Synergistic Effect of Exclusive Enteral Nutrition Formula in Addition to Corticosteroids Therapy to Induce Clinical Remission in Patients With Crohn's Disease: a Pilot Study Involving a Multidimensional Assessment of Potential Mechanisms
Phase: PHASE4
Conditions: Crohn's Disease
Sponsor: McMaster University

Protocol date: October 2018 
1 
SYNERGISTIC EFFECT OF EXCLUSIVE ENTERAL NUTRITION FORMULA IN 
ADDITION TO CORTICOSTEROIDS THERAPY TO INDUCE CLINICAL REMISSION IN 
PATIENTS 
WITH 
CROHN’S 
DISEASE: 
A 
PILOT 
STUDY 
INVOLVING 
A 
MULTIDIMENSIONAL ASSESSMENT OF POTENTIAL MECHANISMS 
 
 
Principal Investigator: Maria Ines Pinto Sanchez  
Co-PI: David Armstrong MD;  
Co-investigators: Premysl Bercik, MD; Andrea Nardelli, MD; Elena F Verdu, MD; Neeraj 
Narula MD; Smita Halder, MD; Usha Chauhan, NP; Frances Tse, MD; Grigorios 
Leontadis, MD; John Marshall, MD; Stephen Collins, MD; Paul Moayyedi, MD; Girish 
Bajaj, MD; Teresa Balart, MD. 
Student: Jeremy Biro 
 
Farncombe Family Digestive Health Research Institute- McMaster University 
 
 
 
 
 
 
 
 
 

Protocol date: October 2018 
2 
 
 
Lay Abstract 
Crohn’s disease (CD) is an inflammatory bowel disease (IBD) characterized by diarrhea, 
abdominal pain and bleeding.  There are several treatment options but the most-widely 
used for acute therapy are corticosteroids (CS); unfortunately, CS are often associated 
with severe side effects. The administration of a formula for exclusive feeding (EEN) is 
well-established as an alternative to CS in children with Crohn’s disease (CD). However, 
this intervention is not routinely used in adults, in part because of uncertainty regarding 
the magnitude of the benefit of EEN reported in previous studies. In fact, few studies have 
examined the effects of EEN in adult patients with active CD. We propose that a polymeric 
formula, provided orally, may help decrease gut inflammation and improve nutritional 
status through modulation of gut bacteria. We will therefore investigate the effect of 
exclusive formula feeding therapy in addition to different regimes of CS therapy compared 
to CS alone in adult patients with active CD, on symptoms and inflammation after 6 weeks 
of treatment. We will collect information through questionnaires that assess gut 
symptoms, quality of life, mood changes and dietary patterns. To investigate potential 
mechanisms, we will collect stool samples to characterize gut bacterial profiles, blood to 
determine inflammatory markers and evaluate gut movements (motility) before, and after 
the treatment. We hope that our results will lead to better understanding of the beneficial 
effect of exclusive formula feeding in addition to CS as a more efficacious alternative than 
CS alone, and to understand the mechanisms of this therapy.  
 

Protocol date: October 2018 
3 
 
BACKGROUND 
Crohn’s disease (CD) is characterized by inflammation of the gastrointestinal (GI) tract, 
diarrhea, pain and rectal bleeding1. Canada has one of the highest prevalences of CD in 
the world with an estimated incidence rate of 16.3 per 100,0002. The pathophysiology of 
CD is not well understood, but a dysregulated immune response to altered microbiota 
may play a key role3. Treatment of CD requires a multi-disciplinary approach involving 
medical therapy, surgery and dietary changes. Corticosteroids (CS) are the first line 
therapy to induce remission; however, they have adverse effects and 30% of patients can 
prove to be steroid resistant or dependent4. Therefore, alternative therapies that can 
effectively induce and maintain disease remission without short and long-term side effects 
are needed5. 
Exclusive enteral therapy (EEN) involves a liquid diet of elemental or polymeric formula 
(PF), given exclusively over a prolonged period6. Elemental formula contains individual 
amino acids, while PF is providing intact proteins7.  Although exclusive enteral nutrition 
(EEN) is used in children as an alternative to CS to induce remission due to its excellent 
safety profile7, it is not routinely used in adults.  
The beneficial effects of EEN in CD were first demonstrated over two decades ago, when 
O’Morain et al8 demonstrated in a controlled study that an elemental diet was as effective 
as CS in achieving remission in adults with active CD. In particular, EEN was shown to 
induce the expression of growth factors, promote changes in intestinal permeability and 
stimulate mucosal healing8, 9. Since then, several studies aimed to investigate this area. 
Meta-analyses of EEN versus CS have found that, although CS are superior to EEN in 

