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Trial registered on ANZCTR


Registration number
ACTRN12624000515594
Ethics application status
Approved
Date submitted
2/04/2024
Date registered
26/04/2024
Date last updated
26/04/2024
Date data sharing statement initially provided
26/04/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Low dose Multi-nut Oral immunotherapy (L-MO)
Scientific title
A head-to-head non-inferiority trial of low vs standard dose multi-nut oral immunotherapy in children under 6 years old.
Secondary ID [1] 311823 0
NA
Universal Trial Number (UTN)
Trial acronym
L-MO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
almond allergy 333429 0
cashew allergy 333430 0
hazelnut allergy 333431 0
walnut allergy 333432 0
peanut allergy 333433 0
Condition category
Condition code
Inflammatory and Immune System 330105 330105 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomised to either a 60mg (intervention) or 300mg (comparator) maintenance dose of multi-nut oral immunotherapy (OIT) (almond, cashew, hazelnut, walnut and/or peanut), Nut OIT will consist of incrementally increasing doses of one or more of the individual nut flours to which the participant is allergic administered over a total period of 18 months. Participants will undergo fortnightly updosing to achieve a maintenance dose of either 60mg or 300mg of each of the nut proteins the child is allergic to. Partcipants will only receive OIT to the nuts they are allergic to, and thus the total combined dose of nut protein will be dependent on how many nuts are included in each individuals OIT.

The individual nut flours are food products, organic defatted nut flour, manufactured by Healthy Food Crew (ABN 85 168 410 482) and supplied by Mini Mixers Pty. Ltd., Ripponlea Victoria (ABN 29 445 850 847). These nut flours will also be used for the OFCs.

OIT doses will be mixed into the participant’s usual food of choice that has been previously tolerated throughout all stages of the study. Parents will receive training on the administration of doses during dose escalation and up-dosing visits at PCH. Other than the daily OIT treatment participants will otherwise follow strict avoidance of the nuts to which they have a confirmed allergy. Participants may continue to eat the nuts they tolerate as part of their normal diet.

Multi-nut dosing schedule
1) Treatment initiation
Subjects receive up to 5 increasing doses of multi-nut flour every 20 minutes to reach a final dose of 15mg of each nut protein (0.5mg, 1mg, 3mg, 10mg, 15mg). If a subject reacts during TI, the next day they will commence dosing at home with the dose immediately below the one that provoked onset of symptoms.

2) Updosing
Updosing will occur approximately every 2 weeks, until a maximum dose of either 60mg or 300mg of each nut protein is reached (30mg, 60mg, 90mg, 120mg, 180mg, 240mg, 300mg). The first dose of each new increment is administered under clinical supervision at PCH during a scheduled up-dosing appointment. Participants will remain under observation for at least 2 hours after an up-dose, or until deemed suitable for discharge.

3) Maintenance
Participants will be randomised to either a 60mg or 300mg maintenance dose of multi-nut OIT. Participants will continue to take daily doses of maintenance multi-nut flour until a total of 18 months of treatment is completed.

4) End of Treatment
After 18 months of treatment, all participants will cease OIT and continue nut avoidance (to the nuts which they are allergic) for a period of 4 weeks. During this period participants will indicate any accidental ingestion of their allergens in their electronic diary. After 4 weeks with no nut exposure, all participants will undergo oral food challenge/s to determine whether they have sustained unresponsiveness to their allergen/s.

Compliance and Adverse Events
Parents will use an electronic daily diary based in the REDCap platform to record information about their daily dosing and any adverse events they experience. Side effects are common with OIT, and it is anticipated that some children will experience mild (pruritus, swelling or rash, abdominal discomfort or other transient symptoms), moderate ( persistent hives, increased abdominal discomfort/ increased vomiting) and severe (anaphylaxis) allergic reactions to their peanut OIT. All adverse events will be recorded in the electronic diary and monitored by study staff.

If allergic symptoms develop following a dose of OIT at home, the parent or guardian will treat the symptoms in line with their prescribed Allergy Action Plan, using rescue medication as required. For any ongoing symptoms, or sudden onset of severe symptoms the families will be requested to alert study staff. The site investigators will decide based on the nature of the symptoms, the plan for continuation of dosing (including plans for reintroduction of dosing and/or extending the period of time before the next up-dose). If ongoing symptoms are noted, the use of antihistamine or another medication for prophylaxis may be initiated by the study team.

If anaphylaxis symptoms develop during home dosing (e.g. wheeze, stridor, difficulty breathing, transient hypotension), the family will be counselled and debriefed on the management of the anaphylaxis. The next dose will be given at home at the previously tolerated dose or under supervision at the same dose via an unscheduled visit, at the discretion of the investigator.
Intervention code [1] 328335 0
Treatment: Other
Comparator / control treatment
"standard dose" 300mg multi-nut OIT
Control group
Dose comparison

Outcomes
Primary outcome [1] 337868 0
Sustained unresponsiveness to each nut the participant is allergic to during an oral food challenge.
Timepoint [1] 337868 0
19 months post treatment initiation.
Secondary outcome [1] 433509 0
Desensitisation
Timepoint [1] 433509 0
18 months post treatment initiation.
Secondary outcome [2] 433510 0
Safety
Timepoint [2] 433510 0
Safety is monitored throughout the entire study, from baseline to 19 months post treatment initiation. During the updosing phase parents enter data about any adverse events into their diary daily, during the maintenance phase this is done weekly.
Secondary outcome [3] 433512 0
tolerability
Timepoint [3] 433512 0
14 weeks, 6 months, 12 months, 18 months post treatment initiation.
Secondary outcome [4] 433514 0
Quality of life
Timepoint [4] 433514 0
Baseline, week 14, 6 months, 12 months, 18 months, 20 months post treatment initiation.
Secondary outcome [5] 433517 0
Parent-reported experience of OIT
Timepoint [5] 433517 0
week 14, 6 months, 12 months, 18 months, 20 months post treatment initiation
Secondary outcome [6] 433520 0
Feasibility
Timepoint [6] 433520 0
20 months post treatment initiation
Secondary outcome [7] 433521 0
treatment-associated costs of OIT
Timepoint [7] 433521 0
20 months post treatment initiation.
Secondary outcome [8] 433522 0
Immunological markers of nut sensitisation
Timepoint [8] 433522 0
Baseline, 14 weeks, 6 months, 12 months, 18 months, 19 months post treatment initiation.
Secondary outcome [9] 433922 0
Quality of life
Timepoint [9] 433922 0
Baseline, week 14, 6 months, 12 months, 18 months, 20 months post treatment initiation.
Secondary outcome [10] 433923 0
Quality of life
Timepoint [10] 433923 0
Baseline, week 14, 6 months, 12 months, 18 months, 20 months post treatment initiation.
Secondary outcome [11] 433924 0
Quality of life
Timepoint [11] 433924 0
Baseline, week 14, 6 months, 12 months, 18 months, 20 months post treatment initiation.
Secondary outcome [12] 433925 0
Quality of life
Timepoint [12] 433925 0
Baseline, week 14, 6 months, 12 months, 18 months, 20 months post treatment initiation.
Secondary outcome [13] 433926 0
Immunological markers of nut sensitisation
Timepoint [13] 433926 0
Baseline, 14 weeks, 6 months, 12 months, 18 months, 19 months post treatment initiation.

Eligibility
Key inclusion criteria
1) Male or female children from 1 until 5 years of age (not yet turned 6)
2) Confirmed or highly probably allergy (as defined below) to at least one of almond, cashew, hazelnut, walnut or peanut.
3) Parents/guardians and subjects willing to comply with all the study requirements during their participation in the study.
6.2.1 Tree nut allergy inclusion definitions (almond, cashew, hazelnut or walnut)
a) Confirmed (entry OFC required):
Positive skin prick test (SPT, mean wheal diameter >3mm) or specific IgE (>0.35 kU/L) at SV1 and allergic reaction to the tree nut during the entry OFC which meets the stopping criteria.
b) Highly probable (entry OFC not required):
i) Clinical history of anaphylaxis to the tree nut in the 24 months prior to SV1, with a positive SPT or sIgE at SV1, or
ii) Clinical history of a mild to moderate allergic reaction, with signs/symptoms meeting protocol-specified stopping criteria for OFC, to the tree nut in the 12 months prior to SV1 with a positive SPT or sIgE at SV1, or
iii) Allergic reaction during an oral food challenge to the nut in the 12 months prior to SV1 (performed as part of usual clinical care), with a positive SPT or sIgE at SV1, or
iv) For walnut only, any one of the below
(1) a skin prick test with mean wheal diameter >8mm in a participant who has no clinical history of reaction to walnut and is avoiding it in their diet, or
(2) a SPT with mean wheal diameter >6mm in a participant AND a previous clinical history of an allergic reaction to walnut prior to SV1
v) For cashew only, any two of the following three criteria:
(1) A previous clinical history of an allergic reaction to cashew prior to screening
(2) Cashew SPT >7mm mean wheal diameter
(3) Cashew component Ana o 3 specific IgE >1 kU/L
6.2.2 Peanut allergy inclusion definitions
a) Confirmed (OFC required): positive peanut SPT (mean wheal diameter >3mm) or specific IgE (>0.35 kU/L) at SV1 and allergic reaction during the entry peanut OFC which meets the stopping criteria
b) Highly probable (OFC not required): any two of the following four criteria:
i) Previous clinical history of allergic reaction to peanut with signs/symptoms meeting stopping criteria
ii) Peanut SPT mean wheal diameter at SV1 >8mm
iii) Peanut sIgE at SV1 >15 kU/L
iv) Ara h 2 sIgE at SV1 >1 kU/L
c) Highly probable (OFC not required): clinical history of anaphylaxis to peanut in the 12 months prior to SV1, with a positive SPT or sIgE to peanut at SV1:
d) Highly probable (OFC not required): allergic reaction during an oral food challenge to peanut in the 12 months prior to SV1 (performed as part of usual clinical care), with a positive SPT or sIgE at SV1.
Minimum age
1 Years
Maximum age
5 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they meet any of the following criteria:
1. History of severe anaphylaxis to any nut prior to study entry, defined as a reaction causing loss of consciousness, persistent hypoxia refractory to treatment, or requiring more than three doses of IM adrenaline or intubation for management of an allergic reaction.
2. Use of beta-blockers
3. Participants currently enrolled in another clinical trial of immunotherapy for food allergy (participants who are enrolled in a follow on study after completing a previous clinical trial are not excluded).
4. Participants currently receiving or planning to commence sublingual immunotherapy for environmental allergens (e.g. house dust mite, grass pollens). Participants who are receiving subcutaneous immunotherapy for environmental or venom allergen desensitisation will be eligible, but OIT doses will be withheld on the day of subcutaneous immunotherapy administration.
5. Persistent, uncontrolled asthma. In participants with asthma, symptom control will be assessed at screening using the expert opinion-based schema in the Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention, whereby uncontrolled asthma is defined as any 3 or more of the following occurring in the preceding 4 weeks
a) Daytime asthma symptoms for more than a few minutes, more than once a week
b) Any activity limitation due to asthma
c) Reliever medication needed more than once a week (excluding reliever taken before exercise)
d) Any night waking or night coughing due to asthma
Participants may be re-screened after asthma treatment is optimised.
6. Confirmed diagnosis of eosinophilic oesophagitis, and/or uncontrolled symptoms of dysphagia, postprandial abdominal pain or vomiting.
7. Children with other significant underlying medical conditions that place them at increased risk of adverse outcomes in the event of an allergic reaction, such as cardiovascular or respiratory diseases. The Principal Investigator or delegated study doctor will review these children and consult with the child’s usual treating specialist, and the Principal Investigator will confirm that the child is not at increased risk of harm from the study procedures by virtue of their underlying medical condition before enrolling the child in the study.
8. Subjects who in the opinion of the investigator will be unable to follow the protocol

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)
Permuted block technique
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Statistical methods / analysis
For this study continuous variables will be presented as mean and standard deviations or medians and interquartile ranges depending on distribution of data. For count data rates will be reported, while categorical variables will be presented as frequencies and proportions. For exploratory variables statistical analyses will be hypothesis generating to inform future studies.

The primary outcome of sustained unresponsiveness will be compared between the groups using a difference in proportions estimated using binomial regression, presented with its 95% confidence interval and corresponding p-value. Non-inferiority will be declared if the 95% confidence interval does not include a 15% or greater decrease in the proportion with SU in the low dose compared with the standard dose group.

Remission to each nut will be reported as proportions and compared between each group using chi-square of Fishers Exact test (when expected cell counts are <5).

For safety and tolerability, the number of participants experiencing an adverse event (ever), type of reaction and severity and will be reported as proportions and compared between each group using chi-square of Fishers Exact test (when expected cell counts are <5). The exposure-adjusted incidence of trAEs will be calculated by dividing the total number of trAEs by the total number of OIT doses taken by all participants. Between group comparisons will be performed using regression with a Poisson or a negative binomial model.

Survey data and immunological markers (including SPT wheal size and IgE) are collected at several time points and will be analysed using linear mixed models, adjusting for baseline score. If there is poor model fit transformations or alterative models will be examined using generalised linear mixed models, where the model chosen will be dependent on the distribution of the data. A mixed model approach is used to account for correlation between repeated measures.

Eliciting doses for each nut will be compared and end of treatment, between groups using simple linear regression.

Feasibility will be examined using number of treatment-related visits, duration of treatment related visits and number of missed doses. Between group differences will be examined using regression with the model chosen dependent on the distribution of the data, with linear or Poisson likely models.

Treatment-associated costs will be determined based on estimated costs of hospital visits attended. Costs will be broken down into categories including visits due to treatment, additional visits due to adverse event and indirect (parental) costs. A median and mean cost per patient will be produced with the median representing the typical value for an individual, with the mean a more informative measure for financial impact of hospitalisation.
For all regression models we will consider adjusting for potential confounders such as age, eczema, number of food allergies, ethnicity and other food allergy.

All analyses will primarily be on all consented participants in an intention-to-treat analysis.
Any eventual deviation from the original statistical plan will be described and justified in the final report, as appropriate. Where individuals do not have a full data set, each variable will be assessed on a case-by-case basis (rather than excluding all data). Any data suspected as false will be treated as missing data. Stata will be used to analyse data and create graphs and/or figures. Alpha will be set at 0.05.

No interim analysis is planned.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
29/04/2024
Actual
Date of last participant enrolment
Anticipated
1/04/2025
Actual
Date of last data collection
Anticipated
31/12/2026
Actual
Sample size
Target
208
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 26392 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 42369 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 316164 0
Charities/Societies/Foundations
Name [1] 316164 0
Channel 7 Telethon Trust
Country [1] 316164 0
Australia
Primary sponsor type
Government body
Name
Child and Adolescent Health Service
Address
Country
Australia
Secondary sponsor category [1] 318343 0
None
Name [1] 318343 0
Address [1] 318343 0
Country [1] 318343 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 314989 0
Child and Adolescent Health Service Human Research Ethics Committee
Ethics committee address [1] 314989 0
Ethics committee country [1] 314989 0
Australia
Date submitted for ethics approval [1] 314989 0
17/08/2023
Approval date [1] 314989 0
29/11/2023
Ethics approval number [1] 314989 0
RGS0000006210

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

Contacts
Principal investigator
Name 133338 0
Dr Michael O'Sullivan
Address 133338 0
Immunology Department Perth Children's Hospital 15 Hospital Avenue, Nedlands, WA, 6009
Country 133338 0
Australia
Phone 133338 0
+61 434582982
Fax 133338 0
Email 133338 0
Michael.O'[email protected]
Contact person for public queries
Name 133339 0
Michael O'Sullivan
Address 133339 0
Immunology Department Perth Children's Hospital 15 Hospital Avenue, Nedlands, WA, 6009
Country 133339 0
Australia
Phone 133339 0
+61 434582982
Fax 133339 0
Email 133339 0
Michael.O'[email protected]
Contact person for scientific queries
Name 133340 0
Michael O'Sullivan
Address 133340 0
Immunology Department Perth Children's Hospital 15 Hospital Avenue, Nedlands, WA, 6009
Country 133340 0
Australia
Phone 133340 0
+61 434582982
Fax 133340 0
Email 133340 0
Michael.O'[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


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
No additional documents have been identified.