The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12613001210763
Ethics application status
Approved
Date submitted
6/06/2013
Date registered
4/11/2013
Date last updated
11/11/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effects of diet and omeprazole in patients with eosinophilic oesophagitis – a multi-centre, randomised controlled trial and investigation of novel disease mechanisms
Scientific title
Effects of a four food elimination diet in children with eosinophilic oesophagitis – a multi-centre, randomised controlled trial and investigation of novel disease mechanisms
Secondary ID [1] 282132 0
Nil
Universal Trial Number (UTN)
U1111-1140-6423
Trial acronym
4-FEED study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
eosinophilic oesophagitis 288629 0
Condition category
Condition code
Oral and Gastrointestinal 288964 288964 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
We aim to conduct the first randomised, controlled trial (RCT) of a dietary intervention for the treatment of eosinophilic oesophagitis (EOE) in children.

Group 1: Active treatment ,Oral Proton Pump Inhibitor (PPI) plus elimination diet)
8-12 week treatment with omeprazole (Losec [registered trademark]) for 8-12 weeks plus, four-food elimination diet (strictly avoiding all foods containing cow’s milk, soy, wheat or egg) during this 8-12 week period (as supervised by paediatric dietitian).
Participant will undergo gastroscopy and biopsies at the start and end of the treatment period to assess for histological response to the intervention.

Omeprazole dosage amount is as follows: 7.5 – 9.9 kg: 5mg mane and 10mg nocte, 10.0 – 14.9 kg:10 mg twice daily, 15.0 – 19.9 kg:15 mg twice daily, >20 kg: 20 mg twice daily. Medication will be dispensed at commencement of the study, after 4 weeks and if participant is currently active on the study at 10 week point also. Medication will be collected at 4 weeks, and at the follow-up endoscopy to measure compliance.

The treatment period of between 8-12 weeks is determined by the demand on endoscopy hospital bookings.

Intervention code [1] 286737 0
Treatment: Other
Intervention code [2] 286738 0
Treatment: Drugs
Comparator / control treatment
Group 2: Control treatment (PPI plus alone)
8-12 week treatment with oral omeprazole (Losec [registered trademark] ) for 8-12 weeks. During this 8-12 week period, participants will maintain an unrestricted diet (as supervised by paediatric dietitian). Participants will undergo gastroscopy and biopsies at the start and end of the treatment period to assess for histological response to the intervention.

Omeprazole dosage amount is as follows: 7.5 – 9.9 kg: 5mg mane and 10mg nocte, 10.0 – 14.9 kg:10 mg twice daily, 15.0 – 19.9 kg:15 mg twice daily, >20 kg: 20 mg twice daily.
Control group
Active

Outcomes
Primary outcome [1] 289091 0
This study will assess if the elimination of the four most common food allergens (cow’s milk, egg, wheat and soy) will induce disease remission in children with EOE.

Primary outcome measures: histological evidence of eosinophilic oeosphagitis on repeat gastroscopic oesophageal biospy (expresses as number of eosinophils per high power microscopic field)
Timepoint [1] 289091 0
Patient will be enrolled at the time of the primary diagnosis of untreated eosinophilic oesophagitis (as defined by the presence of at least 20 eosinophils per high power field) on oesophageal histology. Gastroscopy will be repeated after 8-12 weeks, (after the treatment period has been completed) and biopsy and blood samples collected.
Secondary outcome [1] 301752 0
This study will conduct mechanistic investigations in biopsy and blood specimens regarding the regulation of inflammatory and remodelling changes, including eotaxins, TSLP, fibrosis markers and other related effector molecules.

