Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000946718
Ethics application status
Approved
Date submitted
1/07/2022
Date registered
5/07/2022
Date last updated
29/08/2022
Date data sharing statement initially provided
5/07/2022
Type of registration
Prospectively registered

Titles & IDs
Public title
Early Reintroduction of Nuts for ImmunothErapy (ERNIE)
Scientific title
A single arm feasibility study to evaluate the tolerability and safety of a multi-nut oral immunotherapy study in children under 5 with tree nut allergy/ies.
Secondary ID [1] 307271 0
NA
Universal Trial Number (UTN)
Trial acronym
ERNIE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
almond allergy 326528 0
cashew allergy 326890 0
hazelnut allergy 326891 0
walnut allergy 326892 0
peanut allergy 326893 0
Condition category
Condition code
Inflammatory and Immune System 323793 323793 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention is a multi-nut oral immunotherapy (OIT) (almond, cashew, hazelnut, walnut and peanut) daily for 12 months.

The intervention will consist of incrementally increasing doses of a mixture of five nut flours (almond, cashew, hazelnut, walnut and peanut) that are combined in a fixed ratio to achieve an equal protein content of each nut in a single product administered over a period of 12 months. All participants will receive the same multi-nut flour regardless of which nuts they have a confirmed allergy to.

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.
The multi-nut OIT investigational product will provided to participants in pre-packaged individual daily doses, to ensure accurate daily administration of each nut. The investigational product will be compounded by the Australian Approved Manufacturer, Optima Ovest, Western Australia, in accordance with the Australian Code of Good Manufacturing Practice (TGA licence MI-2012-LI-00060-3). Optima Ovest will prepare all OIT doses (increments from 0.5mg to 250mg of each nut protein), master labelled and provided in batches to Clinical Trials Pharmacy at PCH for participant dispensing.

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 for a minimum of six visits, until a maximum dose of 250mg of each nut protein (total combined dose of 1.25g nut protein) is reached (30mg, 60mg, 90mg, 120mg, 180mg, 250mg). 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 continue to take daily doses of maintenance multi-nut flour until a total of 12 months of treatment is completed. The maintenance dose is 250mg of each nut protein (total combined dose of 1.25g nut protein).

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] 323709 0
Treatment: Other
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 331563 0
The primary outcome of this study is the safety and tolerability of multi-nut oral immunotherapy during the first 6 months of treatment. To measure safety the number and severity of treatment-related adverse events (trAEs) (including adrenaline use) will be evaluated,

All participants will be monitored for AEs from when they sign the consent form up until the end of treatment visit. AEs that occur during on site study visits will be recorded by study staff at the time they occur in the source document. Possible adverse events will also be elicited from participants’ parents via the daily eDiary.

All safety events will be categorised as either:
• Treatment related events
• Food challenge related events
• Accidental food consumption events
• Other adverse events (not related to previous categories)

The causal relationship of the AE to peanut OIT will be attributed by the Investigator or delegate and recorded in the source document, with the following criteria used for guidance:
Related:
• Follows a clear temporal sequence from administration of OIT (e.g. within 1 hour)
• Has no other possible explanation
• Improves on cessation or reduction in dose of OIT (positive de-challenge)
• Recurs or worsens upon recommencing or increasing dose of OIT (positive re-challenge)
Probable:
• Follows a reasonable temporal sequence from administration of OIT (e.g. within 4 hours).
• Could not be reasonably explained by other factors.
• Is a known side effect and/or follows a known pattern of reactions to OIT.
• Positive de-challenge and/or re-challenge
Possible:
• Follows a reasonable temporal sequence from administration of OIT (e.g. within 4 hours).
• Is a known side effect or follows an expected pattern of symptoms following OIT but could be reasonably explained by other factors
Unlikely:
• Does not follow a reasonable temporal sequence from administration of OIT.
• Could be reasonably explained by other factors.
• Does not demonstrate a positive de-challenge / rechallenge
Not related:
• The AE does not meet the above criteria
• There is sufficient information that the AE is not related to OIT.

