The PROFILE Trial – progress report on the first biomarker stratified randomised clinical trial (RCT) for patients living with Crohn’s disease (CD)

The last 2 years have been challenging for everyone, not least for teams running clinical trials and the people who volunteer to take part in them.  Access to clinical trials is particularly important for patients living with chronic diseases such as inflammatory bowel disease (IBD), as they provide access to new treatments or strategies, which may not be available through local routine care.

As the COVID pandemic began to take off in January 2020, the team responsible for the PROFILE trial were looking forward to the final year of recruitment with sites going great guns and the target of 400 patients looking to be within their sights.  With the PROFILE study closing to recruitment at the end of December 2021, we look back on the many successes and challenges overcome by the trial team over the last few years.

The initial response to the COVID pandemic, was a widespread reduction, and in many cases shutdown, of IBD clinical trial activity around the world – with the worrying prospect that many clinical trials might not be able to continue. The achievements of the PROFILE team to complete patient recruitment to this trial during the pandemic are therefore even more impressive.

PROFILE is an investigator-initiated/academic RCT, seeking to assess if a prognostic biomarker can enable delivery of personalised therapy in CD, and whether this approach leads to better clinical outcomes for patients.  The test being used within the trial is PredictSURE IBD, a blood-based biomarker which categorises patients based on their risk of experiencing a frequently relapsing disease course over future months and years.  The test classifies patients into high- or low-risk of having a so-called “aggressive” disease profile. Importantly, many previous studies have already demonstrated that the severity of a patient’s initial presentation (disease activity) is not necessarily indicative of a high-risk of future relapses (disease prognosis).

PROFILE is a pragmatic trial which has been taking place across 40 centres in the UK and enrolled adults with a new or recent diagnosis (<6 months) of active luminal CD.

Figure 1:  Profile Trial

Newly diagnosed patients who were eligible and consented to be enrolled in the trial were first classified using the PredictSURE IBD test into high- and low-risk groups.   Each of those groups was then randomised 50:50 to receive either “Accelerated Step-Up” (standard of care treatment in the UK) or “Top-Down” (in PROFILE this involves starting with infliximab infusions and an immunomodulator) treatment (Figure 1).  The trial is supported by a funding instrument of £4.3 million provided by the Wellcome Trust to PredictImmune.

Why is the trial so important?  To answer that, we need to understand a bit more about CD, which is one of the most common types of IBD.  CD causes inflammation of the digestive tract, leading to both intestinal and extra-intestinal symptoms, including fatigue, joint pains and many other symptoms which can affect quality of life.  CD is part of a family of conditions called immune-mediated inflammatory diseases (IMIDs), which includes multiple sclerosis, systemic lupus erythematosus and rheumatoid arthritis.  All of these IMIDs are thought to be driven by an abnormal immune response to different triggers and typically have a relapsing-remitting disease course – with the exact pattern of disease and response to treatment being highly variable from one patient to another.

Until now, it has not been possible to differentiate, at the point of diagnosis, between those patients who are likely to experience frequent relapses and those who are likely to follow a more quiescent disease course, with long periods with few or no symptoms (remission).  As a consequence, in the UK all patients with IBD are currently treated with the same “standard of care” – this means “stepping up” in an accelerated fashion to more potent therapies (e.g. biologics) in response to continued or new disease activity.  The alternative “top-down” approach, which is more common in some countries such as the USA, utilises the more potent therapies up front – but this has been done without knowledge of their risk for future disease progression.

Neither approach is perfect when applied in a “one-size-fits-all” approach.  The top-down approach risks over-treating those patients who are likely to experience a more quiescent future disease course (Figure 2a). However, the consequences for undertreating “high-risk” patients can be significant; a number of studies have demonstrated that failure to achieve sustained remission within 2 years following diagnosis, can result in disease progression, increased risk of surgery and a poorer quality of life.  Top-down treatment may, therefore, be more appropriate for patients who are likely to experience an aggressive future disease course.

Based on this information, the ideal approach would be to stratify patients based on their likely future disease course as early as possible after diagnosis, and tailor treatment to each individual – a concept often referred to as personalised or precision medicine.