Timepoint [1] 301752 0
Patient will be enrolled at the time of the primary diagnosis of untreated eosinophilic oesophagitis (as defined by the presence of at least 20 eosinophils per high power field) on oesophageal histology. Gastroscopy will be repeated after 8-12 weeks (after the treatment period has been completed), and biopsy and blood samples collected.
Secondary outcome [2] 303398 0
Clinical response (symptom score).
Timepoint [2] 303398 0
Patient will be enrolled at the time of the primary diagnosis of untreated eosinophilic oesophagitis (as defined by the presence of at least 20 eosinophils per high power field) on oesophageal histology. Gastroscopy will be repeated after 8-12 weeks (after the treatment period has been completed), and biopsy and blood samples collected.
Secondary outcome [3] 303399 0
Encoscopic appearance (endoscopy score).
Timepoint [3] 303399 0
Patient will be enrolled at the time of the primary diagnosis of untreated eosinophilic oesophagitis (as defined by the presence of at least 20 eosinophils per high power field) on oesophageal histology. Gastroscopy will be repeated after 8-12 weeks (after the treatment period has been completed), and biopsy and blood samples collected.

Eligibility
Key inclusion criteria
Stage 1: All patients with possible EOE (age 1-18 yrs) undergoing a diagnostic gastroscopy at any of the four participating hospitals (at Royal Children’s Hospital Melbourne, Monash Medical Centre Melbourne, Children’s Hospital at Westmead Sydney, and Women’s and Children’s Hospital Adelaide) will be assessed for inclusion in the study.
Patients undergoing a diagnostic gastroscopy will be assessed for upper gastrointestinal symptoms, including:
* Nausea and vomiting
* Abdominal pain
* Diarrhoea
* FFT/weight loss
* Dysphagia
* Regurgitation
* Food bolus obstruction
* Food refusal
Stage 2: Patients will be inclucded in the randomised trial if a diagnosis of EOE was confirmed based on biopsies from the first gastroscopy. Biospies will be analysed by the hospital’s anatomical pathologist to assess whether the diagnostic criteria for EOE is confirmed. The diagnosis of EOE is based on the presence of at least 20 mucosal eosinophils/HPF in any of the upper or lower oesophageal biopsies.
NB: Patients who are already avoiding a food prior to the study as part of a known food allergy (e.g. egg or peanut allergy) can still be considered for the study if EOE was diagnosed while avoiding the food (which suggests that the food is not causing the EOE).
Minimum age
1 Years
Maximum age
18 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants meeting the following criteria will be excluded from the study.
*The patient does not fulfil the histological criteria for EOE (less than 20 mucosal eosinophils/HPF on histology).
* Recent treatment with systemic corticosteroids (prednisolone) or topical or inhaled corticosteroids (fluticasone aerosol or viscous budesonide) within 3 months of the gastroscopy.
* Recent or current treatment with omeprazole.
* Patient already on multiple food elimination diet
* Previous failure of elimination diets (as it may skew the data towards non-response)
* Inability to obtain informed consent
* Inability to comply with the prescribed four-food elimination diet or PPI treatment
* Contraindications to gastroscopy or general anaesthesia

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)
Stage 1 recruitment: All patients with possible EOE undergoing gastroscopy will be recruited through the paediatric gastroenterology units at one of the four hospitals participating in the research study.
Prior to the patient’s gastroscopy patients/parents will be approached by the research team and invited to participate in the study. Informed written consent will be obtained from all participants/parents.

Stage 2: If EOE is confirmed on histology, participants/ parents will be approached to be recruited into the second stage of the study. These participants will be randomised using a web-based central randomisation by computer randomisation system provided by the Clinical Epidemiology and Biostatistics Unit (CEBU) at RCH.
Participants will be randomised to either drug plus diet, or drug alone. The intervention will be open label, and no placebo medication is used.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be performed using a randomisation list generated by a statistician as per the following requirements:
- Randomization ratio is 1:1 active group to control group.
- Block sizes distributed randomly.
- Blocks pre-assigned to stratification factors, i.e. the 4 participating centres.
- Total anticipated number of patients to be randomized = 98 (based on sample size calculation).
- Randomisation codes sufficient to allow for recruitment of 100 patients in Melbourne and 50 patients in each other centre.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Group comparisons of continuous variables will be performed by Student's t-test, and categorical data (proportions) compared by chi-square analysis. Factors predicting treatment response will be assessed by multivariate analysis (multiple logistic regression). A total of 98 participants required in stage 2 of the study.

