Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616000251426p
Ethics application status
Not yet submitted
Date submitted
14/02/2016
Date registered
23/02/2016
Date last updated
23/02/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Efficacy of enteral nutrition in adult Ileal Crohn's disease- the RICE study
Scientific title
Randomized Ileal Crohn’s disease study of exclusive Enteral Nutrition (RICE study)
Secondary ID [1] 288338 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Crohn's disease 297315 0
Condition category
Condition code
Oral and Gastrointestinal 297514 297514 0 0
Crohn's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Randomized Ileal Crohn’s disease study of exclusive Enteral Nutrition (RICE) is a randomised controlled study for the treatment of ileal Crohn’s disease (CD) randomising EEN versus standard therapy in a single-blinded trial design. In Phase 1 of the study consenting patients with either severe Crohn's disease or symptomatic terminal ileal strictures/ perforation requiring surgical resection are randomised to receive EEN using polymeric formula versus calorie-matched standard of care diet for 6 weeks (in the subgroup of patients requiring surgery this will be taken in the 6 weeks immediately pre-surgery). In phase 2, patients that required surgery will undergo post-operative re-randomization to determine the effects of 6 months of partial enteral nutrition (PEN) on the prevention of post-operative CD. Other post-operative patients who will have resection of the terminal ileum may be recruited directly into phase 2 of the study without having participated in phase 1.
In phase 1 of the study, participants will consume EEN in the form of Nestle Modulen, prescribed by a dietician to meet all their nutritional requirements. The aim is to achieve compliance for >80% of consumed calories in the form of Nestle Modulen, which will be monitored through use of food diaries and regular follow up. In Phase 2 of the study Nestle Modulen will be consumed for about 50-60% of normal daily calorie intake and again adherence will be monitored through the use of a food diary.
Intervention code [1] 293634 0
Treatment: Other
Comparator / control treatment
The comparator in both phase 1 and phase 2 will be standard of care calorie matched dietary advice delivered by a dietitian. It will reflect general healthy eating advice for an individual of that particular age, body weight and sex.
Control group
Active

Outcomes
Primary outcome [1] 297073 0
Primary end point for phase 1 of the study is both clinical remission (defined as CDAI less than or equal to 150) and MRI remission (defined as increase in the terminal ileum cross-sectional lumen area by at least 100% as assessed on MRE by a central blinded GI radiologist), following 6 weeks of EEN versus standard of care calorie-matched diet for Crohn’s disease patients presenting with a severe disease flare or prior to planned surgical resection of the terminal ileum. Patients need to be both in clinical remission and MR remission in order to score the primary outcome.
Timepoint [1] 297073 0
Primary end point in phase 1 of the study will be assessed following 6 weeks of EEN vs standard of care calorie-matched diet.
Primary outcome [2] 297383 0
Primary end point for phase 2 of the study is endoscopic disease recurrence rate following 6 months of PEN versus standard of care calorie-matched diet, post planned surgical resection of the terminal ileum. Endoscopic recurrence is defined as post-resection Rutgeerts score equal to or greater than i2 at the anasthemosis site, assessed by the unblended onsite endoscopist and a blinded centralised endoscopist, the final result being reached via consensus following an over the phone discussion.
Timepoint [2] 297383 0
The primary end point for phase 2 of the study will be assessed following 6 months of partial enteral nutrition, administered immediately post-resection of the terminal ileum.
Secondary outcome [1] 319970 0
Proportion of subjects presenting with bowel obstruction during 6 weeks of EEN versus standard of care calorie-matched diet prior to planned surgical resection of the terminal ileum. This outcome will be assessed by regular weekly review of the patient and history taking, either face to face or over the phone as per the visit schedule.
Timepoint [1] 319970 0
Phase 1, assessed at 6 weeks
Secondary outcome [2] 320888 0
Proportion of subjects undergoing planned primary anastomosis versus end-ileostomy following the 6 weeks of EEN versus standard of care calorie-matched diet. Outcome will be assessed via review of the medical records.
