Low dose Multi-nut Oral immunotherapy (L-MO)
A head-to-head non-inferiority trial of low vs standard dose multi-nut oral immunotherapy in children under 6 years old.
Child and Adolescent Health Service
208 participants
Apr 8, 2024
Interventional
Conditions
Summary
This study will investigate the safety and efficacy of low dose OIT (60mg of each nut protein) compared to standard dose multi-nut OIT (300mg of each nut protein) in children under 6 years old with one or more nut allergies. This study is a head-to-head, open label, randomised non-inferiority trial. A total of 208 children will be randomised 1:1 to low or standard dose multi-nut OIT, stratified by age and number of nut allergies. The primary outcome of this trial is sustained unresponsiveness to all nuts, defined as passing an oral food challenge to all nuts to which a participant was allergic at baseline, after completing 18 months of OIT followed by 4 weeks of nut avoidance. Secondary outcomes are desensitisation after 18 months of OIT (defined as passing an oral food challenge while still on uninterrupted OIT), safety, tolerability, feasibility, immune changes and patient-reported experience and outcomes of multi-nut OIT.
Eligibility
Inclusion Criteria26
- Male or female children from 1 until 5 years of age (not yet turned 6)
- Confirmed or highly probably allergy (as defined below) to at least one of almond, cashew, hazelnut, macadamia, walnut or peanut.
- Parents/guardians and subjects willing to comply with all the study requirements during their participation in the study.
- 2.1 Tree nut allergy inclusion definitions (almond, cashew, hazelnut, macadamia 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
- 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.
Exclusion Criteria14
- Participants will be excluded if they meet any of the following criteria:
- 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.
- Use of beta-blockers
- 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).
- 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.
- 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.
- Confirmed diagnosis of eosinophilic oesophagitis, and/or uncontrolled symptoms of dysphagia, postprandial abdominal pain or vomiting.
- 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.
- Subjects who in the opinion of the investigator will be unable to follow the protocol
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Interventions
Participants will be randomised to either a 60mg (intervention) or 300mg (comparator) maintenance dose of multi-nut oral immunotherapy (OIT) (almond, cashew, hazelnut, macadamia, peanut and/or walnut). 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 8 weeks. During this period participants will indicate any accidental ingestion of their allergens in their electronic diary. After 8 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.
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ACTRN12624000515594