A trial to determine if a special liquid diet (exclusive enteral nutrition) before Crohn's disease surgery improves recovery

Approved 11/07/2023, London City & East REC (Research Ethics Committee Centre, 2nd Floor, 2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 1048171; cityandeast.rec@hra.nhs.uk), ref: 23/LO/0513

Dual primary outcomes at 6 weeks post-surgery:
1. Crohn’s Life Impact Questionnaire (CLIQ; a CD-specific patient reported outcome assessing QoL)
2. Post-surgery complications using the Comprehensive Complication Index (CCI)
If we demonstrate benefit for EEN on either of the primary outcomes this establishes effectiveness

Patient reported:
1. QoL over time using the CLIQ which will be collected post-surgery, fortnightly until 12 weeks post-surgery and then monthly up to 24 weeks post-surgery
2. Post-surgery recovery using the Surgical Quality of Recovery-15 (QoR-15) on day 3 post-surgery (or pre-discharge if discharged before day 3). The QoR-15 is a short form version of the QoR-40 and consists of 15 items each with a numerical rating score of 0-10. The total score therefore ranges from 0 to 150, with higher scores indicating better quality of recovery.

Clinical:
3. Length of post-operative hospital stay (measured in nights in hospital)
4. Length of bowel resected (in centimetres measured along anti-mesenteric border) at time of surgery before being put in formalin
5. Number of anastomoses formed at surgery as documented in the operation notes or from discussion with the operating surgeon
6. Number of participants requiring stoma formation either at index operation or within 30 days of surgery due to re-operation
7. Number of participants who develop an anastomotic leak (either radiological concern or confirmed at reoperation) within 30 days of surgery
8. Number of participants re-admitted within 30 days of date of discharge
9. Number of participants requiring re-operation within 30 days of surgery
10. Number of participants who develop enterocutaneous fistulae within 90 days of surgery. This is defined as any new fistula tract from any point in the gastrointestinal tract opening on to skin at any site from day of surgery to 90 days later. Enterocutaneous fistula diagnosis can be confirmed following clinical assessment. Radiological confirmation is not required.
11. Number of participants who develop clinical recurrence of their CD at 24 and 52 weeks post-surgery as assessed by the Crohn’s Disease Activity Index (CDAI)
12. Number of participants who develop endoscopic disease recurrence assessed endoscopically on colonoscopy performed between 24 and 52 weeks post-surgery as part of standard of care. (66, 67) Modified Rutgeert’s score should be used to grade the severity of recurrence. (67) If endoscopy is not performed but patient has cross sectional imaging (e.g. Magnetic resonance imaging (MRI), Computerised Tomography (CT) or ultrasound) as part of standard of care (routine assessments), the presence or absence of disease recurrence on imaging can be used as an alternative.
13. Number of participants on steroids at baseline who were able to wean off steroids prior to surgery. Steroid usage and dosage (including prednisolone (oral/rectal), Budesonide (oral/rectal), Hydrocortisone (intravenous/oral)) will be recorded at baseline and on day of surgery to determine change in use or dose. Inhaled or topical steroid use is not relevant to this trial.
14. Safety assessed through adverse event and serious adverse event reporting
15. Number of participants whose planned surgery did not proceed due to clinical improvement. If planned surgery is cancelled by the local team because clinical improvement deems it no longer necessary, these participants will continue to follow the trial protocol (e.g., follow-up assessments etc.)
16. Number of participants who required expedited or emergency surgery. This refers to participants whose elective/planned CD surgery date is brought forward due to clinical deterioration.

Economic outcomes:
17. The EuroQoL-5D-5 Level (EQ-5D-5L) questionnaire and an incremental cost-utility analysis will determine the cost per quality-adjusted life year (QALY) gained over the 52 weeks post-surgery. The EQ-5D-5L will be collected pre-operatively, and then at 6 weeks post-operatively, and then also at 24 and 52 weeks post operatively.

Qualitative outcomes:
18. Interviews will be undertaken with participants randomised to both trial groups, and also with staff involved in the trial. This research aims to provide in-depth qualitative data concerning the acceptability and experience of EEN as a pre-surgical intervention.

Exploratory outcomes:
19. Change in the Harvey-Bradshaw Index (HBI) and CLIQ between baseline and pre-operatively to determine if EEN improves HBI and CLIQ.
20. To determine if baseline microbiome compositional and metabolomic signatures, and changes after 6-weeks of EEN, can predict primary and secondary trial outcomes including post-surgical complications and likelihood of disease recurrence at follow-up. The samples are being collected as part of the main trial in order to measure faecal calprotectin. Further analysis will be performed and funded separately by UoG.

COAST sub-study outcomes:
21. COAST will analyse the subset of participants who are having surgery for terminal ileal CD to determine the impact of surgical timing on QoL and cost.

Microbiome analysis outcomes:
22. As an exploratory trial outcome, we will study if baseline microbiome compositional and metabolomic signatures, and changes after 6-weeks of EEN, can predict primary and secondary trial outcomes including post-surgical complications and likelihood of disease recurrence at follow-up.