The LMNOP trial is a novel RCT assessing whether, over a period of 18 months, children
undergoing low dose, multi-nut OIT can safely achieve SU at a higher rate than children under
standard care who develop NT to peanut and tree nuts.
Trial Time Line. Study Entry
- - Children will undergo a screening skin prick test (SPT) to two of peanut,
cashew, almond, hazelnut and/or walnut and OFC.
Children who meet the study eligibility criteria will be randomisation to either the
Multi-Nut OIT Group or Standard Care Group for 18 months.
Multi-Nut OIT Group:
The 18-month treatment phase involves an escalation visit, build-up phase and maintenance
phase. 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. 300 mg per allergen was chosen as the daily
maintenance dose, as this is the lowest dose thus far demonstrated in any trial to
successfully achieve SU.
Each dose will be mixed into a carrier food of the participant's choice (e.g. apple puree,
custard, chocolate pudding etc).
At the end of the 18-month treatment phase, participants will have a SPT and OFC to their
study nuts.
Participants who pass the OFC will cease OIT for 4 weeks. They will then undergo another OFC,
19 months after commencing treatment. Participants who pass this OFC will then enter the Ad
libitum phase for 12 months. The Ad libitum phase involves participants eating the study nuts
as much or as often as they want. To ensure the participant is consuming some nuts, they will
be given advice that at a minimum, participants should have approximately ½ -1 teaspoon of
nut flour, twice per week, for each nut.
At the end of the Ad libitum phase, participants will undergo another OFC.
Standard Care Group:
At the end of the 18-month period, participants will have a SPT and OFC to their study nuts.
Participants who pass their OFC will enter Ad libitum Phase for 12 months. As described for
the Multi-Nut OIT Group, this involves participants eating the study nuts as much or as often
as they want, with advice given that participants should have approximately ½ -1 teaspoon of
nut flour, twice per week for each nut at a minimum.
At the end of the Ad libitum phase, participants will undergo another OFC.
Any Multi-Nut OIT Group participants who fail their OFC to one or both of their study nuts
after the 18-month treatment phase will be asked to cease OIT to that nut(s) and will be
referred back to their regular allergist. Likewise, any Multi-Nut OIT Group participants who
fail their OFC to one or both of their study nuts after the 4 weeks of ceasing OIT will be
asked to avoid the nut/s and will be referred back to their regular allergist. Any Standard
Care Group participants who fail their OFC at this time, will be asked to continue avoiding
that nut(s) and will also be referred back to their regular allergist. Participants in both
groups who fail their OFC to both study nuts will be invited back at the end of the trial for
a clinical assessment, but no OFC.
Primary Aim of the Pilot Phase:
To determine the feasibility of this study design in terms of recruitment into the study and
completion of the escalation and build-up phases for participants in the Multi-Nut OIT Group.
Primary Aim of the Main Trial:
To compare the proportion of participants in the Multi-Nut OIT Group versus the Standard Care
Group who pass the OFC after the 18-month treatment phase. That is, comparing the proportion
of participants in the Multi-Nut OIT Group who achieve SU by passing their OFC after 18
months of OIT, and then passing another OFC after 4 weeks of ceasing OIT, to participants in
the Standard Care Group who achieve NT by passing their OFC after the 18-month period.
Healthy children aged 18-36 months at the screening visit with confirmed/suspected
Immunoglobulin E-mediated (IgE-mediated) allergies to 2 of: peanut, cashew, almond, hazelnut
and/or walnut, and who meet the study criteria, will be recruited into the trial. Children
will be randomised (2:1) for the pilot phase to either: multi-nut OIT (n ~ 8) or standard
care (n ~ 4), and for the main trial
- - multi-nut OIT (n ~ 30) or standard care (n ~ 15).
The
12 pilot participants will be included in the over all total of 45 participants.
Data from the first 12 participants enrolled, denoted the Pilot Phase, will be used to assess
the feasibility of our study design in terms of the screening, recruitment, randomisation and
treatment of participants, and examine the acceptability of low dose, multi-nut OIT in young
children. Once the first 12 participants have been enrolled, we will pause recruitment until
all Pilot Phase participants in the Multi-Nut OIT Group have completed the build-up phase (~
8 months). At this point we will undertake an interim analysis of the feasibility data, and
review whether any adjustments need to be made to the protocol. Following this, and assuming
that there are no major issues with the study protocol and further funding has been secured,
we will continue recruitment into the trial as per the protocol.
Potential participants will be identified from these sources: public and private Allergy
clinics, Centre for Food & Allergy Research (CFAR) and Allergy & Anaphylaxis Australia (A&AA)
websites and social media. For the Pilot Phase, recruitment will begin with distribution of
the 'LMNOP Study Invitation' flyer electronically via the CFAR website and email list (270+
families interested in participating in food allergy research), and on Facebook via the
Murdoch Children's Research Institute (MCRI) and Melbourne Allergy Centre and Children's
Specialists (MACCS) private allergy clinic. Parents who have expressed interest in the study
will be contacted, and those children deemed likely to be eligible for the study according to
study criteria following a screening phone call, will be invited to attend a 2-day screening
assessment at the Melbourne Children's Trials Centre (MCTC), MCRI.
Screening day 1: Following informed parental consent, children will have a SPT and blood will
be drawn. Children with a positive SPT (≥3mm) to 2 of peanut, cashew, almond, hazelnut or
walnut will be offered 2 individual nut OFCs to confirm allergy and reaction thresholds prior
to randomisation. The OFC will not be needed if the child's allergy history meets the study
criteria for a confirmed allergy. The first OFC will take place on Screening day 1.
Screening day 2: Children will have a 2nd individual nut OFC. This will be completed
approximately one week after the first OFC.
Once the child has completed screening and has confirmed IgE-mediated allergy to 2
peanut/tree nuts (positive SPT (≥3mm), and OFC), they will enter the treatment phase, and
will be randomised to either:
Multi-Nut OIT Group: Participants will undergo multi-nut OIT treatment using a personalised
multi-nut flour
- - 2 of peanut, almond, cashew, hazelnut or walnut, 1:1 ratio of allergen
protein.
Multi-Nut OIT Group participants will continue strict avoidance of confirmed
allergens outside of their daily dose of multi-nut flour, and will have 24-hour access to an
on-call study doctor in case of allergic reactions.
Standard Care Group: As per standard clinical care in Australia, families will be instructed
to strictly avoid all confirmed nut allergens over the 18-month period.
The Multi-Nut OIT Group will undergo an 18-month treatment phase consisting of an escalation
visit, build-up phase and maintenance phase as described above. Participants who pass their
OFC after 18 months of OIT, and then another OFC after no OIT for 4 weeks for one or both of
their study nuts, will enter the Ad libitum phase described above. After 12 months of this
unrestricted consumption of the study nuts, with a minimum of approximately 300 mg protein
per nut: ½ -1 teaspoon of nut flour, twice per week for both nuts, participants will be
assessed for induced tolerance (IT) via another OFC. IT is when a child can eat standard
serves of the food 12 months after stopping OIT, without having an allergic reaction.
The Standard Care Group for the 18 months will be instructed to avoid any consumption of the
peanut/tree nuts they are allergic to, as per standard care. Participants who pass the OFC
for one or both of their study nuts at the end of the 18 months will undergo the 12-month Ad
libitum phase. At the end of this 12-month period, participants will then be assessed for
maintaining NT via an OFC. That is, whether they have still outgrown their allergy.
