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Trial registered on ANZCTR


Registration number
ACTRN12617000914369
Ethics application status
Approved
Date submitted
30/05/2017
Date registered
22/06/2017
Date last updated
14/06/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Oral peanut immunotherapy with a modified dietary starch adjuvant for treatment of peanut allergy in children aged 10-16 years.
Scientific title
Oral peanut immunotherapy with a modified dietary starch adjuvant for treatment of peanut allergy in children aged 10-16 years.
Secondary ID [1] 291973 0
NHMRC APP_1104134, CIA_Campbell.
Universal Trial Number (UTN)
U1111-1197-0778
Trial acronym
OPIA
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Peanut allergy 303318 0
Condition category
Condition code
Inflammatory and Immune System 302760 302760 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to receive peanut immunotherapy (study arms A and B) with or without active dietary fibre adjuvant for 12 months. Peanut immunotherapy will use roasted peanut in small and gradually increasing incremental doses starting at 5mg (given in powder form), followed by 10mg (powder), 20mg (powder), 40mg (powder), 80mg (powder), 125mg (one half of a peanut), 250mg (1 peanut), 500mg (2 peanuts), 750mg (3 peanuts), 1000mg (4 peanuts), 1250mg (5 peanuts), 1500mg (6 peanuts), 1750mg (7 peanuts) and 2000mg (8 peanuts) (see below table), Updosing of the roasted peanut will occur during a visit supervised by medical members of the research team approximately every 2 weeks until week 28 (depending on the development of adverse events. The participant will be asked to take a slightly smaller dose at home than what they were given during the updosing visit in hospital. A minimum of 2 weeks will be needed at each dose, however a participant may be on a dose for extended periods if they developed symptoms suggestive of an adverse reaction on a higher dose, or if they missed more than 2 days at during any dose period. A dietary supplement - butyrylated high amylase maize starch (HAMSB) will be ingested daily for 12 months by participants in study arm B. The dose is stratified by weight: those 50kg or over at study entry will have 40g of HAMSB daily; those under 50kg at study entry will consume 20g of HAMSB daily. This can be mixed into a range of foods, such as flavoured milk, juice, custards, pasta sauce. To ensure that any symptoms from peanut OIT are not inaccurately attributed to HAMSB, participants will take HAMSB for 2 weeks prior to starting peanut OIT. The doses will be the same as above and participants will document any adverse events in their diary.
Adherence to the schedule will be assessed by diary reviews (participants will enter the date, time and dose of peanut taken) as well as return of the empty containers that held the peanut doses.

Table: Peanut protein dosing (at visit and taken at home) at visits 4 to 18 and the minimum number of weeks at the dose (cumulative).
Visit:4 At visit: 10mg At home: 5mg
Minimum number of weeks at this dose: 3
Visit:5 At visit: 15mg At home: 10mg
Minimum number of weeks at this dose: 3 (6)
Visit:6 At visit: 25mg At home: 20mg
Minimum number of weeks at this dose: 2 (8)
Visit:7 At visit: 50mg At home: 40mg
Minimum number of weeks at this dose: 2 (10)
Visit:8 At visit: 100mg At home: 80mg
Minimum number of weeks at this dose: 2 (12)
Visit:9 At visit: 150mg At home: 125mg
Minimum number of weeks at this dose: 2 (14)
Visit:10 At visit: 300mg At home: 250mg
Minimum number of weeks at this dose: 2 (16)
Visit:11 At visit: 600mg At home: 500mg
Minimum number of weeks at this dose: 2 (18)
Visit:12 At visit: 800mg At home: 750mg
Minimum number of weeks at this dose: 2 (20)
Visit:13 At visit: 1200mg At home: 1000mg
Minimum number of weeks at this dose: 2 (22)
Visit:14 At visit: 1500mg At home: 1250mg
Minimum number of weeks at this dose: 2 (24)
Visit:15 At visit: 1750mg At home: 1500mg
Minimum number of weeks at this dose: 2 (26)
Visit:16 At visit: 2000mg At home: 1750mg
Minimum number of weeks at this dose: 2 (28)
Visit:17 At visit: 2500mg At home: 2000mg
Minimum number of weeks at this dose: 2 (52)
Visit:18 At visit: 0mg At home: 0mg
Minimum number of weeks at this dose: 6 (58):
Intervention code [1] 298099 0
Treatment: Other
Comparator / control treatment
There are 2 control groups.
1. Peanut immunotherapy control (study arm C): peanut allergic participants continue on standard treatment consisting of peanut avoidance with prescription of an adrenaline auto-injector medication (EpiPen) for accidental exposure. This arm is not blinded.
2. Supplement control (study arm A): participants randomised to receive peanut immunotherapy to receive a low amylose maize starch (LAMS, study arm A) as a dietary adjuvant placebo control Those receiving the LAMS supplement will have the same dose regime. as the HAMSB participants and will be blinded to adjuvant allocation. Similarly this can be combined with a range of foods such as flavoured milk, juice, custards and pasta sauce. All participants will continue in their study arm for 12 months.
Control group
Active

