COVID-19 has presented many unique challenges to the health sector, one of which is the need for the rapid design and delivery of therapeutic clinical trials. From the outset of the pandemic, it was evident that traditional methods of patient recruitment were not going to be sufficient to deliver the insights needed to respond to COVID-19.
The PRINCIPLE trial was created in March 2020 as an urgent public health UK-wide national priority platform to discover COVID-19 treatments for the over 50-year-olds at high risk of complications, which could be taken at home quickly and therefore prevent them needing to go to hospital – providing clear benefits of reducing the burden on the NHS at a time when is under severe pressure; and allowing patients to be treated and recover at home.
The concept was to evaluate whether existing medicines could be used or repurposed to treat COVID-19. PRINCIPLE is a ‘platform trial’ – it allows for several treatments to be evaluated at the same time, and for more people in the trial to receive the most effective treatment.
By early October 2020 the trial had registered 1,630 eligible participants; with several barriers impacting the ability to recruit more people due to the nature of the pandemic itself. It was therefore apparent that standard methods of patient recruitment were failing to meet the required pace and scale of enrolment.
Establish a multi-disciplinary partnership team of experts to work at pace
Convened by the UK National Core Studies Programmes, a multi-disciplinary team was established to solve the technical, ethical and logistical requirements to develop a new approach to use near-real time data to recruit clinical trial participants.
The initiative was a partnership between the PRINCIPLE investigators and coordinating centre at the University of Oxford, the UK National Core Studies Programmes (Therapeutics; Data and Connectivity), the NHS Digital Information Governance Team, the Information Commissioner’s Office, NHS Test and Trace, the NHS DigiTrials Health Data Research Hub, the Department of Health and Social Care (DHSC), and the HDR UK Public & Patient Involvement and Engagement Team.
Utilise and link existing infrastructure to establish near real-time flows from large datasets
First it was determined whether it was feasible for positive test results to be received by the trial team within 24-48 hours of the recipient receiving the result (any longer would reduce the likelihood of the participant being suitable for the trial as they may have deteriorated or be approaching recovery by then). The NHS DigiTrials team mapped the data flow and timing from the NHS Test and Trace App from the point of test receipt to the time the data was received within NHS Digital.
As the test result data needed to be sent to PRINCIPLE as identifiable data to verify eligibility and contact eligible candidates, the team worked with The Information Commissioner’s Office (ICO) and NHS Digital Information Governance teams to ensure that the process adhered to the relevant privacy, data sharing and ethical guidelines.
PRINCIPLE was given unique access to the Summary Care Record (SCR), to ensure safe prescribing to participants who presented to the trial team. This enabled the team to effectively and efficiently verify the information provided by the individual and to ensure safe prescribing of trial medication.
Proactively engage with public and potential participants
In parallel, a survey with 92 members of the public (from HDR UK’s patient and public panels and networks) was developed to understand public perceptions of the proposed approach – 97% of respondents believed this would be an ethical use of data and assuming all concerns were addressed.
Survey respondents were also provided the following scenario for context:
A UK Wide National Priority Clinical Trial, endorsed by all UK Chief Medical Officers, being run by the University of Oxford, is exploring a possible treatment for COVID-19 in the community, and is looking for participants to join within 24-48 hours of receiving a positive COVID-19 test. In particular, they are looking for people 50 years and over to join this clinical trial.
The engagement revealed that 68% of those asked would be comfortable or very comfortable with their test result and contact information being passed to researchers so that they could be invited to participate in a clinical trial into treatments for COVID-19.
Each of the issues raised through the governance and the patient and public survey was reviewed and addressed in the design of the data release and recruitment approach.
Test and adapt the approach, while also consulting patients
Once the data flows were tested, from 13 November 2020, the PRINCIPLE Trial received contact data on 200 people per day aged 50 years plus with positive test results. Using this approach, the PRINCIPLE team was able to contact eligible candidates by phone and signpost them to the trial.
The majority of the 50 years plus age range did not meet the trial criteria as they did not have the required co-morbidities, so the age range was changed to 65-75 years on 24th November. From the 29 November, participants were also offered support during the recruitment call.
From 26 November PRINCIPLE began to receive 300 contacts a day aged 65-75 years from NHS Digital and from 4 December PRINCIPLE received 400 contacts a day.
The tested approach was rolled out with tracked measures of efficiency and patients were asked to provide comments on their experience of the approach.
The work undertaken to support the PRINCIPLE Trial has demonstrated a new way of enhancing early recruitment to a clinical trial in a community setting, via access to SARS-COV-2 test result data and the use of SCR data to ensure efficient and safe prescribing. Potential treatments could therefore be initiated earlier in suitable patients who consented, also shortening the time to results.
Prior to establishing this new data service, the PRINCIPLE trial was registering on average 87 people per week. The number of people registered over the period from 16 November to 20 December increased from 3,080 to 4,092. The registration rate increased from up to 208 people per week to 325 people per week. By 31 March 2021, 4,671 people have been registered to the trial.
Supported by this recruitment, the trial itself has led to some crucial insights in the response to COVID-19, including the discoveries that neither Azithromycin or Doxycycline are generally effective treatments in reducing time to recovery or risk of hospital admission for elderly people with COVID-19.
Even with the development of effective vaccines, there will be many people who continue to require effective treatments for COVID-19. Therefore, the faster effective treatments can be found, affected people may be able to recover quickly and be hospitalised less often. This novel and efficient approach to an acute condition trial may be an important new methodology for acute incident studies in primary care, which are traditionally more difficult to recruit to than trials in long term conditions.
Chris Butler, PRINCIPLE Trial Lead:
“The creative energy that has gone into making the progress you outline could well be saving lives soon. You are making history.”
Helen Rutter – Senior Clinical Research Nurse, University of Oxford:
“I think the biggest thing with PRINCPLE is that we are looking to find a treatment for people with COVID-19. Even now with the vaccine roll out, which is amazing progress in such a short space of time, there will still be people who won’t be able to get the vaccine, or people who will still develop symptoms, so it’s really important we try to find a treatment that can reduce the risk of someone going to hospital, reduce the length of time they have symptoms, and make them feel better quicker!”
Patient/Public Voice Representative:
“I am so pleased that you are looking into this, as this is something that can actually make a difference.”
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Interview with Heather Rutter, Senior Clinical Research Nurse, PRINCIPLE trial
8 January 2021
Interview with Heather Rutter, Senior Clinical Research Nurse, Primary Care Clinical Trials Unit, University of Oxford, Nuffield Department of Primary Care Health Science.