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Trial registered on ANZCTR


Registration number
ACTRN12619000480189
Ethics application status
Approved
Date submitted
25/02/2019
Date registered
22/03/2019
Date last updated
15/11/2019
Date data sharing statement initially provided
22/03/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Randomised, controlled trial evaluating the effectiveness of probiotic and egg oral immunotherapy at inducing desensitisation or tolerance in participants with egg allergy compared with placebo (Probiotic Egg Allergen Oral Immunotherapy for Treatment of Egg Allergy: PEAT study).
Scientific title
A phase 2, dual-centre, randomised, controlled trial evaluating the effectiveness of probiotic and egg oral immunotherapy at inducing desensitisation or sustained unresponsiveness (remission) in participants with egg allergy compared with placebo (Probiotic Egg Allergen Oral Immunotherapy for Treatment of Egg Allergy: PEAT study).
Secondary ID [1] 297147 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Probiotic Egg Allergen Oral Immunotherapy for Treatment of Egg Allergy: PEAT study
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Egg allergy 311177 0
Condition category
Condition code
Inflammatory and Immune System 309797 309797 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised 1:1 into an active (probiotic and egg immunotherapy) or placebo arm (placebo).

The study consists of:
- Screening visit occurs within 1 month prior to Rush Induction Day (T0).



T0 Rush Induction is day 1 of treatment.
- On Rush day, all participants receive increasing doses of egg (or placebo) oral immunotherapy (OIT) every 20 minutes to reach a final dose of egg white protein or placebo, beginning at 0.4 mg.
- Nutritional services or an individual independent of the study will prepare the Rush doses.
- Egg white protein (or placebo) will be mixed with any food (excluding foods that contain egg) the participant enjoys.
- A single dose of probiotic or placebo (one standardised scoop mixed into water, at a temperature NOT exceeding 38°C) and is to be given immediately prior to the egg / placebo dosing.
- Participants will be monitored (including vital signs and general nursing assessment of the skin and chest) for 2 hours after the last dose during the Rush Phase.
- The study doctor and study nurse will always be present during the Rush Induction.
- The Rush Induction will be performed in hospital.
- Spirometry or peak flow will be performed on all participants aged 8 or older, and younger participants who are capable of doing spirometry reproducibly, before the participant receives their first dose of egg oral immunotherapy of Day 1 Rush Induction.
- Participants who complete the Rush protocol without reaction will commence the Buildup Phase at a daily dose of egg white protein on the day after the Rush Induction day.
- If a participant reacts to one of the doses during Rush Induction, the Rush schedule will be ceased, and the participant will commence the Buildup Phase at the dose immediately below the reaction-eliciting dose starting on the day after the Rush Induction day.
- The remaining Rush doses that were not completed on day 1 will be incorporated into the Buildup phase (modified Buildup schedule for that subject) and subsequent incremental dose increases will proceed through all remaining doses of the Rush schedule followed by the doses in the Buildup schedule.
- For example, if a reaction occurs following dose 3, the participant will commence the Buildup phase at the dose 2 amount and will be instructed to start this reduced dose on the following day).

BUILDUP Phase
-During Buildup, the daily dose of egg oral immunotherapy (OIT) (or placebo OIT) is increased every 2 weeks until the maintenance dose is reached.
-Each dose increase will be administered in hospital under medical supervision.
-Hospital visits for dose increases (Updose visits) will be scheduled every 2 weeks (except in unavoidable circumstances when a window of +/- 7 days is allowed). Where indicated, dose adjustments will result in deferment of a dose increase to the next scheduled visit.
-Egg white protein (or placebo) will be mixed with food the participant enjoys.
-A single dose of probiotic or placebo (one standardised scoop mixed into water, at a temperature NOT exceeding 38°C) is given once daily prior to the OIT treatment.
-Subjects will be monitored for 2 hours after the treatment has been administered.

MAINTENANCE Phase
- During Maintenance, participants take a daily top dose (2040 mg) of egg white protein (or placebo) and a daily dose of probiotic or placebo at home and continue until a total of 18 months treatment is completed.
- If the subject has not completed a minimum of 6 months on maintenance dosing at 18 months, the total duration of treatment will be extended to ensure a minimum of 6 months maintenance dosing.

T1 - One Day after final day of maintenance treatment
T2 - 8 weeks after final day of maintenance treatment
Safety follow up (phone call) 30 days (+/- 7 days) after T2

STRATEGIES TO MONITOR ADHERENCE
- Participants will be required to fill in a diary every day to monitor compliance and reactions.
- Pharmacy also count the returned study product to ensure compliance.
Intervention code [1] 313408 0
Treatment: Other
Comparator / control treatment
EGG PLACEBO
Egg placebo is maltodextrin with yellow food colouring and will have a similar appearance, to the active product.

