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Trial registered on ANZCTR


Registration number
ACTRN12608000594325
Ethics application status
Approved
Date submitted
31/10/2008
Date registered
25/11/2008
Date last updated
13/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Study of the effectiveness of Probiotics and Peanut Oral Immunotherapy (P-POIT) in inducing desensitisation or tolerance in children with peanut allergy
Scientific title
Study of the effectiveness of Probiotics and Peanut Oral Immunotherapy (P-POIT) in inducing desensitisation or tolerance in children with peanut allergy
Secondary ID [1] 252052 0
Nil known
Universal Trial Number (UTN)
Trial acronym
P-POIT
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peanut allergy 3872 0
Condition category
Condition code
Inflammatory and Immune System 4069 4069 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Lactobacillus rhamnosus GG (LGG) and Peanut Oral Immunotherapy

LGG - 1 scoop delivering 2x10E10 Colony-forming units (cfu) of LGG taken once daily for 18 months dissolved into water, soy or cow’s milk, at a temperature NOT exceeding 45 °C

Peanut Oral Immunotherapy (OIT) - In the modified rush phase, subjects will receive increasing doses of peanut oral immunotherapy, starting at 0.1mg peanut protein with doubling of the dosage every 30 minutes to reach a final dose of 12mg of peanut protein (in total 8 doses delivered in 1 day, with a cumulative dose of 24mg peanut protein). In the buildup phase, the daily dose of peanut OIT will start at 24mg peanut protein and will be increased every 2 weeks until a maintenance dose of 2g is reached (expected to take 8 months). Dosage increments are as follows :- 24mg, 25mg, 50mg, 75mg, 100mg, 125mg, 150mg, 200mg, 260mg, 330mg, 425mg, 550mg, 715mg, 925mg, 1.2g, 1.55g and 2g. If mild allergic symptoms develop (urticaria, angioedema, vomiting, abdominal pain), the dose is repeated before increasing. If moderate/severe allergic symptoms occur (stridor, wheeze) the dose will be reduced by 25% before proceeding. If severe anaphylaxis develops (reduced BP, loss of consciousness) OIT will be discontinued. The dose is maintained at 2g for about 10 months, but will be shorter for subjects who take longer to reach maintenance dose. Peanut oral immunotherapy will administered orally in all phases with the peanut protein sprinkled and mixed into yoghurt. The overall duration of the intervention is 18 months.
Intervention code [1] 3599 0
Treatment: Other
Comparator / control treatment
OIT placebo is maltodextrin, a glucose polymer mixed with peanut flavour and powdered brown food colouring so it looks, tastes and smells like the peanut product. OIT placebo will be given in exactly the same amount and frequency and for the same duration as the peanut protein as described above and will be administered orally, sprinkled and mixed into yoghurt.

The probiotic placebo will be maltodextrin, administered as 1 scoop once daily for 18 months (the same amount, frequency and duration as the treatment group) dissolved into water, soy or cow’s milk, at a temperature NOT exceeding 45 °C.
Control group
Placebo

Outcomes
Primary outcome [1] 4969 0
To examine whether combined treatment with probiotic and peanut OIT (P-POIT) in children with peanut allergy will induce tolerance to peanut in a greater proportion of children compared with placebo, where tolerance is defined as the ability to tolerate 8g of peanut protein in an oral peanut challenge performed 2 to 12 weeks after discontinuation of P-POIT (in those who pass the first challenge on the last day of P-POIT)
Timepoint [1] 4969 0
2-12 weeks after discontinuation of P-POIT
Secondary outcome [1] 8384 0
To examine whether combined treatment with probiotic and peanut OIT (P-POIT) in children with peanut allergy will result in desensitisation to peanut in a greater proportion of children compared with placebo, where desensitisation is defined as the ability to tolerate >2g of peanut protein in an oral peanut challenge performed on the last day of oral immunotherapy.
Timepoint [1] 8384 0
On day of discontinuation of P-POIT.
Secondary outcome [2] 8385 0
To examine the effects of combined treatment with probiotic and peanut OIT (P-POIT) or placebo on serum levels of peanut specific Immunoglobulin E (IgE) and peanut specific Immunoglobulin G4 (IgG4). and salivary levels of peanut specific Immunoglobulin A (IgA) in children with peanut allergy. IgE will be measured by Capsulated Hydrophobic Carrier Polymer- Radioallergosorbent Test (CAP-RAST) in our laboratory using the UNICAP system (Pharmacia Diagnostics). IgG4 and IgA will be measures by Enzyme-Linked ImmunoSorbent Assay (ELISA) at our collaborator, Wesley Burks' lab in Duke University Medical Centre, USA.
Timepoint [2] 8385 0
4, 8, 12, 18, 22 and 23 months
Secondary outcome [3] 8386 0
To examine the effects of combined treatment with probiotic and peanut OIT (P-POIT) or placebo on peripheral blood T regulatory cell (Treg) and dendritic cell (DC) populations and T helper 1 and T helper 2 cytokine production.

