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Trial registered on ANZCTR


Registration number
ACTRN12616000322437
Ethics application status
Approved
Date submitted
23/02/2016
Date registered
11/03/2016
Date last updated
24/03/2021
Date data sharing statement initially provided
16/09/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A multicentre, randomized, controlled trial of Probiotic and Peanut Oral Immunotherapy (PPOIT) in inducing desensitisation or tolerance in children with peanut allergy compared with Oral Immunotherapy (OIT) alone and with placebo.
Scientific title
A multicentre, randomized, controlled trial evaluating the effectiveness of Probiotic and Peanut Oral Immunotherapy (PPOIT) in inducing desensitisation or tolerance in children with peanut allergy compared with Oral Immunotherapy (OIT) alone and with placebo.
Secondary ID [1] 288591 0
NIL
Universal Trial Number (UTN)
Trial acronym
PPOIT 003
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peanut Allergy 297734 0
Food Allergy 297735 0
Condition category
Condition code
Inflammatory and Immune System 297919 297919 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Peanut Flour (50% peanut protein) that is prepared under food manufacturing regulations.

PROBIOTIC
The probiotic to be used is Lactobacillus rhamnosus ATCC 53103 (Health World Ltd).
Probiotic will be prepared under strict Food Manufacturing Regulations. Supply will be as dry powder pre-packaged in 350g bottles containing 160g of probiotic. The daily dose of 2x10^10 cfu 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 must be stored at 4 degrees Celsius.

1. PPOIT- Probiotic and peanut OIT taken daily for 18 months.
2. OIT - Probiotic placebo and peanut OIT taken daily for 18 months.
3. Placebo - Probiotic placebo and OIT placebo taken daily for 18 months.

The study consists of:
Screening visit occurs within three months prior to Rush Induction Day.

T0 Rush Induction is Day 1 of treatment.
- On Rush day, participants receive eight increasing doses of peanut (or placebo) oral immunotherapy (OIT) beginning at 0.1mg every 20 minutes.
- Nutritional services or an individual independent of the study will prepare the Rush doses.
- Peanut protein (or placebo) will be mixed with food (e.g. yoghurt).
- A single dose of probiotic (or placebo) (one level scoop mixed into water, at a temperature NOT exceeding 38 degrees Celsius) is to be given immediately prior to the peanut/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 Rush Induction.
- The study doctor and study nurse will be present at all times during the Rush Induction.
- The Rush Induction will be performed in hospital.
- Spirometry 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 peanut (or placebo) OIT.
- Participants who complete the Rush protocol without reaction will commence the Buildup Phase at Dose 9 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 6, the subject will commence the Buildup phase at the dose 5 amount and will be instructed to start this reduced dose on the following day).

BUILDUP Phase
- During Buildup, the daily dose of peanut OIT (or placebo OIT) is increased every 2 weeks until a maintenance dose of 2000mg 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.
- Spirometry will not be performed as a routine, but may be performed if indicated.
- Peanut protein will be mixed into food (e.g. yoghurt not containing Lactobacillus rhamnosus ATCC 53103).
- A single dose of probiotic (or placebo) (one level scoop mixed into water, at a temperature NOT exceeding 38°C) is given once daily prior to OIT treatment.
- Subjects will be monitored for 2 hours after the treatment has been administered.

MAINTENANCE Phase
During Maintenance, participants will take a daily dose of 2g of peanut 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. In unavoidable circumstances (e.g. school camps) the window for Maintenance visits can be +/- 7 days to accommodate parent/participant availability

T1 - One Day after final day of maintenance treatment
T2 - 8 weeks after final day of maintenance treatment
T3 - One year after final day of treatment

All groups will be followed up for 1 year after the treatment period. During this time, at 6 months, a telephone interview will be conducted with the participant's parent or guardian to collect information on exposure to peanut/amount of peanut being eaten and allergic reactions.