Protocol date: October 2018 
4 
inducing remission, EEN is also efficacious with expected remission rates of up to 60% 
and provides additional nutritional benefit5,10,20. Although several studies have 
demonstrated effectiveness of elemental EEN in children, the effect of EEN in adult CD 
remain controversial5,7,20.  
Potential mechanisms by which EEN might act include relative bowel rest, reduced 
antigenic load, provision of trophic amino acids, local anti-inflammatory effects, and 
modification of gut microbiota11,20.  However, there is no strong evidence to fully support 
any one of these mechanisms. A recent meta-analysis20 showed that the effects of the 
therapeutic formula on specific bacterial strains were variable and inconsistent among 
studies, possibly due to small sample sizes and methodological limitations. Our 
preliminary data showed that short term dietary changes improve motility in patients with 
low-grade gut inflammation21. However, the effects of EEN on gastrointestinal transit in 
adults has not been yet investigated.  
Evidence for the effect of EEN on quality of life, an essential patient reported outcome, is 
particularly scarce. Guo et al30 found an improvement of quality of life in 13 patients with 
CD receiving EEN for 6 weeks. However, it is currently unknown whether EEN is more 
effective than CS in improving quality of life in adults with CD.  
The potentially synergistic effects of adding EEN to CS therapy have not been explored 
before. Therefore, we designed a randomized controlled trial with the objective to 
investigate the effect of EEN in addition to different regimes of CS therapy (ECS) 
compared to CS alone (CS), for decreasing disease activity and improving quality of life 
in adult patients with CD. We also propose to investigate potential mechanisms 
underlying any beneficial effect of EEN in CD in the context of concomitant CS therapy.  

Protocol date: October 2018 
5 
 
Hypotheses:  
1-  Six weeks of ECS will be more effective than CS in inducing clinical remission in 
patients with active CD 
2- Six weeks of EEN in addition to a short course of CS (ECSC) will have similar 
efficacy than ECS and reduced number of adverse events 
3- Six weeks of ECS will lead to beneficial changes in the composition and/or 
metabolic activity of the intestinal microbiota, gastrointestinal transit and 
inflammatory burden.  
 
Because the effect size of ECS has not been investigated before, we will perform a pilot 
study to assess feasibility and calculate estimates of effect size in order to plan a larger 
trial. Based on the significant number of patients, if the study is feasible, we will consider 
the sample size estimated through this pilot study for the full trial to minimize the possibility 
of recruiting additional patients. 
 
General aim and endpoint: To assess study feasibility and provide estimated effect 
sizes (point estimates with confidence intervals) for all measures of interest in order to 
plan an  adequately powered study. We will assess recruitment rates and acceptability of 
treatment in arms involving exclusive enteral nutrition.  
Primary outcome and endpoint: To assess the efficacy of 6 weeks of ECS in inducing 
remission (CDAI <150) compared to treatment with CS in adult patients with active CD 
(CDAI >220 and either CRP >5 or fecal calprotectin >250 mg/l). 

Protocol date: October 2018 
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Secondary outcomes and endpoints: To determine the beneficial effect of 6 weeks of 
ECS as compared to CS in inducing: 
1. Clinical disease improvement (drop in CDAI >70 or 100) 
2. Improvement in quality of life (using the Inflammatory Bowel Disease 
Questionnaire (increase IBDQ scores)) 
3. Biochemical remission (normalization of either serum CRP and/or fecal 
calprotectin) 
4. Changes in microbiota composition (16S sequencing Illumina) 
5. Normalization of colonic transit (SHAPE 0-5 markers at day 5)34 among those 
with altered transit at baseline 
6. Decrease in anxiety and/or depression scores (decrease >2 points HAD-A and/or 
HAD-D scores) 
7. Increase in body weight and improvement in nutritional status (increased levels 
of micronutrients) 
8. Decrease of indirect markers of mucosal integrity (IFABP2) 
9. Changes in bacterial fermentation profile (SCFAs: acetate (acetic acid), 
propionate (propionic acid), and butyrate (butyric acid) 26,27. 
10. Decreased number of adverse events 
 