Timepoint [2] 320888 0
Phase 1 surgical subgroup, assessed at 6 weeks
Secondary outcome [3] 320889 0
Mean hospital stay following terminal ileum resection between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet. Outcome will be assessed via review of the medical records.
Timepoint [3] 320889 0
Phase 1 surgical subgroup, assessed at 6 weeks following operation
Secondary outcome [4] 320890 0
Proportion of subjects having peri-operative complications, including intra-abdominal sepsis and anastomotic leak within the first 30 days post operation, between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet. Outcome will be assessed via review of the medical records.
Timepoint [4] 320890 0
Phase 1 surgical subgroup, assessed following 30 days from operation
Secondary outcome [5] 320892 0
Hospital readmission rate within 30 days following discharge post terminal ileal resection, between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet. Outcome will be assessed via both patient questionnaire (designed specifically for this study) and review of the medical records.
Timepoint [5] 320892 0
Phase 1 surgical subgroup, assessed following 30 days from operation
Secondary outcome [6] 320894 0
Proportion rescued from surgery between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet. During the 6 week review participants will be asked to indicate weather a decision has been by them and their surgeon to cancel their semi-elective terminal ileal resection, and the reason for this decision (eg symptom improvement to extent that surgery not required, currently unfit for surgery etc).
Timepoint [6] 320894 0
Phase 1 surgical subgroup, assessed following 6 weeks of EEN
Secondary outcome [7] 320895 0
Mean length of intra-operative bowel resected between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet. Length of resected specimens will be measured post resection by the surgeon.
Timepoint [7] 320895 0
Phase 1 surgical subgroup, assessed immediately post-op following 6 weeks of EEN
Secondary outcome [8] 320896 0
Mean Crohn’s Disease Activity Index (CDAI) score at 6 weeks, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1).
Timepoint [8] 320896 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [9] 320897 0
Mean Crohn’s Disease Activity Index (CDAI) score at 6 months postoperative, between subjects randomised to 6 months of post-operative PEN versus standard of care calorie-matched diet (Phase 2)
Timepoint [9] 320897 0
Phase 2, assessed following 6 months of partial enteral nutrition (PEN)
Secondary outcome [10] 320899 0
Proportion achieving steroid-free remission at 6 months following surgical resection of the terminal ileum, between subjects randomised to 6 months of post-operative PEN versus standard of care calorie-matched diet (Phase 2). Outcome assessed via both review of the medical records and patient questionnaire (designed specifically for this study).
Timepoint [10] 320899 0
Phase 2, assessed following 6 months of partial enteral nutrition (PEN)
Secondary outcome [11] 320900 0
Mean Body weight increase at week 6 between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed using a digital scale
Timepoint [11] 320900 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [12] 320901 0
Mean BMI increase at week 6 between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). BMI will be calculated from height and weight obtained from stadiometer and digital scale respectively.
Timepoint [12] 320901 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [13] 320902 0
Mean increase in prealbumin at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed via blood test.
Timepoint [13] 320902 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [14] 320903 0
Mean increase in albumin at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed via blood test.
Timepoint [14] 320903 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [15] 320904 0
Mean decrease in CRP at week 6, as compared to level at week 0, between subjects randomised to 6-8 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed using a blood test
Timepoint [15] 320904 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [16] 320905 0
Mean decrease in white cell count (WCC) at week 6, as compared to level at week 0, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed using a blood test
Timepoint [16] 320905 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [17] 320906 0
Mean decrease in faecal calprotectin at 6 weeks as compared to level at screening visit, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1).
Timepoint [17] 320906 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [18] 320907 0
Comparison of tissue inflammation, fibrosis, mucosal immunology, regulatory T cell profile and tissue proteomics of terminal ileal resection specimens between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet (Phase 1, surgical subgroup). This is a histopathological/ molecular qualitative comparison.
Timepoint [18] 320907 0
Phase 1 surgical subgroup, assessed following 6 weeks of EEN
Secondary outcome [19] 320908 0
Mean increase in grip strength at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed using a Hand Dynamometer.