STRATEGIES TO MONITOR ADHERENCE
We will monitor adherence by daily dosing diary and weighing / counting contents of returned treatment packages.
Intervention code [1] 293987 0
Treatment: Other
Comparator / control treatment
PEANUT PLACEBO:
Peanut Placebo is maltodextrin powder with food colouring and peanut essence that has similar appearance, taste and smell 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] 297435 0
Proportion of participants with 8-week sustained unresponsiveness (passed T1 and T2 challenges - determined by performing a double blind placebo controlled food challenge (DBPCFC)) in PPOIT vs placebo.
Timepoint [1] 297435 0
T2 - 8 weeks after final day of maintenance treatment.
Primary outcome [2] 297453 0
Proportion of participants with 8-week sustained unresponsiveness (passed T1 and T2 challenges - determined by performing a DBPCFC) in PPOIT vs OIT.
Timepoint [2] 297453 0
T2 - 8 weeks after final day of maintenance treatment.
Secondary outcome [1] 321047 0
Proportion of participants who achieve full desensitization (passed T1 challenge-determined by performing a double bling placebo controlled food challenge (DBPCFC)) in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo.
Timepoint [1] 321047 0
T1 - One Day after final day of maintenance treatment
Secondary outcome [2] 321081 0
The cumulative dose tolerated during the T1 challenge- determined by performing a double blind placebo controlled food challenge (DBPCFC)- (cumulative doses below the reaction-eliciting dose if there is a reaction; or total cumulative challenge dose if there is no reaction) in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo.
Timepoint [2] 321081 0
T1 - One Day after final day of maintenance treatment
Secondary outcome [3] 321082 0
Proportion of participants who are eating peanut in their diet without reactions at 12 months after cessation of treatment in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo. This will be assessed by parent-report during the T3 visit.
Timepoint [3] 321082 0
T3 - One year after final day of treatment
Secondary outcome [4] 321083 0
Change in peanut skin prick test wheal size at end of treatment, and at 8 weeks and 12 months after end of treatment) in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo. This outcome is assessed by a skin prick test.
Timepoint [4] 321083 0
T1 - One Day after final day of maintenance treatment. T2 - 8 weeks after final day of maintenance treatment. T3 - One year after final day of treatment.
Secondary outcome [5] 321396 0
Change in immunological measures (sIgE and sIgG4) at end of treatment, and at 8 weeks and 12 months after end of treatment) in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo. This will be determined from blood samples.
Timepoint [5] 321396 0
T1 - One Day after final day of maintenance treatment. T2 - 8 weeks after final day of maintenance treatment. T3 - One year after final day of treatment
Secondary outcome [6] 321633 0
Correlation between change in peanut skin prick test wheal size and sustained unresponsiveness at end of treatment, and at 8 weeks and 12 months after end of treatment) in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo. Sustained unresponsiveness is assessed by a Double Blind Placebo Controlled Food Challenge.
Timepoint [6] 321633 0
T1 - One Day after final day of maintenance treatment. T2 - 8 weeks after final day of maintenance treatment. T3 - One year after final day of treatment.
Secondary outcome [7] 321634 0
Correlation between change in immunological measures (sIgE and sIgG4) and sustained unresponsiveness at end of treatment, and at 8 weeks and 12 months after end of treatment) in: (i) PPOIT vs placebo; (ii) PPOIT vs OIT; and (iii) OIT vs placebo. Sustained unresponsiveness will be determined by a Double Blind Placebo Controlled Food Challenge.
Timepoint [7] 321634 0
T1 - One Day after final day of maintenance treatment. T2 - 8 weeks after final day of maintenance treatment. T3 - One year after final day of treatment.
Secondary outcome [8] 325494 0
Proportion of participants with 8-week sustained unresponsiveness (passed T1 and T2 challenges - determined by performing a DBPCFC) in OIT vs placebo.
Timepoint [8] 325494 0
T2 - 8 weeks after final day of maintenance treatment.
Secondary outcome [9] 345599 0
Peanut intake (accidental or intentional) from end-of-treatment to 12 months post-treatment. This outcome will be reported as total amount ingested. A Peanut Ingestion/Reaction Diary (specifically designed for this study) will be administered from T1 until T3 and checked by study staff at 6 months and 12 months post treatment (T3).
Timepoint [9] 345599 0
T1 - One Day after final day of maintenance treatment. T3 - One year after final day of treatment
Secondary outcome [10] 345600 0
Reactions to peanut from end-of-treatment to 12 months post-treatment. This outcome will be reported as total number of reactions. A Peanut Ingestion/Reaction Diary (specifically designed for this study) will be administered from T1 until T3 and checked by study staff at 6 months and 12 months post treatment (T3).
Timepoint [10] 345600 0
T1 - One Day after final day of maintenance treatment. T3 - One year after final day of treatment
Secondary outcome [11] 374868 0
Incidence and severity of treatment emergent adverse events (TEAEs).
Timepoint [11] 374868 0
TEAEs will be collected until T2 - 8 weeks after final day of maintenance.