METHODS 
Study design 

Protocol date: October 2018 
7 
Randomized control trial; 3 arms of treatment: EEN plus standard or short course of CS 
(ECS, ECSC) vs CS alone (CS) conducted at McMaster University Medical Centre 
(Figure 1).  The study will last 10 weeks and will involve 4 visits. At the screening visit, we 
will assess clinical history and symptoms, perform a physical exam and complete 
bloodwork after the informed consent is signed. Randomization will occur at the second 
visit (pre-treatment), when the inclusion and exclusion criteria and symptoms will be re-
assessed, and baseline stool and urine samples will be collected. In addition, we will 
perform a SHAPE study and patients will be assessed by a dietitian or clinical nutrition 
support specialist to assess dietary factors and estimate energy needs using the Harris 
Benedict equation as detailed below.   
Patients will be instructed to take the allocated treatment and to collect empty bottles/ 
blisters of medication to assess the compliance at the next visit. Six weeks later (visit 3), 
their symptoms will be re-assessed, blood, urine and stool samples collected and SHAPE 
study performed. Patients will be instructed to stop the EEN or decrease the dose of CS, 
as detailed in the section “Follow up after treatment”. In the last visit (4th visit; 10 weeks 
after enrollment) we will collect information on symptoms, stool samples and urine.  
The study protocol will be submitted by the investigator for approval by the Hamilton 
Integrated Research Ethics Board (HiREB).  
 
Randomization process 
The sequence of the treatments will be randomly generated using a computer-based 
pseudo-random number generator (RStudio Team (2015). RStudio: Integrated 
Development for R. RStudio, Inc., Boston, MA) Patients will receive one of challenges A, 

Protocol date: October 2018 
8 
B, or C consisting of CS, ECS or ECSC. A third person not involved in the study will 
perform the randomization to preserve treatment allocation concealed from participants 
and study staff. A block randomization will stratify patients by disease location (colonic/ 
small bowel involvement). Each treatment will be assigned a number according to the 
randomization sequence. On recruitment, the patient will be assigned into one of three 
strata and given the next consecutive randomization number available for that stratum. 
Treatment will be not blinded for patients or study staff.  
Subject recruitment 
Subjects will be recruited from McMaster University Medical Centre (MUMC) Digestive 
Diseases Clinic, identified in an ongoing database organized in 2008 and by recruitment 
flyers posted at McMaster University Medical Centre, Juravinski Hospital and Hamilton 
General Hospital. Patients in the database signed an informed consent agreeing to be 
contacted for future research. Patients will be contacted by study personnel and invited 
to participate in the study. 
After the subject has provided written consent to participate, an inclusion checklist will be 
completed. Subjects will be enrolled after having fulfilled all inclusion criteria, and none of 
the exclusion criteria.  
 
 
Participants 
One hundred adult patients diagnosed with IBD will be recruited at McMaster University 
Medical Centre. This will provide 30 subjects in each treatment arm, allowing for 10% 
dropout rate.  

Protocol date: October 2018 
9 
Inclusion criteria:  
1. Adult patients (age 18-75 years) 
2. Confirmed CD diagnosis for at least 6 months  
3. Clinically active disease (CDAI >220 or HBI>6) or evidence of activity in endoscopy 
4. Biochemical evidence of disease activity (CRP > 5 and/or fecal calprotectin > 250),  
Exclusion criteria:   
1. Current treatment with EEN  
2. Intestinal obstruction, perforation, toxic megacolon, massive gastrointestinal 
bleeding, abdominal abscess, or other criteria considered by the investigator which 
preclude the use of EEN;  
3. Stricturing disease 
4. Previous intestinal resection with a remnant bowel <180 cm  
5. Treatment with prednisone in last 30 days;  
6. New start or change in dose of azathioprine, 6-mercaptopurine, cyclosporine, other 
immunosuppressant or biologics in the last 90 days. Doses of these medications 
must also remain unchanged for the duration of the study. 
7. New start or change in dose of 5ASA in last 30 days. 5ASA dose must remain 
unchanged for the duration of the study.  
8. Treatment with antibiotics or probiotics use in the last 30 days. 
9. Pregnancy or lactation  
10. Any serious illness considered by the investigator that will interfere with the study 
procedure or results. 
 