PROBIOTIC PLACEBO:
Probiotic Placebo is maltodextrin. The daily dose will be measured using a standardised scoop. Participants will be instructed to mix one scoop of the probiotic in water at a temperature NOT exceeding 38 degrees Celsius. The Probiotic should be stored at 2-8 degrees Celsius.
Control group
Placebo

Outcomes
Primary outcome [1] 318763 0
The proportion of participants who attain sustained unresponsiveness in active and placebo groups,
Sustained unresponsiveness will be defined as passing the Double Blind Placebo Controlled Food Challenge (DBPCFC) at T2, 8 weeks after end-of-treatment.
Timepoint [1] 318763 0
T2 - 8 weeks after final day of maintenance treatment.
Secondary outcome [1] 365943 0
The proportion of subjects who attain full desensitisation (at end-of treatment) in active and placebo groups.
Full desensitisation will be defined as passing the T1 DBPCFC and failing the T2 DBPCFC.
Timepoint [1] 365943 0
T1 - One day after final day of maintenance treatment and T2 - Eight weeks after final day of maintenance treatment
Secondary outcome [2] 365946 0
Egg skin prick test (SPT) wheal size at, end-of-treatment, and 8 weeks in active and placebo groups. This outcome is assessed by a skin prick test. Wheal size will be measured with a ruler by a person independent to the study who is trained in measuring SPT.
Timepoint [2] 365946 0
T1 - One day after final day of maintenance treatment & T2 - 8 weeks after final day of maintenance treatment
Secondary outcome [3] 365947 0
Serum/plasma levels of sIgE and sIgG4 to egg and egg components (Gal d 1,2,3) at end-of-treatment, and 8 weeks after end-of-treatment in active and placebo groups. This will be a composite outcome using the blood samples provided.
Timepoint [3] 365947 0
T1 - One Day after final day of maintenance treatment. T2 - 8 weeks after final day of maintenance treatment.
Secondary outcome [4] 365948 0
Change from baseline in quality of life at end-of treatment, and 8 weeks after end-of treatment in active in placebo groups; using the validated Food Allergy Quality of Life Questionnaires (FAQLQ)
Timepoint [4] 365948 0
T1 - One Day after final day of maintenance treatment. T2 - 8 weeks after final day of maintenance treatment.
Secondary outcome [5] 376902 0
The cumulative dose tolerated during T1 challege (cumulative doses below the reaction-eliciting dose if there is a reaction; or total cumulative challenge dose if there is no reaction) in active vs placebo
Timepoint [5] 376902 0
T1 - on day after end of maintenance treatment
Secondary outcome [6] 376903 0
To evaluate the safety and tolerability of probiotic and egg OIT by looking at adverse events. They will be recorded in the study diary, allergy questionnaire and via phone calls when participants call for advice.
Timepoint [6] 376903 0
End of study

Eligibility
Key inclusion criteria
Subjects are eligible for the study if they meet all of the following criteria:
- Aged between 5 and 30 years of age
- Confirmed diagnosis of egg allergy as defined by a failed DBPCFC and a positive SPT or sIgE to egg at screening
Minimum age
5 Years
Maximum age
30 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Subjects are not eligible for the study if they meet any of the following criteria:
• Subjects who are on an egg ladder diet (except baked egg)
• History of severe anaphylaxis (as defined by persistent hypotension, collapse, loss of consciousness, persistent hypoxia or ever needing more than three (3) doses of intramuscular adrenaline (epinephrine) or an intravenous adrenaline (epinephrine) infusion for management of an allergic reaction)
• Severe anaphylaxis during the study entry DBPCFC (defined as persistent hypotension, collapse, loss of consciousness, persistent hypoxia, or requiring more than 3 doses of intramuscular adrenaline (epinephrine) or an intravenous adrenaline (epinephrine) infusion for management of an allergic reaction)
• FEV1 less than 85% predicted at rest and FEV1/FVC is less than or equal to 85% predicted at rest (for those participants able to perform spirometry testing) or ongoing chronic persistent asthma (as per Australian Asthma Foundation guidelines)
• Underlying medical conditions (e.g. cardiac disease) that increase the risks associated with anaphylaxis
• Use of beta-blockers, and ACE inhibitors
• Inflammatory intestinal conditions, indwelling catheters, gastrostomies, immune-compromised states, post-cardiac and/or gastrointestinal tract surgery, critically-ill and those requiring prolonged hospitalisation or other conditions that may increase the risks of probiotic associated sepsis
• Already taking probiotic supplements or food containing probiotics in the last month.
• Reacting to the placebo component during the study entry DBPCFC
• Have received other food immunotherapy treatment in the preceding 12 months
• Currently taking immunomodulatory therapy (including allergen immunotherapy)
• Past or current major illness that in the opinion of the Site Investigator may affect the subject’s ability to participate in the study e.g. increased risk to the participant
• History of suspected or biopsy-confirmed eosinophilic oesophagitis (EoE)
• Subjects who in the opinion of the Site Investigator are unable to follow the protocol
• Another family member already enrolled in the trial (to maintain safety and blinding)
• Non-English speaking participants and families
• Participants 18 years or over (RCH site only)

NOTE: participants with other food allergies are NOT excluded from participating in this trial.