Eligibility
Key inclusion criteria
Children are eligible for the study if they meet all of these criteria:
- Children aged between 1 year and 10 years of age
- greater than 7kg (the weight considered safe for the administration of an Epipen/EpiPen Jr)
- Confirmed diagnosis of peanut allergy as defined by a failed Double-Blind, Placebo-Controlled Food Challenge (CBPCFC) with peanut and a positive SPT or SIgE to peanut at screening.
Minimum age
1 Years
Maximum age
10 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children are not eligible for the study if they meet any of these criteria:
- History of severe anaphylaxis (as defined by persistent hypotension, collapse, loss of consciousness, persistent hypoxia or ever needing more than three doses of intramuscular adrenaline or an intravenous adrenaline 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 three or more doses of intramuscular adrenaline or an intravenous adrenaline infusion for management of an allergic reaction)
- FEV1 less than 85% at rest and FEV1/FVC is less than or equal to 85% at rest 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 within the past 6 months (does not include formula)
- 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
- 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)

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)
Participants will be enrolled and randomized up to one week prior to Rush Induction. Enrolled participants will be randomized to PPOIT, OIT or placebo groups with an allocation ratio of 2:2:1. Randomization will be stratified by study site (RCH, PCH, WCH), and also by age (1-5yr; 6-10yr) and peanut SPT wheal size (less than and equal to 10mm; greater than 10mm).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Each study site will have their own randomization list stratified by age and peanut SPT wheal size. Randomization will be in randomly permuted blocks of variable length. An independent statistician in the Clinical Epidemiology and Biostatistics Unit (CEBU) at Murdoch Childrens Research Institute (MCRI) will provide the randomization schedules to hospital pharmacies at each site. The study pharmacist at each hospital will assign the next available unique Randomisation Number for the participant's appropriate stratum using the randomisation list and notify the trial personnel of that number.
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
Participants will be randomized to one of three groups
1. PPOIT- Probiotic and peanut OIT taken daily for 18 months.
2. OIT- Probiotic placebo and peanut OIT taken daily for 18 months.
3. Placebo- Probiotic placebo and OIT placebo taken daily for 18 months.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
Sample Size Estimation:
The study sample size will be 200 participants, randomly allocated in a 2:2:1 ratio to PPOIT (n=80), OIT (n=80) and placebo (n=40). This ensures sufficient power to support both primary outcomes. Since the study aims to assess two primary endpoints, generalised Bonferroni-adjustment of p-values and confidence interval limits will be applied in order to warrant a global type I error probability of 5%.
For the primary outcome A - PPOIT vs placebo: We conservatively estimate a proportion of 60% of participants will achieve long term sustained unresponsiveness with PPOIT based on the results of our previous Randomized Controlled Trial; and the natural rate of resolution of peanut allergy is conservatively assumed to be equal to or below 15%. Applying a 2:1 ratio for randomization to PPOIT and placebo arms, sample sizes of n=62 and n=31 will provide 90% power with 2-tailed 0.005 significance level (10% of the global significance level) to detect the difference between 60% long term sustained unresponsiveness in the PPOIT group and 15% in the placebo group.