Protocol date: October 2018 
10 
Intervention 
Participants will be randomized to one of the following interventions: 
1. Exclusive enteral nutrition plus corticosteroids 
Patients randomized to ECS or ECSC arms will receive EEN defined as enteral feeds 
given exclusively as sole nutritional source over 6 weeks period in addition to the CS 
therapy. Hypercaloric polymeric formula (Modulen 1.5 kcal /ml; Nestle 22,23) will be used 
for a period of 6 weeks. To increase palatability, patients will be allowed to add the “Nestle 
Nutrition Flavour Mix” (see Appendix).  Daily volumes of formula will be prescribed based 
upon the patient’s estimated energy requirement (EER), calculated using the Harris 
Benedict equation (calculator available at https://manytools.org/handy/bmr-calculator), 
which estimates basal metabolic rate from weight and height and then applies an activity 
factor which ranges from 1.2 to 2.4 (Sedentary AF 1.2; mild activity 1.375, moderate 
activity AF 1.55, heavy activity AF 1.7, extreme AF 1.9 For details, refer to Appendix). 
Actual body weight or ideal body weight for height will be used in the equation depending 
on whether the patient is of an appropriate weight or underweight for height. Oral 
administration will be encouraged wherever possible, with formula volume distributed as 
set meals and snacks throughout the day. Nasogastric (NG) tube insertion for delivery of 
formula will be discussed and offered only if oral supplementation is not possible or not 
tolerated by the patient. Enteral feeding will be prescribed as an exclusive therapy, with 
exclusion of all normal diet for the period of feeding. Patients will be reviewed after 3 
weeks of therapy and, when required, energy intakes will be modified by adjusting formula 
volumes based upon adequacy of weight changes. Volume taken per meal and 
distribution during the day will be recorded in the case report form. No oral foods or fluids 

Protocol date: October 2018 
11 
(except for clear liquids including water and weak tea or coffee) will be allowed during the 
study period. Vitamins and supplements will be allowed if doses have been stable before 
entering in the study, and doses are not changed during the study. 
 
2. Corticosteroids 
Patients in ECS and CS arms will receive oral prednisone 40 mg x day for 2 weeks; with 
subsequent taper of daily dose by 5 mg per week. Patients randomized to ECSC arm will 
receive oral prednisone 40 mg x day for 3 days and taper in 16 days (Figure 1). Patients 
randomized to the CS arm will be asked to maintain their regular diet.  
 
Follow up after treatment 
Following the completion of the period of exclusive enteral feeding, patients receiving 
EEN will be instructed to gradually reintroduce foods by adding one individual item every 
2 days as shown in Table 1 32,33 and Appendix with instructions for food introduction with 
coincident reduction of formula volumes under the supervision of an expert in Nutrition. 
The accelerated introduction of foods was based on a recent study showing similar results 
with additional benefits of 2 days vs 4 days 33.   
 
Treatment compliance 
The subjects will be asked to keep the cans of Modulen and blister packs of prednisone 
during the entire treatment period and bring them back to the investigator at the end of 
that period. Compliance will be recorded in the CRF. In order to improve assessment of 
patient’s compliance, 2 copies of a paper sheet diary will be provided at Visit 1. Patients 

Protocol date: October 2018 
12 
consuming <80% of the prescribed treatment dose throughout the study, or those who 
interrupted therapy for more than three consecutive days will be considered as 
noncompliant. 
 
Measurements before and after treatment  
- Clinical data regarding demographics, disease location and activity (Harvey-Bradshaw 
Index), social life and habits, past and current clinical medical background, previous 
surgeries, nutritional status (malnourishment, weight/ height) will be collected in CRF. 
- Dietitian/ Certified nutrition support clinician: Dietary habits and caloric intake will be 
recorded at baseline with nutritional assessment during visits 
- Bloodwork to assess for inflammatory markers, CRP, fecal calprotectin, ESR, as well as 
CBC, platelets, micronutrients (albumin, vitamin D, B12, A , zinc, copper, chromium ) 
- Questionnaires: McMaster Food frequency questionnaire(Hamilton, ON), quality of life 
(SIBDQOL13), disease activity (CDAI), anxiety and depression (HAD score, Beck 
inventory), and nutritional assessment (Subjective Global Assessment14 Braun 
Nutriscreen program) 
- Gastrointestinal transit (colonic transit: SHAPE study and orocecal transit24,25: patient 
will take one capsule and have an x ray on day five, following R.C. Evans, et al protocol, 
where ≥6 markers indicate delayed transit, therefore ≤5 is normalization of colonic 
transit).34 
- Stool sample (frozen samples) for microbiota composition (16S sequencing Illumina; Dr. 
P Bercik’s lab) metabolomics and metagenomics (Britz-McKibben?) 15 

Protocol date: October 2018 
13 
- Systemic priming to gut bacteria (Verdu Lab using Flow cytometry after incubating 
patients’ serum with cultured fecal bacteria16 
- First urine morning for metabolomics 
- Intestinal permeability – indirect markers of mucosal integrity (FABP2) 
 
Statistical analysis 
There is no previous estimate on the effect of ECS compared to CS in inducing 
symptomatic improvement and associated changes in gut microbiota composition. 
Therefore, a sample size of 30 patients per arm28,29 should be sufficient to estimate the 
results and allow us to plan for future larger study.  We will recruit additional 10 patients 
in total, to account for drop outs rates.  Results will be analyzed as intention to treat (for 
primary outcome) and per protocol (excluding patients non-compliant with EN). The 
results will be expressed as n (%), mean (SD) or median (IQR) as appropriate. We will 
perform logistic regression to assess the association between symptomatic response and 
significant changes in gut microbiota composition in each group. T test or Man Whitney 
U test will be used as appropriate to assess differences between means.  Analysis will be 
performed using SPSS version 21 (San Diego, CA). 
 