Mononuclear cells (MNC) will be separated from heparinised blood by density gradient centrifugation within 8 hours and cryopreserved (20x10E6cells/ml) at each timepoint. Treg and DC populations will be assessed by flow cytometry in freshly thawed and cultured MNC stimulated with anti-CD3, Ara h 2, crude peanut extract or tetanus antigens.

Treg will be identified as CD3+CD4+CD25hiCD127lo cells and CD3+CD4+CD25hiFoxp3+ cells. Proliferating CD4+ cells will be identified by reduced Carboxyfluorescein succinimidyl ester (CFSE) staining and antigen specific Treg will be identified within this population by staining for Foxp3+ or CD127lo cells.

DC will be assessed by flow cytometry - plasmacytoid dendritic cells (pDC) and myeloid dendritic cells (mDC) will be identified as CD11cloCD123whi or CD11chiCD123wlo cells within the lineage-/HLADR+ cell population, respectively.

T helper and Treg cytokines will be assessed in MNC cultures stimulated with PHA, anti-CD3, tetanus toxoid, crude peanut extract, Ara h 2 or media alone at each timepoint. IFN?, IL4, IL13, TGF-beta and IL10 will be assayed by multiplex array.
Timepoint [3] 8386 0
4, 8, 12, 18, 22 and 23 months
Secondary outcome [4] 336881 0
To examine whether combined treatment with probiotic and peanut OIT (P-POIT) in children with peanut allergy will induce long-term tolerance to peanut in a greater proportion of children compared with placebo, where long-term tolerance is defined as the ability to tolerate 4g of peanut protein in an oral peanut challenge performed 3-4 years after discontinuation of OIT.
Timepoint [4] 336881 0
3-4 years after discontinuation of OIT.

Eligibility
Key inclusion criteria
Children are eligible for the study if they:
1) Are aged between 1 year and 10 years of age
2) Are above 10kg
3) There is a confirmed diagnosis of peanut allergy as defined by:
-a positive food challenge to peanut in the past 2 years AND a positive skin prick test (SPT) or Capsulated Hydrophobic Carrier Polymer- Radioallergosorbent Test (CAP-RAST) to peanut
OR
-a positive food challenge or history of reaction to peanut ever AND a positive SPT greater than or equal to 8mm or a CAP-RAST greater than or equal to 15KU/l to peanut
Minimum age
1 Years
Maximum age
10 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Children will not be eligible for the study if they have a history of:
1) severe anaphylaxis (as defined by hypotension , collapse, loss of consciousness or hypoxia)
2) Forced Expiratory Volume in 1 Second (FEV1) of <85% at rest or ongoing chronic persistent asthma (as per Australian Asthma Foundation guidelines)
3) Underlying medical conditions (eg cardiac disease) that increase the risks associated with anaphylaxis
4) Known wheat allergy (the placebo may contain traces of wheat)
5) Use of beta-blockers
6) Inflammatory intestinal conditions, indwelling catheters, gastrostomies or other conditions that may increase the risks of probiotic associated sepsis
7) Cow’s milk allergy, as there may be traces of cow’s milk in the probiotic preparation
8) Already taking probiotics

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)
All screened subjects will be given a screening number and if deemed eligible, will be assigned a study number. This study number will correspond to a number on a computer-generated list to determine which treatment arm the subject is assigned to. This list will be generated at the hospital's Biostatistics Unit and delivered to the Pharmacy Department in a sealed opaque envelope.

Peanut/placebo product is concealed in coloured sachets and only the Pharmacy Department has the codes to unblind the the product.

Probiotic/placebo product is concealed in tins which have been randomized by the supplier (Nestle) and the randomization code was sealed in an opaque envelope and mailed directly to the Pharmacy Department.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be from a computer-generated list of random numbers in short permuted blocks prepared by the Clinical Epidemiology and Biostatistics Unit (CEBU) in the Royal Children's Hospital (RCH) and will be used by the Pharmacy department to distribute oral immunotherapy and probiotic treatments.

Randomisation will be stratified by: 1) age 5 years or less and 6 years or older; and 2) skin prick test (SPT) wheal size 10mm or less and greater than 10mm.

The nurse delivering the oral immunotherapy will not know which intervention arm of the study the patient is in – i.e. the study will be double blind.
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
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
We aim to recruit 90 subjects. N=38 in each group provides greater than 80% power to detect the difference between a 4% rate of tolerance in the placebo group and a 30% rate of tolerance in the treatment group, using a 2 group continuity corrected chi-square test with a 0.05 two sided significance level. Allowing for 15% participant loss, n=45 in each group will be recruited. We will perform intention to treat analysis, and logistic regression with adjustment for potential confounders.