For the primary outcome B - PPOIT vs OIT: A pilot study of peanut OIT reported sustained unresponsiveness in 30% of participants. A sample size of n=70 in PPOIT and OIT groups will provide 80% power with 2-tailed 0.045 significance level (90% of the global significance level) to detect the difference between 60% long term sustained unresponsiveness in the PPOIT group and 35% in the OIT group.

Allowing for 15% loss to follow up, we will recruit 80 children to each of the PPOIT and OIT groups. In our completed RCT, loss to follow up was 10%.

Statistical Analysis:
Data handling, verification and analysis will be performed by an independent clinical research organisation, Datapharm, Australia, in collaboration with the Clinical Epidemiology and Biostatistics Unit at MCRI. Statistical analysis will follow standard methods for randomized trials and the primary analysis will be by intention to treat.
All available data from all participants who received any investigational 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 three groups.

Primary outcome:
The primary outcome is whether a participant has 8 week sustained unresponsiveness (passed T1 and T2 challenges). Results will be summarised as the number and proportion of children with long-term sustained unresponsiveness in the 3 treatment groups.
The primary efficacy analyses for sustained unresponsiveness will be conducted in the ITT population to test for a treatment difference, and will be conducted with two primary comparisons: 1) PPOIT minus placebo and 2) PPOIT minus OIT. While the sample size calculation was based on a Bonferroni analysis approach, the analysis approach is amended as follows: the multiple testing procedure to maintain global type I error for the 2 primary efficacy analysis treatment comparisons will be a “hierarchical” fixed-sequence testing strategy. Confidence intervals for the 2 primary efficacy treatment difference will be reported using alpha levels based on the updated as well as the original testing strategy.

Secondary outcomes:
Group comparisons (PPOIT vs placebo; PPOIT vs OIT; OIT vs placebo) regarding dichotomous outcomes will be performed using odds ratio estimates with 95% confidence intervals (CIs), obtained from a logistic regression analysis with adjustment for the stratification variables (centre, age category and SPT wheal size) used in the randomization.

Continuous outcomes will be compared using differences between mean values, estimated from normal linear regression models with the same stratification adjustments. Peanut SPT wheal size, sIgE and sIgG4 levels will be reported as mean and standard deviation by treatment group, and presented at end of treatment (18 months), at assessment of sustained unresponsiveness (20 months) and at end of study (30 months). The difference in means between groups and the corresponding 95% CI (PPOIT vs placebo; PPOIT vs OIT; OIT vs placebo) will be obtained by using an unadjusted linear regression and the hypothesis of no difference between the groups tested with a t-test. Analogously, quality of life continuous outcome measures will be summarized by treatment group at end of treatment (18 mos) and end of study (30 mos) and presented as a difference in means between groups and the corresponding 95% CI (PPOIT vs placebo; PPOIT vs OIT), obtained by using an unadjusted linear regression. If continuous outcomes don’t follow normal distributions they will be summarized as median and interquartile ranges (IQR) in the three groups, and comparison between groups will be performed by the Wilcoxon rank-sum (Mann-Whitney) test.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
2/05/2016
Actual
4/07/2016
Date of last participant enrolment
Anticipated
31/01/2017
Actual
6/03/2018
Date of last data collection
Anticipated
10/09/2020
Actual
22/12/2020
Sample size
Target
200
Accrual to date
Final
201
Recruitment in Australia
Recruitment state(s)
SA,WA,VIC
Recruitment hospital [1] 5319 0
The Royal Childrens Hospital - Parkville
Recruitment hospital [2] 5320 0
Womens and Childrens Hospital - North Adelaide
Recruitment hospital [3] 5322 0
Princess Margaret Hospital - Subiaco
Recruitment postcode(s) [1] 12782 0
3052 - Parkville
Recruitment postcode(s) [2] 12783 0
6008 - Subiaco
Recruitment postcode(s) [3] 12784 0
5006 - North Adelaide