Early withdrawals: 
The following criteria will be considered as reasons for early discontinuation from the 
study (drop outs): 
• 
Patient’s decision. 

Protocol date: October 2018 
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• 
Physician’s decision in case that the continuation of the patient in the study places 
him/her at risk. 
• 
Patients that that were not compliant with the unauthorized concomitant 
diets/treatments/medication will be considered as non-compliant and considered for the 
ITT analysis. If a subject’s outcome measures worsen to the degree that they meet the 
study’s Exclusion Criteria, study treatment will be withdrawn. Medical care will be 
provided as directed by the study physician and/or the subject’s physician. If the required 
medical care conflicts with the study protocol, the subject will be placed in the intent-to-
treat group. Study safety follow up will continue unless the subject withdraws, and/or is 
withdrawn by the study physician, and/or on the advice of the subject’s physician. 
 
Handling of adverse events 
Reporting and documentation of adverse events 
All adverse events occurring during the study will be reported and recorded whether or 
not they are considered to be non-serious, serious and/or related to the treatment. The 
following information will be required in each case: 
• 
Subject and date 
• 
Description of event 
• 
Duration 
• 
Frequency 
• 
Intensity 
• 
Seriousness 
• 
Action taken 

Protocol date: October 2018 
15 
• 
Outcome and sequel 
• 
Relationship to test product 
Documentation of all adverse events includes completion of the appropriate section of the 
case report form (AE). Documentation of a serious adverse event that requires a separate 
form (SAE) will be completed by the investigators in each case.  
If further information or examinations are required to assess the relationship between an 
adverse event and treatment following the occurrence of the adverse event, all 
examinations or laboratory findings will be noted with their results in the CRF (section UV) 
or attached to a follow up file. Notification of the HiREB will also be performed in the event 
of an SAE during the clinical trial. 
 
Estimated length of study: 2 yrs  
 
 

Protocol date: October 2018 
16 
REFERENCES 
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605. 
2- Rocchi A, Benchimol EI, Berstein C et al. Inflammatory bowel disease: A Canadian 
burden of illness review. Can J Gastroenterol. 2012 Nov; 26(11): 811–817. 
3- Khor B, Gardet A, Xavier R J. Genetics and pathogenesis of inflammatory bowel 
disease. Nature 2011; 474: 307-17 
4-Ruemmele FM. Role of Diet in Inflammatory Bowel Disease. Ann Nutr Metab. 2016;68 
Suppl 1:33-41. doi: 10.1159/000445392. Epub 2016 Jun 30 
5- Wall C, Day AS, Gearry R. Use of exclusive enteral nutrition in adults with Crohn’s 
disease: A review. World J Gastroenterol 2013; 19 (43): 7652-60 
6-Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for induction of remission 
in Crohn’s disease .Review Cochrane. Cochrane Database of Systematic Reviews 2007, 
Issue 1. Art. No.: CD000542 
7-Nahidi L, Day AS, Lemberg DA et al. Paediatric Inflammatory Bowel Disease: A 
Mechanistic Approach to Investigate Exclusive Enteral Nutrition Treatment. Scientific 
2014; 1-9 
8-O’Morain C, Segal AW, Levi AJ. Elemental diet as primary treatment of acute Crohn’s 
disease: a controlled trial. Br. Med. J. (Clin. Res. Ed.) 1984; 288: 1859–62. 
9- Critch J, Day AS, Otley A, et al. Use of enteral nutrition for the control of intestinal 
inflammation in pediatric Crohn disease. J Pediatr Gastroenterol Nutr. 2012;54:298–305. 
10-Grover Z, Burgess C, Muir R et al. Early Mucosal Healing with Exclusive Enteral 