Timepoint [19] 320908 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [20] 320909 0
Comparison of microbiome following 6 weeks , as assessed via DNA pyrosequencing, RNA pyrosequencing and metabolomics with mass spectrometry on feacal specimens, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1).
Timepoint [20] 320909 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [21] 320910 0
Comparison of microbiome at 6 months post terminal ileal resection, as measured via DNA pyrosequencing, RNA pyrosequencing and metabolomics with mass spectrometry, between subjects randomised to 6 months of postoperative partial enteral nutrition versus standard of care calorie-matched diet (Phase 2).
Timepoint [21] 320910 0
Phase 2, assessed following 6 months of PEN
Secondary outcome [22] 320911 0
Mean intestinal permeability (TEER) of terminal ileal resection specimen between subjects randomised to 6 weeks of preoperative EEN versus standard of care calorie-matched diet (Phase 1, surgical subgroup).
Timepoint [22] 320911 0
Phase 1, assessed following 6 weeks of EEN, surgical resection specimen
Secondary outcome [23] 320912 0
Proportion of subjects adhering to prescribed diet between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). All subjects will keep a food diary that will be reviewed by the study dietitian on a weekly basis.
Timepoint [23] 320912 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [24] 320913 0
Proportion of subjects adhering to prescribed diet between subjects randomised to 6 months of post-operative PEN versus standard of care calorie-matched diet (Phase 2). All subjects will keep a food diary that will be reviewed by the study dietitian on a weekly basis.
Timepoint [24] 320913 0
Phase 2, assessed following 6 months of PEN
Secondary outcome [25] 320914 0
Proportion of subjects randomised to 6 weeks of EEN requiring step down diet or nasogastric/ nasojejunal feeding (Phase 1). Outcome will be assessed via review of the medical records.
Timepoint [25] 320914 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [26] 320915 0
Mean daily dose of steroids, thiopurines, methotrexate, 5-aminosalicylates and Non-steroidal anti-inflammatory drugs (NSAIDs) between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Outcome will be assessed via a questionnaire (designed specifically for this study) at weeks 0, 2, 4 and 6. Based on this information an average daily dose of each medication used for the entire 6 week period of phase 1 will be calculated for each participant.
Timepoint [26] 320915 0
Phase 1, assessed following 6 weeks of EEN. The questionnaire will be administered at weeks 0,2,4 and 6 to collect information on doses of medications used. This information will be used to calculate the average daily dose of each medication used by an individual participant for the whole 6 week duration of Phase 1.
Secondary outcome [27] 320916 0
Mean daily dose of steroids, thiopurines, methotrexate, 5-aminosalicylates and Non-steroidal anti-inflammatory drugs (NSAIDs) between subjects randomised to 6 months of post-operative EEN versus standard of care calorie-matched diet (Phase 2). Outcome will be assessed via a questionnaire (designed specifically for this study) at weeks 0, 2, 4 and 6. Based on this information an average daily dose of each medication used for the entire 6 week period of phase 1 will be calculated for each participant.
Timepoint [27] 320916 0
Phase 2, assessed following 6 months of PEN. The questionnaire will be administered at weeks 0,2,4 and 6 to collect information on doses of medications used. This information will be used to calculate the average daily dose of each medication used by an individual participant for the whole 6 week duration of Phase 1.
Secondary outcome [28] 320917 0
Mean total cost of care between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Total cost of care will be estimated via a questionnaire (designed specifically for this study) administered to the patient at week 6.
Timepoint [28] 320917 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [29] 320918 0
Mean total cost of care between subjects randomised to 6 months of post-operative partial enteral nutrition versus standard of care calorie-matched diet (Phase 2). Total cost of care will be estimated via a questionnaire (designed specifically for this study) administered to the patient at month 6.
Timepoint [29] 320918 0
Phase 2, assessed following 6 months of PEN
Secondary outcome [30] 320919 0
Samples taken at week 0 will be stored for future analysis to try to uncover predictive markers for response to therapy. Following samples will be stored: plasma for proteomic and serological markers, eluted DNA for genomic biomarkers, and colonic mucosal tissue biopsies for tissue metabolomics and magnetic resonance spectroscopy.