Funding & Sponsors
Funding source category [1] 292946 0
Government body
Name [1] 292946 0
National Health and Medical Research Council
Country [1] 292946 0
Australia
Primary sponsor type
Other
Name
Murdoch Childrens Research Institute
Address
The Royal Children's Hospital,
Flemington Road,
Parkville,
Victoria
3052
Country
Australia
Secondary sponsor category [1] 291717 0
None
Name [1] 291717 0
Nil
Address [1] 291717 0
Nil
Country [1] 291717 0
Other collaborator category [1] 278848 0
Hospital
Name [1] 278848 0
Women and Children's Hospital Adelaide
Address [1] 278848 0
Women's and Children's Hospital
72 King William Road
North Adelaide
South Australia
5006
Country [1] 278848 0
Australia
Other collaborator category [2] 278849 0
Hospital
Name [2] 278849 0
Princess Margaret Hospital
Address [2] 278849 0
Roberts Road,
Subiaco,
Perth,
Western Australia
6008
Country [2] 278849 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294451 0
The Royal Children's Hospital Human Research Ethics Committee
Ethics committee address [1] 294451 0
Ethics committee country [1] 294451 0
Australia
Date submitted for ethics approval [1] 294451 0
Approval date [1] 294451 0
12/02/2016
Ethics approval number [1] 294451 0
35245D
Ethics committee name [2] 294452 0
The Women's and Children's Health Network (WCHN) Human Research Ethics Committee’s (HREC)
Ethics committee address [2] 294452 0
Ethics committee country [2] 294452 0
Australia
Date submitted for ethics approval [2] 294452 0
Approval date [2] 294452 0
Ethics approval number [2] 294452 0
Ethics committee name [3] 294453 0
Princess Margaret Hospital Ethics Committee
Ethics committee address [3] 294453 0
Ethics committee country [3] 294453 0
Australia
Date submitted for ethics approval [3] 294453 0
Approval date [3] 294453 0
Ethics approval number [3] 294453 0

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

Contacts
Principal investigator
Name 63746 0
Dr Paxton Loke
Address 63746 0
Allergy Immunology
Murdoch Children's Research Institute
Flemington Rd Parkville Victoria 3052
Country 63746 0
Australia
Phone 63746 0
+61 3 9345 5911
Fax 63746 0
+61 3 9345 4848
Email 63746 0
[email protected]
Contact person for public queries
Name 63747 0
Christine Axelrad
Address 63747 0
Allergy and Immune Disorders
Murdoch Childrens Research Institute
Flemington Rd
Parkville
Victoria
3052
Country 63747 0
Australia
Phone 63747 0
+61 3 9345 6974
Fax 63747 0
Email 63747 0
[email protected]
Contact person for scientific queries
Name 63748 0
Paxton Loke
Address 63748 0
Allergy Immunology
Murdoch Children's Research Institute
Flemington Rd Parkville Victoria 3052
Country 63748 0
Australia
Phone 63748 0
+61 3 9345 6974
Fax 63748 0
Email 63748 0
[email protected]

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.
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 Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseStudy protocol of a multicentre, randomised, controlled trial evaluating the effectiveness of probiotic and peanut oral immunotherapy (PPOIT) in inducing desensitisation or tolerance in children with peanut allergy compared with oral immunotherapy (OIT) alone and with placebo (the PPOIT-003 study).2020https://dx.doi.org/10.1136/bmjopen-2019-035871
EmbaseDysbiosis in food allergy and implications for microbial therapeutics.2021https://dx.doi.org/10.1172/JCI144994
EmbaseProbiotic peanut oral immunotherapy versus oral immunotherapy and placebo in children with peanut allergy in Australia (PPOIT-003): a multicentre, randomised, phase 2b trial.2022https://dx.doi.org/10.1016/S2352-4642%2822%2900006-2
N.B. These documents automatically identified may not have been verified by the study sponsor.