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Nutrition is Associated with Improved Outcomes in Newly Diagnosed Children with 
Luminal Crohn’s disease.J Crohn’s Colitis 2016; 1-6 
11- Forbes A. Crohn’s disease: The role of nutritional therapy. Aliment. Pharmacol. Ther. 
2002; 16 (Suppl. 4): 48–52. 
12- Lionetti P, Callegari ML, Ferrari S, et al. Enteral nutrition and microflora in pediatric 
Crohn’s disease. J Parent Enteral Nutr 2005; 29 (Suppl 4):S173– S178; discussion S175–
S178, S184–S188. 
13- Guo Z, Wu R, Zhu W et al. Effect of Exclusive Enteral Nutrition on Health-Related 
Quality of Life for Adults With Active Crohn’s Disease. Nutr Clin Pract. 2013;28:499-505 
14-Sokulmez P, Demirbag AE, Arslan P et al. Effects of enteral nutritional support on 
malnourished patients with inflammatory bowel disease by subjective global assessment. 
Turk J Gastroenterol 2014; 25: 493-507 
15- Ferguson et al, Nutritional modulation of gene expression. Frontiers in Immunology 
2015 
16- Slack E, Hapfelmeier S, Stecher et al. Innate and adaptive immunity cooperate flexibly 
to maintain host-microbiota mutualism. Science. 2009 Jul 31;325(5940):617-20 
17-Alhagamhmad MH, Day AS, Lemberg DA, Leach ST. An update of the role of 
nutritional therapy in the management of Crohn’s disease. J Gastroenterol. 2012;47:872-
882. 
18- Dignass A, Van Assche G, Lindsay JO, et al. The second European evidence-based 
Consensus on the diagnosis and management of Crohn’s disease: Current management. 
J Crohns Colitis 2010; 4: 28-62 

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19-El-Matary W, Otley A, Critch J et al. Enteral Feeding Therapy for Maintaining 
Remission in Crohn’s Disease: A Systematic Review. J Parent Enteral Nutr 2015; 1-10 
20- Gatti S, Galeazzi T, Franceschini E et al. Effects of the Exclusive Enteral Nutrition on 
the Microbiota Profile of Patients with Crohn's Disease: A Systematic Review. Nutrients 
2017 Aug 4;9(8). 
21- Pinto Sanchez MI, Nardelli A, Borojevic R et al. Antigliadin Antibodies Predict the 
Symptomatic Response to Gluten-Free Diet and Improvement in Gastrointestinal Motility 
in IBS Patients. Gastroenterology, 2017: 152 ( 5); S45 
22- EOz HS, Ray M, Chen TS, et al. Efficacy of a Transforming Growth Factor 2 
Containing Nutritional Support Formula in a Murine Model of Inflammatory Bowel 
Disease.  J Am Coll Nutr. 2004 Jun;23(3):220-6. 
23- Fell JM, Paintin M, Arnaud-Battandier F,et al. Mucosal healing and a fall in mucosal 
pro-inflammatory cytokine mRNA induced by a specific oral polymeric diet in paediatric 
Crohn’s disease. Aliment Pharmacol Ther 14:281–289, 2000. 
24- Rana SV, Malik A.  Hydrogen breath tests in gastrointestinal diseases. Ind J Clin 
Biochem 2014; 29 (4): 398–405. 
25- Gasbarrini A, Corazza GR, Montalto M et al. Methodology and indications of H 2-
breath testing in gastrointestinal diseases: final statements from the Ist Rome consensus 
conference.  Al Pharmacol Ther 2009; 29 (1): 32–33. 
26- Tjellstrom, B.; Hogberg, L.; Stenhammar, L.; et al.  Effect of exclusive enteral nutrition 
on gut microflora function in children with Crohn’s disease. Scand. J. Gastroenterol. 2012, 
47, 1454–1459. 

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27- Gerasimidis, K.; Bertz, M.; Hanske, L; et al. Decline in presumptively protective gut 
bacterial species and metabolites are paradoxically associated with disease improvement 
in pediatric Crohn’s disease during enteral nutrition. Inflamm. Bowel. Dis. 2014, 20, 861–
871. 
28- Whitehead AL, Julious SA, Cooper CL et al. Estimating the sample size for a pilot 
randomised trial to minimise the overall trial sample size for the external pilot and main 
trial for a continuous outcome variable. Stat Methods Med Res. 2016 Jun;25(3):1057-73.  
29- Hertzog MA. Considerations in determining sample size for pilot studies. Res Nurs 
Health. 2008 Apr;31(2):180-91.  
30- Guo Z, Wu R, Zhu W et al. Effect of Exclusive Enteral Nutrition on Health-Related 
Quality of Life for Adults With Active Crohn’s Disease. Nutr Clin Pract 2013; 28 (4): 499– 
505 
31- Irvine EJ, Greenberg GR, Feagan BG et al. Quality of Life Rapidly Improves with 
Budesonide Therapy for Active Crohn’s Disease. Inflamm Bow Dis 2000; 6(3): 181-7 
32- Sanderson IR, Udeen S, Davies PS et al. Remission induced by an elemental diet in 
small bowel Crohn's disease. Arch Dis Child. 1987 Feb;62(2):123-7. 
33- Faiman A, Mutalib M, Moylan A,et al. Standard versus rapid food reintroduction after 
exclusive enteral nutritional therapy in paediatric Crohn's disease. Eur J Gastroenterol 
Hepatol. 2014 Mar;26(3):276-81 
34- Evans RC, et al. The normal range and simple diagram for recording whole gut transit 
time. Int J Colorect Dis (1992) 7:15-17 
 
