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.
