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Empty street due to coronavirus lockdown

Launching a new clinical trial involves months of preparation and careful assessment, but even the most comprehensive plans don’t usually account for a global pandemic. During spring 2020, when the first wave of coronavirus rippled across the world, many clinical research projects ground to a halt as clinicians were redeployed to COVID-19 wards, and lockdowns prevented face-to-face appointments. These trials included large, national and international studies investigating treatments for chronic diseases that themselves cause millions of deaths each year.

With so much time and resource already invested in these trials – and with the results being so important for future healthcare – too much was at stake to simply abandon them. Yet suddenly adapting a trial during such uncertain times, whilst ensuring participant safety and data integrity, was a daunting task. This was made even harder due to remote working and redeployment of collaborating hospital teams. Nevertheless, united by innovation and determination, NDPH trialists and the hundreds of clinical teams in the UK and around the world who collaborate with us have enabled important health research to continue against the odds. Here we profile three non-COVID-19 clinical trials that didn’t let coronavirus stop them, and the lessons they could offer for future pandemic situations.

Lesson 1 Reassure trial participants

When the pandemic first erupted, both EMPA-KIDNEY and ORION-4 had already recruited thousands of participants. Many of them had appointments already scheduled, during which they would provide blood samples and be resupplied with their study treatment. With national governments ordering the public to stay at home, participants were naturally concerned about whether or not they should remain in the study. As Dr Marion Mafham, UK Lead Investigator for ORION-4, said, reassuring trial participants as quickly as possible became a key priority.

‘One of the first things we did was to mail a letter to every ORION-4 participant in the UK stating that scheduled appointments were suspended for the time being, but that we would be in touch in the near future. Just this task alone was a mammoth exercise, given the number of participants we had already recruited.’ Similarly, EMPA-KIDNEY rapidly released information for participants in the necessary different languages both on the study website and via the local research sites. This reassured them that the trial leadership were investigating ways of delivering the treatments in a COVID-19 safe manner.

Lesson 2 Follow up from afar

Both EMPA-KIDNEY and ORION-4 were designed on the basis that study visits would happen in the clinic. During lockdown, with face-to-face appointments suspended, it simply wasn’t feasible to collect physical measurements (such as blood samples, weight and blood pressure) from participants. Furthermore, as it wasn’t clear how long this would be the case, decisions had to be made about whether and how trials should continue to collect important study data. ‘Our biggest issue early on was lack of clarity and not knowing how long the situation would last. But we had to make decisions about the participants already recruited into the trial’ said Marion Mafham of ORION-4. Both EMPA-KIDNEY and ORION-4 adopted a telephone follow-up model so that they could collect essential safety information about the study treatments, including any side effects. 'The ORION-4 study already had a telephone follow-up option available, so the research staff could enter the same data as if the participant was being seen in person. The only difference was that blood samples could not be collected until the participant returned to the clinic' said Dr Mafham.

Meanwhile, the LENS protocol had used a remote follow-up system from the start. Once recruited into the trial, participants receive a telephone call from a research nurse every six months during which they share information about their health and any treatment they have needed for diabetic eye disease. ‘Since the protocol for LENS has a heavy emphasis on remote methods, it has been relatively robust to the effects of the pandemic’ said LENS Chief Investigator, Associate Professor David Preiss.

Lesson 3 Send the treatment to the participant

With clinics closed during the lockdowns, it wasn’t possible for trial participants to collect their treatment in person. The only alternative was to send the treatment to the participant. As it happened, the LENS trial already sent their participants the study treatment, fenofibrate (or a placebo), by post. This approach had also been used for the ASCEND trial: a study involving over 15,000 participants which investigated whether aspirin and/or omega-3 fatty acids reduced the risk of heart attacks and strokes in people with diabetes. But using a postal delivery system was new for EMPA-KIDNEY, and perhaps the biggest change to the trial’s procedures, as Associate Professor Will Herrington, one of the principal investigators for the trial, said. ‘Fortunately, the study treatment, empagliflozin, is a stable pill that is easy to transport and administer, so using a courier system worked well within the existing protocol. Thanks to this, around 94% of participants are still taking the study treatment. However, returning to face-to-face study clinics is critically important for complete follow-up information to be collected.’

But not all treatments can simply be delivered by post. Inclisiran, the treatment being investigated by ORION-4, can only be given by injection from a trained health professional. Fortunately, this only needed to be administered once every six months, so many participants were able to have their injections during the relative calm over the summer months, when study sites could reopen. But when a second COVID-19 wave seemed imminent, the trial leaders trained registered nurses to give inclisiran injections to some participants in their homes, in a coronavirus-secure manner. Over the winter of 2020/21, this proved essential to administer the treatment to participants in regions where study clinics had been forced to close once more. ‘The support from the UK sites to do home visits has been fantastic, and is evidence of the great collaboration we had already established’ said Dr Mafham. ‘For instance, a local investigator whose site was closed phoned me between ward rounds at the height of the pandemic in early 2021 to enable the home injections to get started.’