The severity of each AE will be assessed by the investigator using the following categories and recorded in the source document.
• Mild: The AE was transient and easily tolerated by the subject
• Moderate: The AE caused discomfort and interference with the subject’s general condition
• Severe: The AE caused considerable interference with the subject’s general condition and may have been incapacitating.

To assess tolerability we will measure treatment adherence from participant diaries and health related quality of life during the first 6 months of treatment.
Timepoint [1] 331563 0
6 months after commencing multi-nut OIT
Secondary outcome [1] 410303 0
To describe clinical outcome of OIT will be assessed by performing oral food challenges at end of treatment (EOT) (i.e. after 12 months of OIT) to each of the nuts that a participant was allergic to at baseline. We will report median and range of eliciting doses for each nut, as well as the proportion of participants who have an eliciting dose of (i) at least 300mg and (ii) at least 600mg nut protein, and (iii) who complete the oral food challenge without reaction at EOT.
Timepoint [1] 410303 0
12 months after commencing multi-nut OIT
Secondary outcome [2] 410304 0
Tolerability of OIT treatment during ongoing maintenance from Month 7 to Month 12 of treatment as assessed by exposure-adjusted incidence of treatment related adverse events and proportion of participants discontinuing OIT during that time period, and change in health related quality of life from baseline to 12 months and from 6 months to 12 months.
Timepoint [2] 410304 0
12 months after commencing multi-nut OIT
Secondary outcome [3] 410305 0
Changes in immunological markers of nut sensitisation (serum specific Immunoglobulin E (sIgE) from blood, and skin prick test (SPT)) from baseline to end of treatment (EoT). All participants will have almond, cashew, hazelnut, walnut and peanut sIgE measured (ImmunoCAP system, Thermo Fisher Scientific) and SPTs performed at baseline (SV1) and EOT. We will compare the mean change in nut sIgE and SPT wheal size between baseline and EOT.
Timepoint [3] 410305 0
12 months after commencing multi-nut oral immunotherapy

Eligibility
Key inclusion criteria
1) Male or female children from 1-4 years of age (i.e. first visit to occur on or after the participant’s first birthday, and prior to their fifth birthday).

2) Confirmed or highly probably allergy, to at least one of almond, cashew, hazelnut or walnut. Children with other nut allergies (including peanut allergy) are eligible for inclusion, however they must also have a confirmed or highly probable allergy to at least one of almond, cashew, hazelnut or walnut.

3) Parents/guardians and subjects willing to comply with all the study requirements during their participation in the study.

Tree nut allergy inclusion definitions (almond, cashew, hazelnut or walnut)
a) Confirmed (entry OFC required):
Positive 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 12 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 4 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, 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