Outcomes
Primary outcome [1] 302149 0
The proportion of participants who tolerate at least 1400mg of roasted peanut at a double blinded, placebo-controlled food challenge (DBPCFC) after receiving peanut immunotherapy and dietary supplement (HAMSB) for 12 months and then ceasing all therapy for 6 weeks compared with the proportion of participants who tolerate at least 1400 mg of roasted peanut after 12 months of peanut immunotherapy and LAMS dietary supplement and then ceasing all therapy for 6 weeks and those participants on standard therapy (peanut avoidance).
The DBPCFC will occur 6 weeks after stopping the peanut immunotherapy and dietary supplement,Tolerability will be defined as the lack of allergic reaction to peanut in a DBPCFC. Challenge outcome and stopping criteria is determined as detailed in the PRACTALL consensus criteria which uses a graded system to score signs and symptoms present to help diagnosis an allergic reaction: cutaneous (pruritis, urticarial, rash); upper respiratory tract (rhinorrhoea, sneezing, nasal itch, ocular itch, periorbital oedema); lower respiratory tract (wheeze, dyspnoea, throat clearing, throat tightness, hoarse voice, dry cough, stridor); gastrointestinal (abdominal pain, nausea, vomiting, diarrhoea); and cardiovascular/neurological (tachycardia, hypotension, cardiovascular collapse, altered mental status,unconsciousness)
Timepoint [1] 302149 0
13 months and 2 weeks (13.5 months) after randomisation.
Secondary outcome [1] 334973 0
The relative change in the number of grams ingested prior to the development of an allergic reaction to roasted peanuts (i.e. the relative change in participants clinical threshold) in a DBPCFC comparing the intervention and control groups between baseline challenge and challenge at 13.5 months.
Timepoint [1] 334973 0
The determination of the clinical threshold for peanut tolerance will be assessed at the DBPCFC at 13.5 months and 24 months after randomisation.

Secondary outcome [2] 335481 0
Change in the quality of life (QoL) assessment score using a validated questionnaire called "The food allergy quality of life questionnaire" for participants and their parents.
Timepoint [2] 335481 0
At randomization (baseline), 6 and 12 months following randomization.
Secondary outcome [3] 335482 0
The proportion of participants reporting adverse reactions, and the type of reaction, to the peanut immunotherapy and/or the dietary supplement, HAMSB.
All AEs will be collected by home diary and by frequent monitoring study visits. SAEs will be recorded and reported in accordance with GCP standards.
A review of the patient's home diary, which includes symptom reporting sheets, will be performed at all visits.
Timepoint [3] 335482 0
Continuous monitoring at home. Ongoing review of symptoms recorded in the home diary. Contact by the family via email or phone regarding adverse events for notification and/or advice purposes for the 25.5 months.
Secondary outcome [4] 335483 0
Compliance with the study protocol using a diary and butyrate faecal analysis, expressed as the number of doses missed and comparison of faecal butyrate content, respectively .
Timepoint [4] 335483 0
Diary review for assessment will occur at all visits which occur at 3 weeks post randomization, and second weekly thereafter until 28 weeks, then at 52 and 58 weeks.
Stool collection will occur at after a 2 week run in (those allocated dietary supplementation will take the supplement for 2 weeks prior to commencing peanut immunotherapy to allow any gastrointestinal symptoms to settle), 6 and 12 months following randomization.
Secondary outcome [5] 335485 0
Changes in the regulatory immune responses:
- phenotype inducible CD4+FOXP3+Helios- T reg cells, Th1 and Th2 cells, and tolerogenic dendritic cells using flow cytometry; the function of Treg cells. All cells are expressed as 10^9 cells/L, flow cytometry is expressed in copies per million.
- total IgE levels, peanut-specific IgE binding capacity, IgG4 to whole peanut and correlate with changes in clinical tolerance. All immunoglobulins are measured in g/L.
Timepoint [5] 335485 0
Blood collection will occur at randomization (baseline), 6 and 12 months following randomization.
Secondary outcome [6] 335487 0
Changes in the gut microbiome composition as expressed by the amount and types of bacteria present.
Timepoint [6] 335487 0
Stool collection will occur at randomization (baseline), 6 and 12 months following randomization. Participants receiving HAMSB and LAMS will also supply a stool sample 2 weeks after commencing supplement consumption.
Secondary outcome [7] 335488 0
The proportion of participants with sustained peanut tolerance for a 12 month following the DBPCFC at 13.5 months post randomisation as assessed with a DBPCFC.
Timepoint [7] 335488 0
25.5 months post randomisation