 

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Figure 1 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Standard corticosteroids tapering regimen (ECS) 
 
Week 
 
1 
 
2 
 
3 
 
4 
 
5 
 
6 
 
7 
 
8 
 
9 
 
10 
 
CS 
mg/day 
 
 
40 
 
40 
 
35 
 
30 
 
25 
 
20 
 
15 
 
10 
 
5 
 
5 mg every 
other day  
*Short course corticosteroids tapering regimen (ECSC) 
 
Day 
 
1 
 
4 
 
7 
 
10 
 
13 
 
16 
 
 
 
 
 
CS 
mg/day 
 
 
40 
 
30 
 
20 
 
10 
 
5 
 
5 
every 
other 
day 
 
0 
 
0 
 
0 
 
0 
R 
V4 
(10 weeks) 
Informed 
consent 
BW 
Provide kit stool 
Questionnaires 
Randomization 
Diaries 
Collect stool,  
Urine,  
SHAPE 
nutritional 
assessment 
V2 
Baseline 
6 weeks – diaries  
Phone call: 3 weeks- re-
estimation weight and 
treatment compliance   
V3 
(6 weeks) 
ECS: Prednisone 40 
mg/day x 2 weeks and 
then tapering*+ Modulen 
1,5 kcal/ml (30 kcal/kg) 
Questionnaires 
Diaries 
Collect stool, urine, 
BW 
SHAPE 
 
Nutritional 
assessment 
Instructions food 
reintroduction in 
EEN arm** 
Questionnaires 
Diaries 
Collect stool, 
urine, BW 
SHAPE 
Nutritional 
assessment 
End of the study 
CS: Prednisone 
1mg/kg/day x 2 weeks and 
then tapering*+ Regular 
V1 
Screening 
ECSC: Prednisone 40 
mg/day then rapid 
tapering*+ Modulen 1,5 
kcal/ml (30 kcal/kg) 

Protocol date: October 2018 
21 
 
INSTRUCTIONS FOR FOOD REINTRODUCTION AFTER 6 WEEKS OF EXCLUSIVE 
ENTERAL NUTRITION 
https://www.qegateshead.nhs.uk/sites/default/files/users/user1/leaflets/IL382%20Modul
en%20IBD%20-%20Reintroduction%20of%20foods.pdf 
 
After 6 weeks on exclusive formula feeding, it is time to reintroduce all of the food you 
have removed during the program. The purpose of doing this very slowly is to give time 
to the gut to adapt to the diet. Transition to normal foods must be done with care, foods 
should be gradually reintroduced over a period of two to four weeks, however, it may be 
necessary to reintroduce foods more slowly.  
In order to accomplish this, please introduce each of the following food groups for the 
period of time suggested in each stage, ideally respecting the order. If you do have a 
reaction, such as headache, rash, brain fog, fatigue, digestive reaction or other 
symptom you are familiar with, write it down in the food reintroduction chart below or a 
food journal so you don’t forget later. If you discover a particular food isn’t good for you, 
remove it again. The food reaction should go away within a day or 2. If you are not used 
to take any of the foods from the list, it is ok to skip it. When you have finished 
reintroducing all the foods from the list, a free diet is allowed.  
 
Start date: .................................................  
 
Stage 1: (Two days) with ½ of IBD formula 
Initially fluids not containing dairy, eg tea or coffee black or with soya milk, fruit juice, 
fruit squash, Oxo, carbonated drinks, sieved soup, jelly or ice lollies.  
 
Stage 2: (Five days) with ½ of IBD formula 
Introduction of a few soft foods eg fish, chicken, egg, rice and potato. Small frequent 
snacks should be encouraged instead of one or two larger meals.  
 