Whilst participants may have a peanut allergy alongside one or more tree nut allergies, it will not affect eligibility for the study
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, or requiring more than three doses of IM adrenaline, an IV adrenaline infusion or intubation for management of an allergic reaction.
2. Use of beta-blockers
3. Participants receiving immunotherapy for food allergy, or who have received immunotherapy for food allergy in the preceding 3 months.
4. Participants currently receiving other oral or sublingual allergen immunotherapy
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
Non-randomised 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
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
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 exposure-adjusted incidence of treatment-related adverse events will be calculated by dividing the total number of trAEs reported by all participants by the total number of OIT doses taken by all participants over a specified time period, and presented with a 95% confidence interval of the estimate. Furthermore, we will separately calculate the exposure-adjusted incidence of trAEs by phase of treatment (treatment initiation, updosing, maintenance), location of dose administration (hospital vs home), and severity of trAE (mild, moderate, severe).
We will report the frequencies of treatment-related AEs requiring adrenaline, and the proportion of participants experiencing at least one trAEs requiring adrenaline.
To investigate changes in immunological outcomes and HRQL during the intervention we will compare continuous variables (SPT, sIgE, and HRQL questionnaires) over multiple timepoints (baseline, 3, 6 and 12 months). Linear mixed models will be used where ID is entered as a random effect. Time will be treated as a categorical variable with baseline the reference category. Model fit will be examined and if required the data will be transformed or non-parametric methods will be used (Friedman’s test). We will also calculate the proportion of participants who record a meaningful change in FAQLQ scores (an increase or decrease in scores >0.5) from baseline to each time point.
Data from the participant daily eDiary will be used for the assessment of treatment adherence. Compliance will be defined as a treatment rate of 80%. Analysis will primarily be on all participants in an intention-to-treat analysis. In addition, we will perform a per-protocol analysis which will exclude those participants who had <80% compliance and those who withdrew due to reasons other than tolerance or safety of the intervention. Those participants who withdrew due to side effects will be recorded as a treatment failure in the per protocol analysis.
To describe the outcomes of the OFC, the median and range of eliciting doses for each nut will be reported. The change in OFC eliciting dose from baseline to EOT will be examined using paired T-test or Wilcoxon signed ranked test. In addition, the rate of no reaction per number of challenges will be reported at eliciting doses 300mg, 600mg, and 3000mg in intention-to-treat and per protocol analyses. For the intention-to-treat analysis, any participants who do not complete a scheduled EOT challenge visit, including due to treatment discontinuation, will be classified as having an eliciting dose of <300mg. We will also report the severity of reactions at EOT, by describing the frequency of mild, moderate or severe reactions.
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
Recruiting
Date of first participant enrolment
Anticipated
31/07/2022
Actual
Date of last participant enrolment
Anticipated
31/12/2022
Actual
Date of last data collection
Anticipated
31/12/2023
Actual
Sample size
Target
25
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 22482 0
Perth Children's Hospital - Nedlands
Recruitment postcode(s) [1] 37716 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 311569 0
Charities/Societies/Foundations
Name [1] 311569 0
Channel 7 Telethon Trust
Country [1] 311569 0
Australia
Primary sponsor type
Government body
Name
Child and Adolescent Health Service
Address
Level 5, Perth Children's Hospital, 15 Hospital Avenue, Nedlands WA 6009
Country
Australia
Secondary sponsor category [1] 312985 0
None
Name [1] 312985 0
NA
Address [1] 312985 0
NA
Country [1] 312985 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 311017 0
Child and Adolescent Health Service
Ethics committee address [1] 311017 0
Ethics committee country [1] 311017 0
Australia
Date submitted for ethics approval [1] 311017 0
21/09/2021
Approval date [1] 311017 0
18/11/2021
Ethics approval number [1] 311017 0
RGS0000004986

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

Contacts
Principal investigator
Name 119710 0
Dr Michael O'Sullivan
Address 119710 0
Immunology Department
Perth Children's Hospital
15 Hospital Avenue, Nedlands, WA, 6009
Country 119710 0
Australia
Phone 119710 0
+61 434582982
Fax 119710 0
Email 119710 0
Michael.O'Sullivan@health.wa.gov.au
Contact person for public queries
Name 119711 0
Michael O'Sullivan
Address 119711 0
Immunology Department
Perth Children's Hospital
15 Hospital Avenue, Nedlands, WA, 6009
Country 119711 0
Australia
Phone 119711 0
+61 434582982
Fax 119711 0
Email 119711 0
Michael.O'Sullivan@health.wa.gov.au
Contact person for scientific queries
Name 119712 0
Michael O'Sullivan
Address 119712 0
Immunology Department
Perth Children's Hospital
15 Hospital Avenue, Nedlands, WA, 6009
Country 119712 0
Australia
Phone 119712 0
+61 434582982
Fax 119712 0
Email 119712 0
Michael.O'Sullivan@health.wa.gov.au

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.