Lesson 4 Embrace new delivery models

Another major pivot for both EMPA-KIDNEY and ORION-4 was changing their training programme for clinicians involved in the study that had previously been delivered face-to-face. In EMPA-KIDNEY’S case, this turned out to be particularly important since, having brought the pandemic under control, China was ready to start recruiting participants in late spring 2020. But with the trial’s coordinators under lockdown in Oxford, there was no way that they could deliver the training in person. Instead, Carol Knott, Head of Monitoring and International Nurse Coordinator for NDPH, and the team developed a new virtual training programme from scratch, including a way to check that this was being followed. ‘We used a combination of a bespoke, new online training course developed from the face-to-face materials, emailing practice materials to perform on the trial’s demo IT system, and teleconferences’ said Will Herrington. ‘We also trained regional coordinators in China to provide training-related advice and to visit sites as mentors when the first participants joined the study. Although our training team’s travel has dropped significantly, it feels as though our workload has increased.’ Later in 2020, this virtual training model was used to help also successfully launch EMPA-KIDNEY in Italy.

Lesson 5 Keep things streamlined

When healthcare systems are stretched, streamlined trials that optimise existing health systems, such as the NHS, are well-placed to cope even during a pandemic. As David Preiss described: ‘The LENS protocol was designed to avoid duplicating effort. Most of the information on important clinical events like worsening of diabetic eye disease comes from linking to data routinely collected by the NHS (for instance, NHS Scotland’s retinal screening programme), rather than setting up a separate system of monitoring. This approach considerably cuts down the resources and clinicians that you need to run the study.’ Similarly, EMPA-KIDNEY also intends to draw on NHS data to substitute for the missed face-to-face appointments with participants, as Will Herrington explained. ‘Even when research face-to-face visits were not possible, many participants continued to attend essential creatinine monitoring appointments to check their kidney function. We hope to link participant study data with the blood samples that were collected during these appointments.’

Meanwhile, the central operating model for ORION-4 in the UK enabled the study to act swiftly and coordinate action across all sites, as Marion Mafham outlined. ‘In most trials, individual sites manage the details of their participants, but we have a central model of recruitment. This meant we could support the sites more throughout the pandemic, for instance in providing updates to the participants.’

Looking forward

Even before COVID-19, clinical trials often required prohibitive investments of money, time and labour. As David Preiss noted, the lessons learnt in adapting to the pandemic could help increase the value and efficiency of many trials in the future. ‘Where a simple approach can be used – sending out study treatments to the participants and linking to NHS data to get information on outcomes – this would considerably lessen the burden on participants and clinicians, besides reducing costs.’

Indeed, a simple, streamlined approach to clinical trials was pioneered by Professor Sir Richard Peto and Professor Sir Rory Collins for the International Studies of Infarct Survival (ISIS), a series of randomised trials which recruited around 140,000 patients worldwide between 1985 and 1993. These assessed the effects of widely usable treatments on survival following a heart attack. This innovative approach paved the way for other successful trials designed and delivered by NDPH and informed the design of the Randomised Evaluation of COVid-19 thERapY (RECOVERY) trial, launched in March 2020, and of SOLIDARITY, the international COVID-19 treatment trial led by the World Health Organization. The streamlined design of these trials enabled large numbers of participants to be randomised quickly to provide reliable and timely results.

RECOVERY, led by NDPH and the Nuffield Department of Medicine, is the world’s largest investigation into effective treatments for patients hospitalised with COVID-19 and was designed to minimise the burden on front-line hospital clinicians. Patients are recruited using a simple form that takes minutes to complete, and are then randomly allocated to receive either one of the study treatments (prescribed by the doctors in the hospital), or standard care. Participant outcomes are collected using a simple one-page online form supplemented by linking to routine healthcare data stored within NHS databases and national registries. The simplicity of the trial’s design allowed thousands of patients to be rapidly recruited – leading to the discovery, within a year, that two existing treatments (dexamethasone and tocilizumab) were effective against COVID-19.

As for our three trials, where are they now? Recruitment for ORION-4 is continuing, and the trial leaders hope to reach their target in the near future. Meanwhile, EMPA-KIDNEY and LENS have already surpassed their aims: over 1,140 participants have now been recruited to LENS, whilst EMPA-KIDNEY has finished recruiting, with a final total of 6,609 participants.

It just shows that, with a bit of ingenuity and united determination, a clinical trial can continue against the odds.

Read more

Find out more about how methods to streamline clinical trials developed by NDPH researchers informed the design of COVID-19 trials in our report on our response to the pandemic.

Find out how new guidelines being developed by the Good Clinical Trials Collaborative could support further innovation.

Read how NHS DigiTrials is improving the efficiency and quality of four key aspects of clinical trials.