Timepoint [30] 320919 0
Samples will be taken at week 0 and will be analysed retrospectively
Secondary outcome [31] 321015 0
Mean Patient Reported Outcome- 2 (PRO2) score at 6 weeks, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1).
Timepoint [31] 321015 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [32] 321016 0
Mean IBD Questionaire (IBDQ) score aat 6 weeks, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1).
Timepoint [32] 321016 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [33] 321017 0
Mean IBD-disability index score at 6 weeks, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1).
Timepoint [33] 321017 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [34] 321018 0
Mean Patient Reported Outcome- 2 (PRO2) score at 6 months postoperative, between subjects randomised to 6 months of post-operative PEN versus standard of care calorie-matched diet (Phase 2)
Timepoint [34] 321018 0
Phase 2, assessed following 6 weeks of partial enteral nutrition (PEN)
Secondary outcome [35] 321019 0
Mean IBD Questionaire (IBDQ) score at 6 months postoperative, between subjects randomised to 6 months of post-operative PEN versus standard of care calorie-matched diet (Phase 2)
Timepoint [35] 321019 0
Phase 2, assessed following 6 weeks of partial enteral nutrition (PEN)
Secondary outcome [36] 321020 0
Mean IBD-disability index score at 6 months postoperative, between subjects randomised to 6 months of post-operative PEN versus standard of care calorie-matched diet (Phase 2)
Timepoint [36] 321020 0
Phase 2, assessed following 6 weeks of partial enteral nutrition (PEN)
Secondary outcome [37] 321021 0
Mean increase in ferritin at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed via a blood test.
Timepoint [37] 321021 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [38] 321022 0
Mean increase in serum zinc at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed via a blood test.
Timepoint [38] 321022 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [39] 321023 0
Mean increase in haemoglobin at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed via a blood test.
Timepoint [39] 321023 0
Phase 1, assessed following 6 weeks of EEN
Secondary outcome [40] 321024 0
Mean increase in muscle ultrasound density at week 6, between subjects randomised to 6 weeks of EEN versus standard of care calorie-matched diet (Phase 1). Assessed by a competent dietitian using an ultrasound machine.
Timepoint [40] 321024 0
Phase 1, assessed following 6 weeks of EEN

Eligibility
Key inclusion criteria
Participant must meet all of the inclusion criteria below at time of enrolment to be eligible to participate in phase 1 of the study
1. Crohn’s disease involving the terminal ileum, established diagnosis >6 months
2. Aged 18 – 70 inclusive
3. Ileal complicated Crohn’s disease requiring laparoscopic / open ileal (or small bowel segmental) resection, OR severe ileal Crohn’s disease

Participant must meet all of the inclusion criteria below at time of surgery to be eligible to participate in phase 2 of the study:
