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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT05049512




Registration number
NCT05049512
Ethics application status
Date submitted
8/09/2021
Date registered
20/09/2021
Date last updated
20/09/2021

Titles & IDs
Public title
Low Dose Multi-Nut Oral Immunotherapy in Pre-schoolers With a Multi-Nut Allergy
Scientific title
Low Dose Multi-Nut Oral Immunotherapy in Pre-schoolers (LMNOP): a Pragmatic Randomised Controlled Trial of Low Dose Multi-Nut Oral Immunotherapy Versus Standard Care for the Treatment of Multi-Nut Allergies in Young Children
Secondary ID [1] 0 0
74540
Universal Trial Number (UTN)
Trial acronym
LMNOP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Allergy, Nut 0 0
Condition category
Condition code
Inflammatory and Immune System 0 0 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - Multi-nut OIT

Experimental: Multi-nut OIT - Participants will have a personalised combination of two nuts they are allergic to for their multi-nut OIT (a. peanut, b. almond, c. cashew, d. hazelnut, e. walnut). In the escalation visit, participants will receive 5 increasing doses of personalised multi-nut OIT in clinic at 20-minute intervals: 1 mg, 3 mg, 6 mg, 12 mg, 24 mg total nut protein, 12 mg/nut. The build-up phase will consist of daily home doses of multi-nut OIT and clinic visits every 2 weeks for up-dosing, up to a maintenance dose of 600 mg total protein, 300 mg/nut, over 3-8 months. In the maintenance phase, participants will continue to take their multi-nut OIT dose of 600 mg total protein each day at home for the remainder of the 18 months, with visits to the clinic every 3 months.

No Intervention: Standard Care - Strict avoidance of the 2 study nuts the participants are allergic to over 18 months - a. peanut, b. almond, c. cashew, d. hazelnut, e. walnut, as per standard care instructions for children with allergies in Australia.


Other interventions: Multi-nut OIT
Finely ground pure peanut, almond, cashew, hazelnut, and walnut.

Intervention code [1] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Main Trial: Comparison of the number of participants who pass their OFC after the 18-month treatment phase for both study nuts between the Multi-Nut OIT Group and Standard Care Group - In both groups, passing requires participants tolerating all OFC doses for both of their study nuts. For the Multi-Nut OIT Group, participants must pass their OFC at the end of the 18-month treatment phase, and then pass another OFC after 4 weeks of no OIT. For the Standard Care Group, participants must pass their OFC after the 18-month period. Participants have a personalised combination of two nuts: a. peanut, b. almond, c. cashew, d. hazelnut, e. walnut, as nominated at study screening.
Timepoint [1] 0 0
At 18 months post commencement of treatment
Secondary outcome [1] 0 0
Main Trial: Difference between the Multi-nut OIT Group in comparison to the Standard Care Group in the proportion and severity of reported adverse events (AE) related to study nut ingestion during the 18-month treatment phase - Number and severity of AEs as assessed by standardised predetermined criteria, related to study peanut/tree nut ingestion from randomisation to end of the 18-month treatment phase collected via OFC and clinic visit observations and medical history taken, and parent questionnaire diaries.
Timepoint [1] 0 0
During the 18-month treatment phase
Secondary outcome [2] 0 0
Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from screening to 18 months in quality of life scores for the children, measured by the Food Allergy Quality of Life-Parent Form (FAQL-PF) - The Food Allergy Quality of Life Questionnaires (FAQLQ) are disease-specific health-related quality of life questionnaires for patients with food allergy. The FAQL-PF completed by parents of children aged 0-12 years, consists of 30 items over 3 domains: emotional impact, food anxiety, social and dietary restrictions. Total and domain scores are calculated by dividing the sum of completed items by the number of competed items.
Timepoint [2] 0 0
Screening and at 18 months
Secondary outcome [3] 0 0
Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from screening to 18 months in quality of life scores for the parents using the ICEpop CAPability measure for Adults (ICECAP-A) - The ICECAP-A questionnaire is a measure of capability well-being for adults. It has been developed in the United Kingdom (UK) using in-depth and semi-structured qualitative research with adults over the age of 18; values for the UK, obtained using best-worst scaling, are available. The instrument contains five attributes - stability, attachment, autonomy, achievement, and enjoyment, each with four levels. Research on the instrument's validity, reliability, feasibility of use and sensitivity to change are still ongoing.
Timepoint [3] 0 0
Screening and at 18 months
Secondary outcome [4] 0 0
Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from screening to 18 months in State/Trait anxiety using the State/Trait Anxiety Inventory (STAI) - The STAI is a psychological inventory based on a 4-point Likert scale and consists of 40 questions on a self-report basis. The STAI measures two types of anxiety - state anxiety, or anxiety about an event, and trait anxiety, or anxiety level as a personal characteristic. Higher scores are positively correlated with higher levels of anxiety.
Timepoint [4] 0 0
Screening and at 18 months
Secondary outcome [5] 0 0
Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the number of allergy-related healthcare visits from randomisation to 18 months - Captured per number of hospitalisations, Emergency Room (ER) visits, physician office visits, and medications/number of prescriptions using linked data to Medicare healthcare usage (Medical Benefits Scheme (MBS) and Pharmaceutical Benefits Scheme (PBS)) and Victorian Data Linkage for hospital presentations (Victorian Admitted Episodes Dataset (VAED)).
Timepoint [5] 0 0
Randomisation to 18 months
Secondary outcome [6] 0 0
Main Trial: Difference between the two groups in change in SPT wheal size at screening and at 18 months - Measured by SPT wheal size for each child's study nuts at screening and at 18 months.
Timepoint [6] 0 0
Screening and at 18 months
Secondary outcome [7] 0 0
Main Trial: Difference between the two groups in change in levels of specific Immunoglobulin E (sIgE) at screening and at 18 months - Measured by levels of sIgE for each child's study nuts at screening and at 18 months.
Timepoint [7] 0 0
Screening and at 18 months
Secondary outcome [8] 0 0
Main Trial: Difference between the two groups in change in levels of specific Immunoglobulin G4 (sIgG4) at screening and at 18 months - Measured by levels of sIgG4 for each child's study nuts at screening and at 18 months.
Timepoint [8] 0 0
Screening and at 18 months
Secondary outcome [9] 0 0
Main Trial: Difference between the two groups in change in levels of component-resolved diagnostic (CRD) at screening and at 18 months - Measured by levels of CRD for each child's study nuts at screening and at 18 months. CRD is an approach utilised to characterize the molecular components of each allergen involved in a sIgE-mediated response.
Timepoint [9] 0 0
Screening and at 18 months
Secondary outcome [10] 0 0
Main Trial: Difference between the two groups in change in levels of basophil activation test (BAT) at screening and at 18 months - Measured by levels of BAT for each child's study nuts at screening and at 18 months.
Timepoint [10] 0 0
Screening and at 18 months
Secondary outcome [11] 0 0
Main Trial: Total number of missed doses overall (all participants) in the Multi-Nut OIT Group over the 18 month treatment phase - Compliance will be measured by daily parent diary records of doses consumed. Total number of missed daily doses overall (all participants).
Timepoint [11] 0 0
During the 18-month treatment phase
Secondary outcome [12] 0 0
Main Trial: Mean number of missed daily doses per participant in the Multi-Nut OIT Group over the 18 month treatment phase - Compliance will be measured by daily parent diary records of doses consumed. Total number of missed daily doses averaged per participant.
Timepoint [12] 0 0
During the 18-month treatment phase
Secondary outcome [13] 0 0
Main Trial Ad Libitum Phase: Comparison of the number of participants who pass their OFC after the 12 month Ad Libitum phase for both study nuts between the Multi-Nut OIT Group and Standard Care Group - In both groups, passing requires tolerating all OFC doses for both of their study nuts.
Timepoint [13] 0 0
At 32 months
Secondary outcome [14] 0 0
Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the proportion and severity of reported AEs related to study nut ingestion during the 12-month Ad libitum phase - Number and severity of AEs as assessed by standardised predetermined criteria, related to study peanut/tree nut ingestion from the start to the end of the 12-month Ad libitum phase collected via end of trial OFC observation and medical history, and parent 1-monthly questionnaires.
Timepoint [14] 0 0
During the 12 month Ad libitum phase
Secondary outcome [15] 0 0
Main Trial: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from the start to the end of the Ad libitum phase in quality of life scores for the children, measured by the FAQL-PF - The Food Allergy Quality of Life Questionnaires (FAQLQ) are disease-specific health-related quality of life questionnaires for patients with food allergy. The FAQL-PF completed by parents of children aged 0-12 years, consists of 30 items over 3 domains: emotional impact, food anxiety, social and dietary restrictions. Total and domain scores are calculated by dividing the sum of completed items by the number of competed items.
Timepoint [15] 0 0
At the 18-month treatment phase assessment and at the 12 month Ad libitum phase assessment
Secondary outcome [16] 0 0
Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from the start to the end of the Ad libitum phase in quality of life scores for the parents using the ICECAP-A - The ICECAP-A questionnaire is a measure of capability well-being for adults. It has been developed in the UK using in-depth and semi-structured qualitative research with adults over the age of 18; values for the UK, obtained using best-worst scaling, are available. The instrument contains five attributes - stability, attachment, autonomy, achievement, and enjoyment, each with four levels. Research on the instrument's validity, reliability, feasibility of use and sensitivity to change are still ongoing.
Timepoint [16] 0 0
At the 18-month treatment phase assessment and at the 12 month Ad libitum phase assessment
Secondary outcome [17] 0 0
Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in mean change from the start to the end of the Ad libitum phase in State/Trait anxiety using the STAI - The STAI is a psychological inventory based on a 4-point Likert scale and consists of 40 questions on a self-report basis. The STAI measures two types of anxiety - state anxiety, or anxiety about an event, and trait anxiety, or anxiety level as a personal characteristic. Higher scores are positively correlated with higher levels of anxiety.
Timepoint [17] 0 0
At the 18-month treatment phase assessment and at the 12 month Ad libitum phase assessment
Secondary outcome [18] 0 0
Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the number of allergy-related healthcare visits during the 12-month Ad libitum phase - Captured per number of hospitalisations, ER visits, physician office visits, and medications/number of prescriptions using linked data to Medicare healthcare usage (MBS/PBS) and Victorian Data Linkage for hospital presentations (VAED)
Timepoint [18] 0 0
During the 12-month Ad libitum phase
Secondary outcome [19] 0 0
Main Trial Ad Libitum Phase: Difference between the two groups in change in SPT wheal size from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment - Measured by SPT wheal size for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.
Timepoint [19] 0 0
At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment
Secondary outcome [20] 0 0
Main Trial Ad Libitum Phase: Difference between the two groups in change in levels of sIgE from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment - Measured by levels of sIgE each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.
Timepoint [20] 0 0
At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment
Secondary outcome [21] 0 0
Main Trial Ad Libitum Phase: Difference between the two groups in change in levels of sIgG4 from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment - Measured by levels of sIgG4 for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.
Timepoint [21] 0 0
At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment
Secondary outcome [22] 0 0
Main Trial Ad Libitum Phase: Difference between the two groups in change levels of CRD from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment - Measured by levels of CRD for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment. CRD is an approach utilised to characterize the molecular components of each allergen involved in a sIgE-mediated response.
Timepoint [22] 0 0
At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment
Secondary outcome [23] 0 0
Main Trial Ad Libitum Phase: Difference between the two groups in change levels of BAT from 18-months treatment phase assessment to the 12-month Ad libitum phase assessment - Measured by levels of BAT for each child's study nuts at the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment.
Timepoint [23] 0 0
At the 18-month treatment phase assessment and at the 12-month Ad libitum phase assessment
Secondary outcome [24] 0 0
Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the amount of study nut consumption during the Ad libitum phase - Amount of study nut consumption during the Ad libitum phase based on parent 1-monthly questionnaires.
Timepoint [24] 0 0
During the 12-month Ad libitum phase
Secondary outcome [25] 0 0
Main Trial Ad Libitum Phase: Difference between the Multi-Nut OIT Group in comparison to the Standard Care Group in the frequency of study nut consumption during the Ad libitum phase - Frequency of study nut consumption during the Ad libitum phase based on parent 1-monthly questionnaires.
Timepoint [25] 0 0
During the 12-month Ad libitum phase
Secondary outcome [26] 0 0
Pilot Phase: Number of children at screening who refuse, are eligible, or are ineligible - Pilot Phase: At screening, number of children who:
refuse to participate
are eligible
are ineligible (and reason)
Timepoint [26] 0 0
At study screening, up to 4 weeks before starting treatment
Secondary outcome [27] 0 0
Pilot Phase: Number of children at recruitment who agree or refuse to participate - At recruitment, number of eligible children who:
agree to be in the study
who refuse to be in the study
Timepoint [27] 0 0
At study recruitment, up to 4 weeks before starting treatment
Secondary outcome [28] 0 0
Pilot Phase: Number of participants in the Multi-Nut OIT Group who complete escalation - Number of children in the Multi-Nut OIT Group who complete all escalation doses
Timepoint [28] 0 0
At completion of first day of treatment
Secondary outcome [29] 0 0
Pilot Phase: Number of participants in the Multi-Nut OIT Group who complete the build-up phase - Number of participants in the Multi-Nut OIT Group who complete build-up
Timepoint [29] 0 0
At completion of build-up, between 3-8 months after commencing treatment
Secondary outcome [30] 0 0
Pilot Phase: Number of participants in the Multi-Nut OIT Group and the Standard Care Group who withdraw, discontinue, and/or experience 1 or more protocol violations - Number of participants in either arm who:
withdraw
discontinue the treatment prior to 18 months
experience 1 or more protocol violations
Timepoint [30] 0 0
During the 18 month treatment phase
Secondary outcome [31] 0 0
Pilot Phase: Number and severity of AEs during the screening OFC for all participants - Number and severity of AEs as assessed by standardised predetermined criteria during the screening OFC.
Timepoint [31] 0 0
At study screening, up to 4 weeks before starting treatment
Secondary outcome [32] 0 0
Pilot Phase: Number and severity of AEs for the Multi-Nut OIT Group during escalation - Number and severity of AEs as assessed by standardised predetermined criteria during escalation.
Timepoint [32] 0 0
At completion of first day of treatment
Secondary outcome [33] 0 0
Pilot Phase: Number and severity of AEs for the Multi-Nut OIT Group during the build-up phase - Number and severity of AEs as assessed by standardised predetermined criteria during build-up.
Timepoint [33] 0 0
During the build-up phase, between 3-8 month period after commencing treatment
Secondary outcome [34] 0 0
Pilot Phase: Total number of missed doses overall (all participants) in the Multi-Nut OIT Group over the build-up phase - Based on parent diary entries. Number of missed daily doses overall (all participants).
Timepoint [34] 0 0
During the build-up phase, between 3-8 month period after commencing treatment
Secondary outcome [35] 0 0
Pilot Phase: Mean number of missed daily doses per participant in the Multi-Nut OIT Group over the build-up phase - Based on parent diary entries. Number of missed daily doses averaged per participant.
Timepoint [35] 0 0
During the build-up phase, between 3-8 month period after commencing treatment

Eligibility
Key inclusion criteria
- Is between the ages of 18 and 36 months at the time of Screening visit 1

- Has a legally acceptable representative capable of understanding the informed consent
document and providing consent on the participant's behalf

- IgE-mediated allergy to 2 of peanut, almond, cashew, hazelnut or walnut, confirmed by:

Nut 1 pre-screening:

For at least one of almond, cashew, hazelnut or walnut (Nut 1)*:

1. History of ingestion with IgE-mediated reaction (birth to present) AND

2. History of SPT =3mm OR History of sIgE =0.35 number of kilounits per liter (KuL) AND

Nut 2 pre-screening:

For a second nut out of peanut, almond, cashew, hazelnut or walnut (Nut 2):

History of SPT =3mm OR History sIgE =0.35 KuL

In clinic screening: Participants meeting pre-screening criteria for Nuts 1 and 2 above
will be invited for in-clinic screening

1. SPT: wheal size =3mm at Visit 1 for 2 of peanut, almond, cashew, hazelnut or walnut
AND

2. OFC: react to =3000 mg protein top dose (4449 mg cumulative) in open, single nut OFC
for 2 of peanut, almond, cashew, hazelnut or walnut

OFC not needed if:

History of failed OFC within past 3 months (confirmed by investigator review of discharge
summary) OR History of anaphylaxis after ingestion within past 3 months based on
investigator judgement +/- review of ER/Ambulance/medical notes

*Peanut is not included as Nut 1 to reduce the incidence of screening children with a
peanut allergy only - children with peanut allergy may have been advised to avoid all other
nuts. We require children to have eaten and reacted to at least one tree nut, and then the
2nd nut, which children may or may not have eaten, can be peanut or a tree nut.
Minimum age
18 Months
Maximum age
36 Months
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- History of severe anaphylaxis (as defined by persistent hypotension, collapse, loss of
consciousness, persistent hypoxia or ever needing more than 2 doses of intramuscular
adrenaline or an intravenous adrenaline infusion for management of an allergic
reaction)

- Severe anaphylaxis at study screening OFC (defined as persistent hypotension,
collapse, loss of consciousness, persistent hypoxia, or requiring more than 2 doses of
intramuscular adrenaline or an intravenous adrenaline infusion for management of an
allergic reaction)

- Fails either screening OFC on dose 1 (0.5 mg).

- Underlying medical conditions that increase the risks associated with anaphylaxis
(e.g., cardiac disease or poorly controlled asthma (defined below))

- Confirmed eosinophilic esophagitis (EoE) or history indicating EoE

- Current use of beta-blockers or angiotensin-converting enzyme (ACE) inhibitors

- Receiving systemic immunomodulatory treatment

- Not commenced or unable to eat solid food

- Weight <7.5kgs (recommended minimum weight for EpiPen Jr (adrenaline autoinjector))

- Has a sibling in the study

Defining uncontrolled asthma (Global Initiative for Asthma. Asthma management and
prevention for adults and children older than 5 years)

In the past 4 weeks, has the patient had:

Daytime symptoms more than twice/week? Any night waking due to asthma? Short Acting Beta
Agonist (SABA) reliever needed more than twice/week? Any activity limitation due to asthma?
Uncontrolled - answered yes to 3-4 of these

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
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] 0 0
Murdoch Children's Research Institute - Parkville
Recruitment postcode(s) [1] 0 0
3052 - Parkville

Funding & Sponsors
Primary sponsor type
Other
Name
Murdoch Childrens Research Institute
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The LMNOP trial will be a 2-armed, open-label, randomised controlled trial (RCT), 2:1. Over a
period of 18 months, children in the Multi-Nut Oral Immunotherapy Treatment (OIT) Group
(experimental arm) will undergo low dose OIT to two nuts they are allergic to. At this time,
children in the Standard Care Group (control arm) will be instructed to strictly avoid
consuming two nuts they are allergic to. Avoiding consuming nut allergens is the standard
care advice for children with peanut/tree nut allergies in Australia. The trial will assess
the difference in the proportion of participants undergoing Multi-Nut OIT who can achieve
sustained unresponsiveness (SU) compared to the proportion of participants avoiding nuts who
develop natural tolerance (NT), i.e. grow out of their allergy. SU is when a participant can
pass an oral food challenge (OFC) after having paused OIT treatment for several weeks.
Participants will be between the ages of 18 and 36 months at the time of screening. The first
12 participants enrolled will be part of the pilot phase, with a total of n = 45 for the main
trial.

It is hypothesised that there will be a higher proportion of participants in the Multi-Nut
OIT Group versus the Standard Care Group who pass the OFC following the 18-month treatment
phase. That is, a higher proportion of participants in the Multi-Nut OIT Group will achieve
SU compared to participants in the Standard Care Group achieving NT.
Trial website
https://clinicaltrials.gov/show/NCT05049512
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Kirsten Perrett, MBBS FRACP
Address 0 0
Murdoch Children's Research Institute
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Kirsten Perrett, MBBS FRACP
Address 0 0
Country 0 0
Phone 0 0
039936
Fax 0 0
Email 0 0
kirsten.perrett@rch.org.au
Contact person for scientific queries

Summary results
For IPD and results data, please see https://clinicaltrials.gov/show/NCT05049512