Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE)

Lead Research Organisation: University of Oxford

Abstract

We do not yet have any treatments for COVID-19 patients, so we are now running a clinical trial to test out drugs which may work. Most COVID 19 cases are managed in the community and it is essential that we find treatments that help reduce hospital admission and speed recovery. The risk of complications from suspected COVID-19 infection is generally greater in people aged 50 years and older with underlying health conditions and in those aged 65 years and older. Therefore, we will ask these two groups to take part in our trial. The first drug we will evaluate is hydroxychloroquine, which is already used for other illnesses, but but it has not been tested in patients with suspected COVIS-19 in the community. Therefore, we do not yet know if hydroxychloroquine, (or any future treatments that we include in the trial), given to COVID-19 patients, will help reduce the need for hospitalisation or speed up recovery. All people initially included in the study will have a test for COVID-19, and will either receive usual best care, or usual best care plus the drug we are testing, currently hydroxychloroquine. We will include 3000 people in the study in the first instance.

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.

COVID-19 disproportionately affects people = 50 years old with comorbidities and those = 65 years old. No specific treatment has yet been proven in rigorous clinical trials to be effective against COVID-19. Most clinical trials are hospital-based. Yet, most cases are managed in the community, so interventions proven to be effective are urgently in primary care that prevent hospitalisation and speed recovery.

PRINCIPLE will be a Phase III, platform, response-adaptive, open-label randomised controlled trial in primary care. The platform trial will operate under a master protocol that allows the addition or replacement of further interventions.

Outcome data will be analysed as the trial is in progress: if evidence emerges that one arm is more effective, we might be able to allocate more people to that arm.

PRINCIPLE will, in the first instance, evaluate usual care plus hydroxychloroquine 200mg twice a day for 7 days. This drug is already in wide use, but not for this indication. The comparator will be usual care without a study drug.

Eligible patients will be aged =50-64 years with a defined comorbidity, and patients aged =65 with or without comorbidity presenting within 7 days since onset of symptoms with a new continuous cough and/or high temperature during time of prevalent COVID-19 infection.

Approximately 3000 eligible participants will need to be randomised in the first instance in order to determine whether the first drug we plan to evaluate is more effective than usual care alone in preventing hospital admission and/or death in people with suspected COVID-19.
 
Description Clinical alert to all NHS clinicians informed by findings from the PRINCIPLE Trial.
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
 
Description Platform Randomised trial of INterventions against COVID-19 In older peoPLE (PRINCIPLE)
Amount £17,706,579 (GBP)
Funding ID MC_PC_19079 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2020 
End 09/2021
 
Title Platform randomised open trial with response adaptive randomisation 
Description Principle is one of the first trials ever to use a platform trial design with responsive adaptive randomisation. This allows multiple interventions to be evaluated within the same trial. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? Yes  
Impact The Lancet paper describing azithromycin treatment for COVID-19 in the community describes the platform trial design. A protocol paper with further information is in press 
 
Description Working with NIHR Clinical Research Network 
Organisation National Institute for Health Research
Country United Kingdom 
Sector Public 
PI Contribution The NIHR Clinical Research Network as made an invaluable contributioon in recruiting participants into this national urgent public health trial seeking to identify interventions for use in the community against COVID-19
Collaborator Contribution We meet with the NIHRCRN national specialty group every two weeks. We meet with a core group also every two weeks. The regions in the CR can promote the research amongst primary care practitioners and help with awareness raising and, critically, recruitment
Impact Please see the paper in the Lancet describing the findings from the principal trial for azithromycin as a treatment for COVID-19. Findings from the principal trial featured in a NIHR clinical alert to all clinicians in the NHS
Start Year 2020
 
Title Chief investigator of the PRINCIPLE Trial 
Description The principal trial has evaluated azithromycin, and doxycycline. It currently has colchicine and inhaled budesonide in the trial 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2020
Development Status Closed
Clinical Trial? Yes
Impact The PRINCIPLE Trial has shown that he is through Meissen and doxycycline are not useful treatments for COVID-19 in the community. This information informed a clinical alert to all NHS clinicians, and is therefore influencing practice and has enhanced the evidence base for the primary care management of the pandemic. 
 
Description European Respiratory Society Congress 2020 virtual talk. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The Principal trial was presented and there was great interest in the innovative research methods and progress of the trial: it seems to be the only successful currently active platform randomise control trial in primary care for COVID-19 treatment in the community
Year(s) Of Engagement Activity 2020
 
Description European Respiratory Society Congress presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I presented the design of the principal trial and progress to date at the European Respiratory Society conference as part of a panel, and it was well attended with several questions are
Year(s) Of Engagement Activity 2020