The sample size calculation is based on an expected response rate of 60% to the elimination diet plus PPI, compared to 30% to PPI treatment (power 80%, significance level p<0.05).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,SA,VIC
Recruitment hospital [1] 1087 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 1088 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [3] 1089 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment hospital [4] 1090 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 6944 0
3052 - Parkville
Recruitment postcode(s) [2] 6946 0
3168 - Clayton
Recruitment postcode(s) [3] 6945 0
5006 - North Adelaide

Funding & Sponsors
Funding source category [1] 286901 0
Government body
Name [1] 286901 0
National Health and Medical Research Council (NHMRC Project Grant #1029972)
Address [1] 286901 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 286901 0
Australia
Primary sponsor type
Charities/Societies/Foundations
Name
Murdoch Childrens Research Institute
Address
Royal Children's Hospital
Flemington Road
Parkville VIC 3052
Country
Australia
Secondary sponsor category [1] 285688 0
None
Name [1] 285688 0
None
Address [1] 285688 0
None
Country [1] 285688 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288961 0
The Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 288961 0
50 Flemington Rd
Parkville 3052
Ethics committee country [1] 288961 0
Australia
Date submitted for ethics approval [1] 288961 0
21/02/2012
Approval date [1] 288961 0
27/07/2012
Ethics approval number [1] 288961 0
32059

Summary
Brief summary
Eosinophilic oesophagitis (EOE) is a recently discovered condition which involves allergic inflammation in the oesophagus. This research project aims to conduct the first study of a dietary intervention for the treatment of EOE in children. As part of the research we also aim to mechanistic studies into the pathophysiology of this condition.

This study is being completed in two stages. In Stage 1, children with suspected EOE undergoing gastroscopy will be invited to take part into the study. Only patients with confirmed EOE will progress to stage 2 of the study.

In Stage 2, children with confirmed EOE will be randomly allocated to one of two interventions: four-food elimination diet (avoiding cow's milk, egg, soy and wheat) plus omeprazole, versus omeprazole alone as the control intervention (for 8 -12 weeks in each arm of the study).
Trial website
Not available
Trial related presentations / publications
Nethercote M, Heine RG, Kansal S, Ho SCS, Chow CW, Cameron D, Alex G, Erbas B, Osborne N, Stevens L, Davidson D, Allen KJ. Clinical features of eosinophilic esophagitis in a consecutive series of pediatric patients in an Australian tertiary referral center. Journal of Food Allergy 2012;1:160-9.
Public notes
Not available

Contacts
Principal investigator
Name 38518 0
Dr Ralf Heine
Address 38518 0
Department of Gastroenterology & Clinical Nutrition
The Royal Children's Hospital
50 Flemington Rd
Parkville VIC 3052
Country 38518 0
Australia
Phone 38518 0
+61 3 9345 5060
Fax 38518 0
+61 3 9345 6240
Email 38518 0
ralf.heine@rch.org.au
Contact person for public queries
Name 38519 0
Ms Cassandra Quick
Address 38519 0
Gastroenterolgy and Food Allergy Group
Murdoch Childrens Research Institute
50 Flemington Rd
Parkville
3052
Country 38519 0
Australia
Phone 38519 0
+61 3 9936 6601
Fax 38519 0
Email 38519 0
cassandra.quick@mcri.edu.au
Contact person for scientific queries
Name 38520 0
Dr Ralf Heine
Address 38520 0
Department of Gastroenterology & Clinical Nutrition
The Royal Children's Hospital
50 Flemington Rd
Parkville VIC 3052
Country 38520 0
Australia
Phone 38520 0
+61 3 9345 55060
Fax 38520 0
Email 38520 0
ralf.heine@rch.org.au

No information has been provided regarding IPD availability
Summary results
No Results