Figure 2: a)  in the absence of a reliable prognostic test, it is not possible to distinguish between patients likely to follow a quiescent disease path and those likely to follow a more aggressive, relapsing-remitting course, so all patients are treated the same.  b) the PredictSURE IBD test enables patients to be stratified based on risk of following an aggressive disease course, with those at high-risk likely to benefit from top-down therapy and close monitoring.  Low-risk patients are likely to benefit from a less aggressive step-up approach. 

The ability of PredictSURE IBD to reliably classify patients into high- or low-risk of following a frequently relapsing disease course has been previously demonstrated during development and validation clinical studies. Further validation studies are planned or ongoing in different cohorts around the world, including the PRECIOUS trial which is recruiting across the USA. PROFILE is the first randomised clinical trial of this biomarker, and is assessing whether use of this blood test to guide initial treatment strategy will result in better clinical outcomes for patients.  The economic impact of this biomarker-stratified approach will also be assessed as part of the PROFILE trial analyses.

The study started recruiting in December 2017 and has been delivered by a multidisciplinary team led by the Chief Investigator Professor Miles Parkes and Clinical Research Fellow Dr Nuru Noor.  The trial is managed by the Cambridge Clinical Trials Unit and is co-sponsored by Cambridge University Hospitals NHS Foundation Trust and University of Cambridge.  PROFILE is overseen by an international team of independent experts in IBD, clinical trials, and statistics.

Prior to the COVID pandemic, PROFILE had opened to recruitment at 40 sites around the UK with recruitment reaching 15 patients per month by the end of 2019 and a total 215 participants recruited.  With 14 months to go, the target of 400 patients was looking very achievable.  Then the world changed with the spread of the COVID-19 pandemic.

The effects of the pandemic were felt immediately, as hospitals switched focus to COVID-19 clinical care and COVID-19 research projects only. Recruitment to the PROFILE trial dropped dramatically in the first quarter of 2020 before stopping completely in April 2020.

The PROFILE trial team felt it was important to keep the trial open for patients and implemented several modifications to make the trial protocol more patient-centred and allow increased flexibility of data collection for both researchers and patients. These modifications included the possibility for home delivery of medications, virtual data collection, greater use of non-invasive or point of care investigations, and the option for remote monitoring visits.

This was a decision welcomed by many sites and patients around the country.  Sites were able to open to recruitment later in the summer of 2020 with the number of sites able to recruit increasing as the year progressed. PROFILE was highlighted by the National Institute for Health Research as a national exemplar trial on how to make modifications and continue successful delivery as part of a national research recovery programme in the post-pandemic period. PROFILE was also designated as a national priority non-COVID research studies around the UK, due to its impact on patients living with CD both in the UK and around the world.

As a consequence of the pandemic and rising recruitment rates in the latter half of 2020, the trial team and funders supported the decision to continue recruiting new participants until the end of 2021.  The trial closed for recruitment in December 2021 with a total of 369 patients enrolled.  PROFILE is the largest academic interventional IBD trial ever conducted in the UK and one of the largest academic IBD trials ever conducted worldwide.  The trial follows all participants for 12 months, ending with a final trial visit and end of trial procedures.  This follow-up period should complete in December 2022, with several months of data cleaning, central reading and statistical analysis required before results can be reported.

The whole team is excited about seeing the final results and sharing them with IBD clinicians and patients alike.  We expect the results to be presented and submitted for publication during 2023.  We are excited about the impact these results may have on clinical management in CD, anticipating that there will be demonstrable clinical benefit by using a prognostic risk stratified approach to guide treatment of CD patients.  Such an outcome could lead to the PredictSURE IBD test being adopted as a routine tool to help guide treatment decisions and make personalised medicine a reality for patients living with IBD.

Successfully completing recruitment to the PROFILE trial, despite the challenges encountered over the last two years, is a real achievement and a testament to the hard work and determination of everyone involved in trial.  We would like to thank the central trial team and leadership, collaborators, patients and public involvement representatives, company stakeholders, and especially to all the participants who enrolled in the trial itself for making it such a huge success.