1. Crohn’s disease involving the terminal ileum, established diagnosis >6 months
2. Aged 18 – 70 inclusive
3. Ileal complicated Crohn’s disease undergoing laparoscopic / open ileal (or small bowel segmental) resection
4. Terminal ileum can be reached by colonoscopy.
Minimum age
18 Years
Maximum age
70 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participant must not meet any of the exclusion criteria below at time of enrolment to be eligible to participate in either phase 1 or phase 2 of the study
1. Unable to consent, comply or complete the study and associated procedures (such as understanding of questionnaires)
2. Requirement for emergency small bowel resection eg. those with uncontrolled sepsis or peritonitis or complete bowel obstruction
3. Short bowel syndrome or any other significant gastrointestinal disease (eg irritable bowel syndrome, active neoplasm, diverticulitis etc)
4. Colectomy, stoma formation ie. non-primary anastomosis, or strictureplasty without small bowel resection
5. Resection for malignancy or known colorectal dysplasia (apart from polyps that have been completely removed)
6. Pregnancy, lactation or unwillingness to practice an effective method of contraception during the study period
7. Ulcerative colitis or IBD unclassified
8. Comorbidity or psychiatric disorder sufficiently severe to jeopardize participation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Computer based randomisation will be performed. Block randomisation will be performed centrally via an online random sequence generator. Each randomization code will be sealed in an opaque envelope, and these will be sent to the various study sites. Once a study participant signs an informed consent sheet and is deemed to meet all the inclusion criteria and none of the exclusion criteria, the study site investigator is to open the envelope and phone the principal investigator or research coordinator with the code contained in the envelope, in order to reveal to what group that particular participant has been randomised to. The envelop is only to be opened when informed consent sheet is signed. Record will be kept of every person requesting a code. The above method would allow for allocation concealment.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
As detailed above an online random sequence generator will be used.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Type of endpoint/s
Efficacy
Statistical methods / analysis
The study is designed and statistically powered with the pre-specified intention of demonstrating a clinically meaningful difference between the treatment and control arm (as opposed to a statistically significant but clinically inconsequential difference).
The study is to be powered such that there is a >80% probability of demonstrating a difference with a p value of 0.05 using a two tailed t-test.
Based on radiological remission rates from an open-labelled study of 54%, the predicted study rates based on available data and anecdotal experience are as follows: remission rate 60%, control response 40%, drop-out rate 20%.
Sample size analysis: assuming a two-sided alpha of 0.05, a treatment remission rate of 60%, control remission rate of 40% and a drop out rate of up to 20% in each arm, randomising 2 : 1 ratio with non-inferiority margin of -0.1, 30 patients in control group and 60 in the active treatment group (i.e. 90 patients in total) has a power of > 80% in an intention-to-treat analysis.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
90
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD
Recruitment outside Australia
Country [1] 7528 0
New Zealand
State/province [1] 7528 0

Funding & Sponsors
Funding source category [1] 292724 0
Hospital
Name [1] 292724 0
Concord Hospital, Department of Gastroenterology
Country [1] 292724 0
Australia
Funding source category [2] 292725 0
Commercial sector/Industry
Name [2] 292725 0
Nestle Health Sciences
Country [2] 292725 0
Switzerland
Primary sponsor type
Hospital
Name
Concord Hospital, Department of Gastroenterology
Address
Concord Hospital Hospital Rd, Concord NSW 2139
Country
Australia
Secondary sponsor category [1] 291455 0
Commercial sector/Industry
Name [1] 291455 0
Nestle Health Sciences
Address [1] 291455 0
Nestle Institute of Health Sciences S.A.
EPFL Innovation Park
Batiments (Buildings) G & H
1015 Lausanne
Switzerland
Country [1] 291455 0
Switzerland

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 294212 0
HUMAN RESEARCH ETHICS COMMITTEE (HREC) - Concord Repatriation General Hospital
Ethics committee address [1] 294212 0
Ethics committee country [1] 294212 0
Australia
Date submitted for ethics approval [1] 294212 0
23/02/2016
Approval date [1] 294212 0
Ethics approval number [1] 294212 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 62794 0
Prof Rupert Leong
Address 62794 0
Department of Gastroenterology
Concord Repatriation General Hospital
Hospital Road, Concord NSW 2139
Country 62794 0
Australia
Phone 62794 0
+61 2 9767 6111
Fax 62794 0
+61 2 9767 6767
Email 62794 0
[email protected]
Contact person for public queries
Name 62795 0
Nikola Mitrev
Address 62795 0
Department of Gastroenterology
Concord Repatriation General Hospital
Hospital Road, Concord NSW 2139
Country 62795 0
Australia
Phone 62795 0
+61 2 9767 6111
Fax 62795 0
+61 2 9767 6767
Email 62795 0
[email protected]
Contact person for scientific queries
Name 62796 0
Nikola Mitrev
Address 62796 0
Department of Gastroenterology
Concord Repatriation General Hospital
Hospital Road, Concord NSW 2139
Country 62796 0
Australia
Phone 62796 0
+61 2 9767 6111
Fax 62796 0
+61 2 9767 6767
Email 62796 0
[email protected]

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