Recruitment
Recruitment status
Completed
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

Funding & Sponsors
Funding source category [1] 4054 0
Charities/Societies/Foundations
Name [1] 4054 0
Food Allergy and Anaphylaxis Network (FAAN)
Address [1] 4054 0
11781 Lee Jackson Hwy., Suite 160
Fairfax, VA 22033-3309
Country [1] 4054 0
United States of America
Funding source category [2] 4055 0
Commercial sector/Industry
Name [2] 4055 0
Macquarie Bank Foundation
Address [2] 4055 0
No 1 Martin Place
Sydney NSW 2000
Country [2] 4055 0
Australia
Funding source category [3] 257154 0
Other
Name [3] 257154 0
Murdoch Children's Research Institute
Address [3] 257154 0
FLemington Rd, Parkville, VIC 3052
Country [3] 257154 0
Australia
Funding source category [4] 295798 0
Charities/Societies/Foundations
Name [4] 295798 0
Financial Markets Foundation for Children
Address [4] 295798 0
GPO Box 3655
Sydney NSW 2000
Country [4] 295798 0
Australia
Funding source category [5] 295799 0
Charities/Societies/Foundations
Name [5] 295799 0
Jack Brockhoff Foundation
Address [5] 295799 0
501/685 Burke Road
Camberwell VIC 3124
Country [5] 295799 0
Australia
Funding source category [6] 295800 0
Charities/Societies/Foundations
Name [6] 295800 0
Perpetual Philanthropy
Address [6] 295800 0
GPO Box 4172, Sydney NSW 2000
Country [6] 295800 0
Australia
Funding source category [7] 295801 0
Charities/Societies/Foundations
Name [7] 295801 0
CASS Foundation
Address [7] 295801 0
Level 2, 111 Collins Street
Melbourne Victoria 3000
Australia
Country [7] 295801 0
Australia
Funding source category [8] 295802 0
Government body
Name [8] 295802 0
National Health and Medical Research Council
Address [8] 295802 0
GPO Box 1421
Canberra ACT 2601
Country [8] 295802 0
Australia
Primary sponsor type
Hospital
Name
Royal Children's Hospital
Address
Royal Children's Hospital
Flemington Road,
Parkville Vic. 3052
Country
Australia
Secondary sponsor category [1] 3650 0
Other Collaborative groups
Name [1] 3650 0
Murdoch Children's Research Institute
Address [1] 3650 0
Royal Children's Hospital
Flemington Road,
Parkville Vic. 3052
Country [1] 3650 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 6132 0
RCH Human Research Ethics Committee
Ethics committee address [1] 6132 0
Royal Children's Hospital
Flemington Road, Parkville
Victoria 3052
Ethics committee country [1] 6132 0
Australia
Date submitted for ethics approval [1] 6132 0
Approval date [1] 6132 0
11/08/2008
Ethics approval number [1] 6132 0
27086

Summary
Brief summary
A two arm randomised-controlled trial to test a novel therapy (Peanut Oral Immunotherapy with a Probiotic adjunct) against placebo. The findings of this study will provide much needed evidence on whether OIT combined with a probiotic adjunct can induce tolerance in children with peanut allergy.
Trial website
Trial related presentations / publications
Primary outcome data have been published - MLK Tang, AL Ponsonby, F Orsini, D Tey, M Robinson, EL Su, P Licciardi, W Burks, S Donath. Administration of probiotic with peanut oral immunotherapy, a randomized trial. J Allergy Clin Immunol 2015;135:737-44.
Public notes

Contacts
Principal investigator
Name 29070 0
Prof Mimi Tang
Address 29070 0
Royal Children's Hospital
Department of Allergy and Immunology
Flemington Rd
Parkville VIC 3052
Australia
Country 29070 0
Australia
Phone 29070 0
+61 3 9345 5733
Fax 29070 0
Email 29070 0
mimi.tang@rch.org.au
Contact person for public queries
Name 12227 0
Prof Prof Mimi Tang
Address 12227 0
Department of Allergy and Immunology
Royal Children's Hospital
Flemington Road,
Parkville Vic. 3052
Country 12227 0
Australia
Phone 12227 0
+61 3 9345 5733
Fax 12227 0
+61 3 9345 4848
Email 12227 0
mimi.tang@rch.org.au
Contact person for scientific queries
Name 3155 0
Prof Prof Mimi Tang
Address 3155 0
Department of Allergy and Immunology
Royal Children's Hospital
Flemington Road,
Parkville Vic. 3052
Country 3155 0
Australia
Phone 3155 0
+61 3 9345 5733
Fax 3155 0
+61 3 9345 4848
Email 3155 0
mimi.tang@rch.org.au

No data has been provided for results reporting
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary