will be added when they become available.
Technical Summary
This COVID-19 Rapid Response award is jointly funded (50:50) between the Medical Research Council and the National Institute for Health Research. The figure displayed is the total award amount of the two funders combined, with each partner contributing equally towards the project.
Medicines to prevent and effectively treat 2019 coronavirus disease (COVID-19), especially severe lower respiratory tract (LRT) illness, would save lives and reduce healthcare pressures. Randomised controlled trials (RCTs) are ongoing in China of lopinavir/ritonavir [ChiCTR2000029308] and remdesivir [NCT04257656 and NCT04252664]. Additional potential therapeutics are being considered by the WHO. Building on our existing experience and capabilities, we are proposing to implement a multi-arm, multi-stage (MAMS) RCT. This trial will be designed to evaluate up to four experimental therapeutics in a flexible, adaptive framework. MAMS designs have been shown to be more efficient than sequential RCTs or factorial designs.
The trial will enrol patients hospitalised with laboratory confirmed COVID-19. Patients will initially be randomised equally to receive one of up to 4 active treatments or control. Should not all active arms be available at study onset, patients will be randomized between available active arms and control. The trial will commence with two active arms, lopinavir/ritonavir and low dose dexamethasone. Additional active arms will be added as data and drug availability allow.
Medicines to prevent and effectively treat 2019 coronavirus disease (COVID-19), especially severe lower respiratory tract (LRT) illness, would save lives and reduce healthcare pressures. Randomised controlled trials (RCTs) are ongoing in China of lopinavir/ritonavir [ChiCTR2000029308] and remdesivir [NCT04257656 and NCT04252664]. Additional potential therapeutics are being considered by the WHO. Building on our existing experience and capabilities, we are proposing to implement a multi-arm, multi-stage (MAMS) RCT. This trial will be designed to evaluate up to four experimental therapeutics in a flexible, adaptive framework. MAMS designs have been shown to be more efficient than sequential RCTs or factorial designs.
The trial will enrol patients hospitalised with laboratory confirmed COVID-19. Patients will initially be randomised equally to receive one of up to 4 active treatments or control. Should not all active arms be available at study onset, patients will be randomized between available active arms and control. The trial will commence with two active arms, lopinavir/ritonavir and low dose dexamethasone. Additional active arms will be added as data and drug availability allow.
Organisations
People |
ORCID iD |
Peter Horby (Principal Investigator) | |
Martin Landray (Co-Investigator) |
Publications
Vousden N
(2023)
Facilitating participation in clinical trials during pregnancy.
in BMJ (Clinical research ed.)
Boffito M
(2021)
Toward Consensus on Correct Interpretation of Protein Binding in Plasma and Other Biological Matrices for COVID-19 Therapeutic Development.
in Clinical pharmacology and therapeutics
Horby PW
(2020)
Hydroxychloroquine for COVID-19: Balancing contrasting claims.
in European journal of internal medicine
Xu J
(2020)
Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis.
in Frontiers of medicine
WHO Rapid Evidence Appraisal For COVID-19 Therapies (REACT) Working Group
(2020)
Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis.
in JAMA
Wang C
(2020)
A novel coronavirus outbreak of global health concern.
in Lancet (London, England)
RECOVERY Collaborative Group
(2022)
Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
in Lancet (London, England)
RECOVERY Collaborative Group
(2021)
Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
in Lancet (London, England)
RECOVERY Collaborative Group
(2022)
Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.
in Lancet (London, England)
Wang Y
(2020)
Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.
in Lancet (London, England)
Description | Changed global treatment for COVID-19 |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Implementation circular/rapid advice/letter to e.g. Ministry of Health |
Impact | Clinical treatment guidelines for hopitalised COVID-19 patients have been updated in multiple countries as a result of the RECOVERY trial. Results include - no effect of lopinavir/ritonavir, hydroxychloroquine, azithromycin, convalescent plasma, colchicine - benefit of dexamethasone, tocilizumab Guidance has been updated by the World Health Organisation, UK NHS, US National Institutes of Health, European Medicines Agency and many others. |
URL | https://www.covid19treatmentguidelines.nih.gov/therapeutic-management/ |
Description | RECOVERY - India: STRENGTHENING UK - INDIA CLINICAL TRIALS |
Amount | £634,289 (GBP) |
Funding ID | 204765-112 |
Organisation | Foreign Commonwealth and Development Office (FCDO) |
Sector | Public |
Country | United Kingdom |
Start | 08/2021 |
End | 07/2023 |
Description | RECOVERY/Phase 2 Therapeutic Trials Reconfiguration |
Amount | £17,999,777 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 12/2020 |
End | 11/2022 |
Description | Wellcome Therapeutics Accelerator grant, 'RECOVERY International' |
Amount | £3,665,372 (GBP) |
Funding ID | 222406/Z/21/Z |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2020 |
End | 05/2023 |
Title | Dexamethasone |
Description | Corticosteroids now standard of care globally for hospitalised COVID-19 patients who require respiratory support. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Wide-scale adoption |
Year Development Stage Completed | 2020 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Estimated to have saved approximately 650,000 (240,000 - 1,400,000) lives globally between July and December 2020. See: Potential health and economic impacts of dexamethasone treatment for patients with COVID-19. Águas R, Mahdi A, Shretta R, Horby P, Landray M, White L; CoMo Consortium. Nat Commun. 2021 Feb 10;12(1):915. |
URL | https://www.who.int/news-room/feature-stories/detail/who-updates-clinical-care-guidance-with-cortico... |
Title | Tocilizumab |
Description | Tocilizumab 400 mg to 800 mg (depending on weight) given intravenously for hospitalised COVID-19 patients with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein =75 mg/L). Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76-0·95; p=0·0028). Consistent results were seen in all pre-specifiedsubgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital alive within 28 days (57% vs. 50%; rate ratio 1·22; 95% CI 1·12-1·33; p<0·0001). In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the level of respiratory support and were additional to the benefits of systemic corticosteroids. |
Type | Therapeutic Intervention - Drug |
Current Stage Of Development | Wide-scale adoption |
Year Development Stage Completed | 2021 |
Development Status | Under active development/distribution |
Clinical Trial? | Yes |
Impact | Adopted into routine care in UK, U.S and elsewhere. |
URL | https://www.sps.nhs.uk/articles/summary-of-covid-19-medicines-guidance-critical-care/ |
Description | RECOVERY Trials - Patient and Public Involvement and Engagement |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | • Review of Patient Information Sheets - 6 NDPH public advisory panel members reviewed • Review of consent form - as above • Review of animation storyboard - 4 members of NDPH public advisory panel • Provision of public-facing website information including short videos on trial treatments/results • Review of newsletters to participants/parents and carers of child participants - 11 people reviewed and the newsletters were revised considerably as a result, splitting out the most scientific detail into a separate section. • Initiation of a new process with NHS Digital to enable mailing to participants (test case for the NHS DigiTrials Communications Service) • Media outreach including liaison with participants for case studies/media interviews, 16,100 items of coverage to date • Social media activity (>19,000 uses of #RECOVERYtrial in 2020) • Development of case studies, eg for Understanding Patient Data • Public-facing webinar with NIHR (participant, husband and clinician in discussion) • Swindon Science Festival materials (ML panel event, and online 'Anatomy of clinical trials' resource for schools) • 'One year on' event being planned for April • In process of setting up a public advisory panel • To co-opt public members to the TSC once the panel is in place |
Year(s) Of Engagement Activity | 2020,2021 |
URL | https://www.recoverytrial.net |