Stage 3: (Five days) with ¼ of IBD formula 
Gradually increase the variety of foods in the diet continuing to keep the fibre and fat 
content low, eg red meat, stewed or peeled fruit, very well-cooked vegetables. The 
portion size of meals should be gradually increased with the number of snacks reduced.  
 
Stage 4: (Three days) with ¼ IBD formula 
Addition of bread and other gluten containing foods ie pasta, cereal, bread, biscuits, 
crackers, cakes, sausages.  
 
Stage 5: (Three days) No IBD formula 
Inclusion of milk or milk derivatives (if you are not lactose intolerant) ie margarine, 
butter, milk, cream, ice cream, yoghurts, fromage frais, milk pudding, custard.  
 
Stage 6: Gradually increase dietary fibre, fried and spicy food if desired. It may be an 
idea to keep a food and symptom diary recording the food you eat. See below for an 
example.  

Protocol date: October 2018 
22 
If you have any reaction to any food or food group, avoid adding anymore new foods. 
After three days you may return to the food reintroduction avoiding any suspect foods 
 
 
 
 
FOOD REACTION LOG 
 
Date 
Food/drink 
Symptoms 
Severity (1-5) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Protocol date: October 2018 
23 
 
 
Table : Food reintroduction (Sanderson et al, Arch Dis Child 1987; 61:123-127) 
 
Rationale for rapid introduction of foods vs standard (Faiman A, et al. Standard versus 
rapid food reintroduction after exclusive enteral nutritional therapy in paediatric Crohn's 
disease. Eur J Gastroenterol Hepatol. 2014 Mar;26(3):276-81) 
 
 
 
 
 
 
 

Protocol date: October 2018 
24 
Appendix 2-Steroids adverse events assessment (visit 2) 
 
Yes/no 
Comments 
1. Moon face 
 
 
2. Bloating 
 
 
3. Swelling 
 
 
4. Weight gain 
 
 
5. Increase appetite 
 
 
6. Hair loss 
 
 
7. Acne 
 
 
8. Stretch marks 
 
 
9. Insomnia, restlessness 
and or trouble sleeping 
 
 
10. Anxiety or nervousness 
 
 
11. Depression 
 
 
12. Anger/irritability 
 
 
13. Generalized weakness 
or fatigue 
 
 
14. Joint pain 
 
 
15. Hot flushes 
 
 
16. Visual problems (light 
sensitivity, decreased 
visual acuity) 
 
 
17. Nausea, vomiting 
 
 
18. Diarrhea 
 
 
19. Dizziness 
 
 
20. Headaches 
 
 
21. Hypertension 
 
 
22. High glucose levels 
 
 
 

Protocol date: October 2018 
25 
 

Protocol date: October 2018 
26 
 

Protocol date: October 2018 
27 
 
Harris JA, Benedict FG. A biometric study of human basal metabolism. Proc 
Natl Acad Sci USA 1918;4(12):370-3. 
Harris Benedict Equations: 
BMR calculation for men (metric)  
BMR = 66.47 + ( 13.75 x weight in kg ) + ( 5.003 x height in cm ) - ( 6.755 x 
age in years ) 
 
 
BMR calculation for women (metric)  
BMR = 655.1 + ( 9.563 x weight in kg ) + ( 1.850 x height in cm ) - ( 4.676 x 
age in years ) 
 
Activity factor: 
Sedentary.  Little to no regular exercise.   
(factor 1.2) 
 
Mild activity level: Intensive exercise for at least 20 minutes 1 to 3 times per 
week. This may include such things as bicycling, jogging, basketball, 
swimming, skating, etc.  If you do not exercise regularly, but you maintain a 
busy life style that requires you to walk frequently for long periods, you meet 
the requirements of this level.   
(factor 1.375) 
 
Moderate activity level: Intensive exercise for at least 30 to 60 minutes 3 to 
4 times per week. Any of the activities listed above will qualify.    (factor 1.55) 
 
Heavy or (Labor-intensive) activity level: Intensive exercise for 60 minutes 
or greater 5 to 7 days per week (see sample activities above).  Labor-
intensive occupations also qualify for this level.  Labor-intensive occupations 
include construction work (brick laying, carpentry, general labor, etc.). Also 
farming, landscape worker or similar occupations.     (factor 1.7) 
 
Extreme level: Exceedingly active and/or very demanding 
activities:  Examples include:  (1) athlete with an almost unstoppable training 
schedule with multiple training sessions throughout the day  (2) very 
demanding job, such as shoveling coal or working long hours on an assembly 
line. Generally, this level of activity is very difficult to achieve.  (factor 1.9) 
Calculator: http://www.globalrph.com/harris-benedict-equation.cgi