Eligibility
Key inclusion criteria
Children aged 10-16 years with a diagnosis of peanut allergy with a positive skin prick test to a commercially available peanut extract (wheal at least 3mm larger than the negative control) and confirmation of clinical reactivity to roasted peanut in a double blind, placebo-controlled food challenge (DBPCFC) with a cumulative threshold of >9mg but <3000mg of peanut protein; tolerant of soy (DBPCFC is given in a soy-based matrix) at a food challenge; parents, or legal guardians, must give informed consent and the child must also agree to partake in the study.
Minimum age
10 Years
Maximum age
16 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Previous admission to intensive care unit for the management of a peanut allergic reaction; clinically significant chronic disease other than eczema, rhinitis or asthma; poorly controlled asthma in the last 3 months (as defined by clinican judgement with reference to the ICON consensus) or asthma requiring oral corticosteroids in the previous 3 months; those in the first year of immunotherapy (subcutaneous or sublingual) for respiratory allergens; those receiving anti-IgE therapy, oral immunosuppressants, beta-blockers or ACE inhibitor therapy; a clinical allergy to soya or sunflower seed; tolerance to roasted peanut in a double blind, placebo-controlled food challenge with thresholds <10mg or 3000mg or more peanut protein; pregnancy; or unwilling or being unable to fulfil study requirements.

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)
Online permuted block stratification 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
Intervention assignment
Parallel
Other design features
Research staff are blinded in the initial DBPCFC as to whether participants attending that day are being given peanut protein or a placebo.
Research staff and participants will not be blinded to peanut immunotherapy in either immunotherapy arm- but will be blinded to the dietary supplement allocation (HAMSB vs LAMS) taken by the participant. Participants in the standard therapy control arm will not be blinded.
Phase
Not Applicable
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Primary analysis will be performed on an intention-to-treat basis with a secondary analysis being performed an a per-protocol basis. The Chi-squared test with a significance level of p<0.05 will be used for the primary outcome (i.e. the proportion of participants able to tolerate at least 1400mg of peanut protein following 12 months of peanut immunotherapy and HAMSB at a double blind, placebo-controlled food challenge 13.5 months after randomisation and 6 weeks after ceasing intervention compared to the standard treatment control group and the peanut immunotherapy and placebo dietary supplement group.)
Secondary endpoints will be analysed using a two-sided test for non-parametric data with a significance level of p<0.05: relative changes in clinical threshold to roasted peanut at baseline, 6 and 12 months in all 3 study arms [using no observable adverse event level (NOAEL), lowest observable adverse event level (LOAEL)]; numerical immunological outcome measures pre- and post-12 months of immunotherapy (Mann-Whitney); and change in quality of life assessments at baseline, 6 and 12 months after randomisation (paired and group comparisons by non-parametric testing).
The Fisher's exact test generated Chi-squared p value will be used to determine the differences in proportions for categorical immunological parameters and adverse events between all 3 study arms.
Logistic regression will be used to assess the contribution of age, gender, asthma status and prior history of anaphylaxis has on the efficacy of immunotherapy, tolerance and incidence of adverse events.

