R15 - The Platform Randomised trial of INterventions against COVID-19 in older peoPLE (PRINCIPLE) trial

This Data Sharing Agreement permits the retention and processing of the data provided under a previous iteration of this Agreement. No new data will be disseminated under this Agreement.

University of Oxford are running the Platform Randomised trial of INterventions against COVID-19 In older people (PRINCIPLE) Trial.

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 in the UK and internationally. So far, there are no specific treatments for COVID-19 that have been proven in rigorous clinical trials to be effective. Most cases are being managed in the community. It is essential that we urgently identify interventions that may favourably modify progression of the infection. An ideal intervention would be 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.

Setting up a bespoke randomised controlled trial for each potential intervention that might become available will be inefficient. The University of Oxford therefore propose establishing a platform, randomised controlled trial in primary care that can be rapidly deployed to evaluate low risk interventions for high risk people. Using an efficient open clinical trial design, with procedures embedded in existing health service structures and capabilities as afar as possible, 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 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 the trial is already in progress, should such suitable interventions become available for this kind of evaluation.(5) This means that a new trial does not need to be started afresh each time an additional suitable intervention becomes available, and it also means that existing controls can be used efficiently to give rapid answers about the effectiveness of new interventions. This is particularly important as new candidate interventions are being considered on a regular basis.

In order to carry out these studies, the personal data (which includes special categories of data) will be processed, in accordance with the General Data Protection Act 2016 Article 6 (1) (e) - processing is necessary for the performance of a task carried out in the public interest - and Article 9 (2) (j) - processing is necessary for archiving purposes in the public interest, scientific or historical research purposes.

The University of Oxford’s primary purpose is the advancement of education and research which are deemed to deliver a public benefit. All research is conducted in accordance with the University’s Code of Practice for Research. The results from studies utilising this data will benefit health and social care and therefore the use of this data in this way is considered to be in the public interest.

The trial will be implemented in the first instance by the Oxford Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) general practices. This is one of Europe's oldest sentinel systems. RCGP RSC has produced a weekly report of influenza, respiratory and other infections in primary care for over 50 years. RCGP RSC works closely with Public Health England (PHE). More information at: www.rcgp.org.uk/rsc. The RCGP RSC Network has over 500 practices, including 100 practices currently swabbing patients with suspected COVID-19 in partnership with Public Health England (PHE).

Trial aspects will be managed by the UK Clinical Research Collaboration Registered University of Oxford Primary Care and Vaccines Clinical Trials Unit.

The trail participants will be consented into the trial and will be made up of Patients ≥50-64 years with comorbidities, and 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 infections. Recruitment has commenced and at the time of writing approx. 1500 patients are enrolled. A sperate agreement is in place with NHS Digital to aid and boost recruitment of individuals into the trial.

Primary objective of PRINCIPLE - To assess effectiveness of trial treatments in reducing the need for hospital admission or death, for patients aged ≥50 years with comorbidity, and aged ≥65 with or without comorbidity and suspected COVID-19 infection during time of prevalent COVID-19 infections.

Primary objective outcome measures: Hospital admission or mortality related to suspected COVID-19.

Secondary objectives - To explore whether trial treatment reduces

1) Duration of severe symptoms

2) Time taken to self-report recovery

3) Contacts with the health services

4) Consumption of antibiotics

5) Hospital assessment without admission

6) Oxygen administration

7) Intensive Care Unit admission

8) Mechanical ventilation

9) To determine if effects are specific to those with the infections syndrome but who test positive for COVID-19

10) Duration of hospital admission

Secondary objective outcome measures:

1-2 Patient report on day they feel to have recovered (Daily online symptoms score. Telephone call or text day 7, 14 and 28 if data not being received online).

3. Contacts with health services reported by patients and captured by reports of patients linked medical records where the practice is a member of RSC (GP notes review through RCGP RSC network after 28 days and linkages to HES/ECDS/SUS/CHESS)

4. Bi-weekly reports from participants primary care medical records (RSC)

5-8 and 10 patient report/carer report/linked medical records from primary care and hospital care (HES/SUS/MORTALITY/CHESS/RSC data linkage after 28 days where patients have been assessed in hospital)

9. Swab results for COVID-19 will indicate an “Intention to Treat Infected” group within the overall cohort for sub analysis from national laboratory infrastructure (RSC/SGSS)

Organisations Involved:

The University of Oxford are the sole data controller for this request.

Public Health England (PHE):

For the purposes of the PRINCIPLE trial PHE do not hold any data controllership responsibilities. However members of the statistical team are based at PHE working under the direction of the data controller and are therefore lusted as data processors.

PHE staff will only see generic variables related to specific Health Protection needs. E.g. PHE combine GP record and other records of a positive COVID-19 case; hospital admissions plausibly due to COVID; ditto for ICU, and death.

Royal College of General Practitioners (RCGP):

For the purpose of the PRINCIPLE trial RCGP are not a data controller. The RCGP are joint data controllers for the RCGP RSC collected data which is being linked to the cohort data. The RCGP play no role in determining the means by which or the purpose for which the data will be processed for the PRINCIPLE trial.

The University of Surrey:

The RCGP Research Surveillance Centre (RCGP RSC) was based at the University of Surrey but has transferred to the University of Oxford. The RCGP RSC is a growing network of over 1200 GP surgeries based in England.

An existing secure network at the University of Oxford houses the RCGP RSC data. This data collection is known as (ORCHID secure).

The trial participants data will be linked with the RCGP RSC Database . The RCGP RSC dataset includes individual patient level up-to-date primary and secondary care data which can be easily queried. Primary care/general practice data is rich in terms of diagnosis and information about the process of care. For example, the database contains the following variables for each patient (where present):

• Detailed demographic and risk factor data.

• COVID-19 appointments: including information on whether or not a virology swab was taken and the outcome of the swab

• Non-COVID-19 appointments.

• Detailed data for the 32 conditions monitored by RCGP RSC on behalf of PHE

• Vaccination status: date of vaccination, type of vaccination

• Co-morbid conditions

• Medication which may be associated with better or adverse outcomes.

• Test results

• Referrals made

• A & E visits

• Inpatient appointments, including critical care

• Outpatient appointments

• Mortality data (if applicable).

Participants who have consented to the PRINCIPLE Trial will have their data initially linked with the primary care data which is already held as part of the Royal College of General Practitioners (RCGP RSC) Research and Surveillance Network database.

• The University of Surrey, on behalf of the University of Oxford for the PRINCIPLE trial, provided NHS Digital with a list of NHS numbers and date of births along with a unique Study ID for the PRINCIPLE cohort..

• NHS Digital sent back to University of Surrey the linked cohort data with SUS/CHESS and Mortality data included.

• The data has been transferred from the University of Surrey to the University of Oxford. The University of Surrey has no further part in the processing of data under this Agreement.

The general practices in the RCGP RSC take virology swabs and serology samples to know if someone has a COVID-19 or a range of other infections, including influenza. These results are being passed back to the patients GP for their clinical care. However, a pseudonymised copy will go to the RCGP RSC. The COVID-19 status will be shared with the PRINCIPLE trial team (who also pseudonymise NHS number to allow this linkage).

NHS Digital data being accessed by a statistician in the USA will be aggregated with small numbers suppressed. All record level data will be held and stored within England and Wales.

Specific outputs for this trial are:

PRINCIPLE will publish the results of each CTIMP investigated in open-access journals with summary reports made publicly available through the study website (https://www.principletrial.org/).

PRINCIPLE will work with patient and public representatives to ensure that such reports are communicated in an appropriate manner for a lay audience. The Investigators will be involved in reviewing drafts of the manuscripts, abstracts, press releases and any other publications arising from the study. Authors will acknowledge that the study was funded by UKRI/NIHR and any other funding that is secured. Authorship will be determined in accordance with the ICMJE guidelines and other contributors will be acknowledged. All outputs are expected to be submitted by the end of 2022.

Guidance how to manage cases of COVID-19 on presentation to primary care or other community services will be produced.

There is an urgent need to report the data from the >1,500 patients who have joined the trial. The results may have immediate impact on management of suspected COVID-19 infection and this study rightly has urgent public health status.

The extracted data will identify whether there is undetected community transmission of COVID-19. For cases of COVID-19 PRINCIPLE will report the effectiveness of different treatments given early in the disease on health outcomes. For cases of COVID-19 the associations between demographics, comorbidity and medications on the likelihood of developing COVID-19 and subsequent complications (e.g. hospitalisation, admission to an intensive care unit, death).

For PRINCIPLE linked data allows the primary and secondary objectives of the trial to be achieved as detailed in the previous "objective" section. It also allows validation and enhancement of sociodemographic and comorbidity data for PRINCIPLE participants.

PRINCIPLE provide twice weekly reports which are incorporated into the PHE disease monitoring and help shape national policy. Unique is PRINCIPLE'S provision of samples (for virology wider analysis that just COVID) and serology blood samples for population immunity.