PRINCIPLE [COVID-19] [UPH]
Research type
Research Study
Full title
Platform Randomised trIal of treatmeNts in the Community for epIdemic and Pandemic iLlnEsses
IRAS ID
281958
Contact name
Christopher Butler
Contact email
Sponsor organisation
University of Oxford / Clinical Trials and Research Governance
Eudract number
2020-001209-22
ISRCTN Number
ISRCTN86534580
Duration of Study in the UK
2 years, 0 months, 1 days
Research summary
COVID-19 disproportionately affects people over 50 years old with comorbidities and those over 65 years old. The infection causes considerable morbidity and mortality in this population group in particular, and is having a devastating effect on people's health and society internationally. So far, there are no treatments for COVID-19 that have been proven in rigorous clinical trials to be effective. It is essential to identify interventions that may favourably modify progression of the infection. An ideal intervention would one that is safe, with few side-effects, helps prevent disease progression, and can be administered in the community using existing NHS processes and capability.
We propose establishing a platform randomised controlled trial in primary care that can be rapidly deployed to evaluate low risk interventions for high risk people. In the first instance this platform will evaluate a drug called hydroxychloroquine. This is a drug that is already available within the NHS but that has not been subject to randomised controlled trials for this indication in Europe or in community healthcare settings with the aim of reducing the need for hospital assessment. Using a simple, streamlined open trial design, with procedures embedded in existing health service structures and capabilities, our trial aims to give a rapid answer about the effectiveness of trial treatments in modifying the disease course. The goal is to prevent disease progression such that affected individuals will recover sooner, but critically, avoid the need for hospital assessment and admission. The platform trial will be flexible in that it will operate under a master protocol that will allow the addition of further interventions into the trial while it is in progress, should such suitable interventions become available.
The trial will be implemented in the first instance by the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) general practices.
SUMMARY OF RESULTS
The PRINCIPLE Trial was a large response-adaptive, platform, randomised, open-label clinical trial based in the UK investigating repurposed medications for the Treatment of COVID-19 in the community. This trial design allowed for several treatments to be included in the study at the same time and for more to be added even once the trial was under way to achieve faster time to results and improve efficiency, thus improving the evidence supporting care during the COVID-19 Pandemic. The PRINCIPLE trial recruited 11,768 participants in total and tested seven different potential treatments for COVID-19 compared to standard NHS care in reducing recovery time and hospital admissions. PRINCIPLE produced the first, robust evidence from primary care that:
The antibiotics Azithromycin (The Lancet, March 4 2021. DOI: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fdoi.org%252F10.1016%252FS0140-6736&data=05%7C02%7Cberkshire.rec%40hra.nhs.uk%7C641edf24887f4dbacd8508dca4c3753f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638566406598114105%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=7qBRM9Vw18Awr3%2B8EGYLuHBuOPmgD%2BHLClvCdFNLMNY%3D&reserved=0(21)00461-X)/NBTI/Qay2AQ/AQ/f95f27df-c46c-4f82-89bb-d1317c5d7fdd/2/RoNFfMGaor and doxycycline (Lancet Respir Med , July 27 2021. DOI: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fdoi.org%252F10.1016%252F%2FNBTI%2FQay2AQ%2FAQ%2Ff95f27df-c46c-4f82-89bb-d1317c5d7fdd%2F3%2FfjubGTycI3&data=05%7C02%7Cberkshire.rec%40hra.nhs.uk%7C641edf24887f4dbacd8508dca4c3753f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638566406598123621%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=Vnelf0JMtmb9ggJj8b1%2FdV1QxOLBfVnT4vD%2BREGIAao%3D&reserved=0 S2213-2600(21)00310-6) did not work for COVID-19. These findings have made a considerable contribution to antimicrobial stewardship as well as enhancing the evidence base for care of COVID in the community.
Inhaled budesonide a cheap, safe inhaled steroid used for asthma) treatment helped people recover faster and had a high probability of reducing the need for hospital care. The Lancet, August 10, 2021: DOI: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fdoi.org%252F10.1016%252FS0140-6736&data=05%7C02%7Cberkshire.rec%40hra.nhs.uk%7C641edf24887f4dbacd8508dca4c3753f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638566406598131602%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=9qed1I%2F5A5IK50GrhqBLnJ9QwxR6uWtS%2B7jKknQmRcU%3D&reserved=0(21)01744-X/NBTI/Qay2AQ/AQ/f95f27df-c46c-4f82-89bb-d1317c5d7fdd/4/ZMhyB_9FhR
The anti-inflammatory colchicine does not help people with COVID recover any quicker. MedRxiv, September 23 2021. DOI: https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fclick.pstmrk.it%2F3ts%2Fdoi.org%252F10.1101%252F2021.09.20.21263828%2FNBTI%2FQay2AQ%2FAQ%2Ff95f27df-c46c-4f82-89bb-d1317c5d7fdd%2F5%2FgmiF0gQz0u&data=05%7C02%7Cberkshire.rec%40hra.nhs.uk%7C641edf24887f4dbacd8508dca4c3753f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638566406598139002%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=ByrrfBk%2B3vcVaWkqa%2B1BneK4NJA0v%2B0%2BKVY5Avzofpg%3D&reserved=0
Ivermectin, an anti-parasitic drug, 19 is unlikely to provide clinically meaningful improvement in recovery, hospital admissions, or longer-term outcomes. Further trials of ivermectin for SARS-Cov-2 infection in vaccinated community populations appear unwarranted. The Journal of Infection, March, 2024: DOI:https://gbr01.safelinks.protection.outlook.com/?url=https%3A%2F%2Fdoi.org%2F10.1016%2Fj.jinf.2024.106130&data=05%7C02%7Cberkshire.rec%40hra.nhs.uk%7C641edf24887f4dbacd8508dca4c3753f%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638566406598147067%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C0%7C%7C%7C&sdata=MJvqIXFx07IfNbgzd%2FPm0orj4pO%2BTJNZkDShYYkkGN8%3D&reserved=0
We currently have the results for two further medicines (hydroxychloroquine and Favipiravir) under consideration with journals:
The antimalarial hydroxychloroquine arm was closed early due to external factors: nevertheless, the data were able to analyse revealed no evidence of meaningful benefit from this treatment for COVID-19. The paper describing the results have been submitted to the British Journal of General Practice in June 2024.
Favipiravir, an anti-viral drug, moderately shortened recovery time at home but did not reduce hospital admissions or death outcomes in a largely vaccinated population, and effects in the longer term were also modest. The paper was submitted to Journal of Infection in April 2024.REC name
South Central - Berkshire Research Ethics Committee
REC reference
20/SC/0158
Date of REC Opinion
24 Mar 2020
REC opinion
Favourable Opinion