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
Recruitment hospital [1] 8031 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 16018 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 296482 0
Government body
Name [1] 296482 0
NHMRC
Address [1] 296482 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 296482 0
Australia
Primary sponsor type
Government body
Name
Sydney Children's Hospital Network
Address
Sydney Children's Hospital Network
Locked Bag 4001
WESTMEAD NSW 2145
Country
Australia
Secondary sponsor category [1] 295440 0
None
Name [1] 295440 0
Address [1] 295440 0
Country [1] 295440 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297704 0
SCHN Human Research Ethics Committee
Ethics committee address [1] 297704 0
Sydney Childrens Hospitals Network Human Research Ethics Committee
Locked Bag 4001
WESTMEAD NSW 2145
Ethics committee country [1] 297704 0
Australia
Date submitted for ethics approval [1] 297704 0
03/10/2016
Approval date [1] 297704 0
23/11/2016
Ethics approval number [1] 297704 0
HREC/16/SCHN/372

Summary
Brief summary
Childhood peanut allergy is increasing, affecting 3% of Australian children. It is the food allergy that persists into adult life, and the most likely to be associated with death due to accidental exposure. It involves the allergy antibody, IgE, which stimulates allergy cells to release chemicals that cause allergic symptoms. There is no current cure. Management is by avoidance with emergency plans and medication in case of accidental exposure.
Immunotherapy (IT) is thought to be the most likely strategy to offer a “cure” for food allergy. Immunotherapy has been shown to be effective in the management of aeroallergen and venom allergy. This technique involves regular and prolonged exposure to the allergen in question, initially starting with very small doses and then increasing the dose over a period of time to a level where the person does not respond with an allergic reaction when re-exposed to it. Food immunotherapy trials have so far only had a few participants and often achieved only temporary desensitization which is lost rapidly when treatment is stopped, and also have a high rate of side effects.
Gut microbes are implicated in food allergy. They can increase the levels of small chain fatty acids (SCFA), namely acetate, butyrate and propionate, in the gut by fermenting fibre- leading to significant changes to bacteria present in the gut (i.e. the gut microbiome), with increased beneficial bacteria promoting a non-allergic environment.
Experiments in mice fed a high-fiber diet or SCFAs found they were protected from food allergy. In particular, they had increased oral tolerance to peanuts with an increase in the number and function of immune cells important in controlling allergic reactions .
This study aims to examine whether using a dietary fibre supplement which is high in a key short chain fatty acid- butyrate -whilst using small and increasing daily doses of peanut in peanut allergic children and teenagers will provide them with sustained unresponsiveness to peanut and render them non allergic (or tolerant ) to peanut.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74890 0
Prof Dianne Campbell
Address 74890 0
Department of Allergy and Immunology
The Children's Hospital at Westmead
Cnr Hawkesbury Rd and Hainsworth St
WESTMEAD NSW 2145
Country 74890 0
Australia
Phone 74890 0
+61298543420
Fax 74890 0
+61298453421
Email 74890 0
dianne.campbell1@health.nsw.gov.au
Contact person for public queries
Name 74891 0
Dr Michelle Barnes
Address 74891 0
Department of Allergy and Immunology
The Children's Hospital at Westmead
Cnr Hawkesbury Rd and Hainsworth St
WESTMEAD NSW 2145
Country 74891 0
Australia
Phone 74891 0
+61298453509
Fax 74891 0
+61298453421
Email 74891 0
Michelle.Barnes@health.nsw.gov.au
Contact person for scientific queries
Name 74892 0
Dr Michelle Barnes
Address 74892 0
Department of Allergy and Immunology
The Children's Hospital at Westmead
Cnr Hawkesbury Rd and Hainsworth St
WESTMEAD NSW 2145
Country 74892 0
Australia
Phone 74892 0
+61298453509
Fax 74892 0
+61298453421
Email 74892 0
Michelle.Barnes@health.nsw.gov.au

No data has been provided for results reporting
Summary results
Not applicable