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PRedicting Outcomes For Crohn’s dIsease using a moLecular biomarkEr (PROFILE): protocol for a multicentre, randomised, biomarker-stratified trial
  1. Miles Parkes1,
  2. Nurulamin M Noor1,
  3. Francis Dowling2,
  4. Harvey Leung2,
  5. Simon Bond2,3,
  6. Lynne Whitehead4,
  7. Sara Upponi5,
  8. Paul Kinnon6,
  9. Andrew P Sandham6,
  10. Paul A Lyons1,6,
  11. Eoin F McKinney1,6,
  12. Kenneth G C Smith1,6,
  13. James C Lee1
  1. 1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke’s Hospital, Cambridge, UK
  2. 2 Cambridge Clinical Trials Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
  3. 3 Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK
  4. 4 Clinical Trials Pharmacy, Addenbrooke’s Hospital, Cambridge, UK
  5. 5 Department of Radiology, Addenbrooke’s Hospital, Cambridge, UK
  6. 6 PredictImmune Ltd, Babraham Research Campus, Cambridge, UK
  1. Correspondence to Dr Miles Parkes; miles.parkes{at}addenbrookes.nhs.uk and Dr James C Lee; jcl65{at}cam.ac.uk

Abstract

Background The course of Crohn’s disease (CD) varies substantially between individuals, but reliable prognostic markers do not exist. This hinders disease management because patients with aggressive disease are undertreated by conventional ‘step-up’ therapy (in which treatment is gradually escalated in response to refractory or relapsing disease) while those with more indolent disease would be exposed to unnecessary treatment-related toxicity if a more aggressive ‘top-down’ approach was indiscriminately used. The Predicting outcomes for Crohn’s disease using a molecular biomarker trial will assess whether a prognostic transcriptional biomarker, that we have developed and validated, can improve clinical outcomes by facilitating personalised therapy in CD. This represents the first the biomarker-stratified trial in inflammatory bowel disease.

Methods and analysis This biomarker-stratified trial will compare the relative efficacy of ‘top-down’ and ‘accelerated step-up’ therapy between biomarker-defined subgroups of patients with newly diagnosed CD. 400 participants from ~50 UK centres will be recruited. Subjects within each biomarker subgroup (IBDhi or IBDlo) will be randomised (1:1) to receive one of the treatment strategies until trial completion (48 weeks). The primary outcome is the incidence of sustained surgery and steroid-free remission from the completion of induction treatment through to week 48. Secondary outcomes include mucosal healing, quality-of-life assessments and surrogate measures of disease burden including number of flares, cumulative steroid exposure, number of hospital admissions and number of Crohn’s-related surgeries (assessed hierarchically). Analyses will compare the relative benefit of the treatment strategies in each biomarker-defined subgroup, powered as an interaction analysis, to determine whether the biomarker can accurately match patients to the most appropriate therapy.

Ethics and dissemination Ethical approval has been obtained and recruitment is under way at sites around the UK. Following trial completion and data analysis, the results of the trial will be submitted for publication in peer-reviewed journals and presented at international conferences.

Trial registration number ISRCTN11808228; Pre-results.

  • genetics
  • inflammatory bowel disease
  • immunology
  • gastroenterology
  • clinical trials

This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/.

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Footnotes

  • MP and NMN contributed equally.

  • Contributors MP, NMN, FD, KGCS and JCL wrote the full trial protocol. HL, PK and APS reviewed and edited draft versions of the protocol. The Statistics and data analysis sections of the trial protocol were written by SB. LW contributed to the Trial treatment section of the protocol, and SU contributed to the Radiology section. PAL, EFM, MP, KGCS and JCL were the initiators of this trial. All authors took part in reading and final approval of the manuscript.

  • Funding This trial is funded by the Wellcome Trust via an investment in PredictImmune (200448/Z/16/Z). The Apex Healthcare Consulting survey and biomarker development work described herein was funded by a Wellcome Trust Interim Translational Award (099450/Z/12/Z). The trial is cosponsored by Cambridge University Hospitals NHS Foundation Trust and University of Cambridge. The sponsors are not involved in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication. EFM and JCL are supported by Wellcome Trust Intermediate Clinical Fellowships (104064/Z/14/Z and 105920/Z/14/Z respectively).

  • Competing interests PAL, EFM, KGCS and JCL are coinventors on a patent covering the method of assessing prognosis in IBD. PAL, EFM and KGCS are cofounders and consultants for PredictImmune. PK and APS are employees of PredictImmune. JCL is a consultant for PredictImmune.

  • Patient consent Not required.

  • Ethics approval East of England Cambridge South Research Ethics Committee.

  • Provenance and peer review Not commissioned; peer reviewed for ethical and funding approval prior to submission.

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