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)
Central randomisation by computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Randomisation will be to active or placebo groups with an allocation ratio of 1:1.
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
SAMPLE SIZE ESTIMATION
The study sample size will be 80 participants, randomly allocated in a 1:1 ratio to active (n=40), and placebo (n=40). An effective treatment for food allergy should induce sustained unresponsiveness in at least 50% of subjects to be worthwhile.

Allowing for a 30% drop-out rate, 40 participants in each group provides 90% power to detect the difference between a 35% rate of sustained unresponsiveness in the placebo group and a 70% rate in the active group, using a 2 group continuity corrected chi2 test with 0.05 two sided significance.

STATISTICAL ANALYSIS
- Data handling, verification and analysis will be performed within the Clinical Epidemiology and Biosatisics Unit at MCRI. Statistical analysis will follow standard methods for randomised trials and the primary analysis will be by intention to treat.
- All available data from all participants who received any investigation product will be included in the analysis of the safety data (referred to as the safety population).
- All demographic and baseline continuous outcomes will be presented as mean and standard deviation (or medians and interquartile ranges for skewed data), whilst categorical outcomes will be presented as absolute and relative frequencies in the two groups.

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)
VIC
Recruitment hospital [1] 12968 0
The Royal Childrens Hospital - Parkville
Recruitment postcode(s) [1] 25446 0
3052 - Parkville
Recruitment outside Australia
Country [1] 21217 0
Singapore
State/province [1] 21217 0

Funding & Sponsors
Funding source category [1] 298561 0
Government body
Name [1] 298561 0
National Health and Medical Research Council
Address [1] 298561 0
Level 1
16 Marcus Clarke Street
Canberra ACT 2601
Country [1] 298561 0
Australia
Primary sponsor type
Other
Name
Murdoch Children's Research Institute
Address
The Royal Children's Hospital,
Flemington Road,
Parkville,
Victoria 3052
Country
Australia
Secondary sponsor category [1] 297709 0
None
Name [1] 297709 0
N/A
Address [1] 297709 0
N/A
Country [1] 297709 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299528 0
Royal Children's Hospital Ethics committee
Ethics committee address [1] 299528 0
50 Flemington Road,
Parkville, 3052, Victoria
Ethics committee country [1] 299528 0
Australia
Date submitted for ethics approval [1] 299528 0
06/12/2018
Approval date [1] 299528 0
18/07/2019
Ethics approval number [1] 299528 0

Summary
Brief summary
The primary purpose of the study is to evaluate the efficacy of probiotic and egg oral immunotherapy compared to placebo in achieving sustained unresponsiveness in participants with egg allergy 8 weeks after end-of-treatment.
The trial will include proven egg allergic people from 5 to 30 years of age. They will be randomised 1:1 into active and placebo groups. This study is expected to run for 4 years from the start of participant screening to the last participant finishing the study. The length of the treatment period for each participant is 18 months and the follow up period is 3 months.

The discovery of a safe and tolerable treatment for food allergy will have great public health benefit.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80734 0
Prof Mimi Tang
Address 80734 0
Murdoch Children's Research Institute
50 Flemington Road
Parkville, 3052, Victoria
Country 80734 0
Australia
Phone 80734 0
+61393455911
Fax 80734 0
Email 80734 0
mimi.tang@rch.org.au
Contact person for public queries
Name 80735 0
Miss Sigrid Pitkin
Address 80735 0
Murdoch Children's Research Institute
50 Flemington Road
Parkville, 3052, Victoria
Country 80735 0
Australia
Phone 80735 0
+61393456068
Fax 80735 0
Email 80735 0
sigrid.pitkin@mcri.edu.au
Contact person for scientific queries
Name 80736 0
Prof Mimi Tang
Address 80736 0
Murdoch Children's Research Institute
50 Flemington Road
Parkville, 3052, Victoria
Country 80736 0
Australia
Phone 80736 0
+61393455911
Fax 80736 0
Email 80736 0
mimi.tang@rch.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
The study protocol, documentation, data and all other information generated will be held in strict confidence. No information concerning the study or the data will be released to any unauthorised third party, without prior written approval of the sponsoring institution.
Authorised representatives of the sponsoring institution may inspect all documents and records required to be maintained by the Site Investigator, including but not limited to, medical records (office, clinic or hospital) and pharmacy records for the participants in this study.
All laboratory specimens, evaluation forms, reports and other records that leave the site will be identified only by the Participant Identification Number (SID) to maintain participant confidentiality. Clinical information will not be released without written permission of the participant, except as necessary for monitoring by HREC or regulatory agencies.
What supporting documents are/will be available?
No other documents available
Summary results
No Results