A Randomized Controlled Trial to Investigate the (Cost)Effectiveness of Oral Immunotherapy With Different Allergens in Young Children With an Established Food Allergy
Phase: NA
Conditions: Food Allergy
Sponsor: Deventer Ziekenhuis

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Study protocol version 3  
November 2023 
 
 
 
 

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PROTOCOL TITLE: A randomized controlled trial to investigate the (cost)effectiveness of oral 
immunotherapy with different allergens in young children with an established food allergy. 
 
Protocol ID 
NL81774.075.22 
Short title 
Oral immunotherapy in young children with food allergy 
Version 
3 
Date 
17/10/2022 
Project leader 
Dr. T. Klok, email: klok@dz.nl 
Coordinating investigator 
Dr. J. Faber, email: j.faber@dz.nl 
Principal investigator(s)  
 
Dr. T. Klok, Deventer ziekenhuis 
Drs. D. Verhoeven (Reinier de Graaf gasthuis Delft) 
Dr. A. Kamps (Martini Ziekenhuis Groningen) 
Dr. H.K. Brand (Emma kinderziekenhuis, Amsterdam 
UMC) 
Sponsor  
Deventer ziekenhuis, email: d.creemers@dz.nl 
Subsidising party 
Zorginstituut Nederland, email 
veelbelovendezorg@zinl.nl 
Independent expert (s) 
Drs. R. Witteveen, paediatrician, email: 
r.witteveen@isala.nl 
Laboratory sites  
Deventer hospital 
Amsterdam 
Delft  
Groningen 

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PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Head of Department: 
R. Wachters, Deventer ziekenhuis 
 
 
Coordinating Investigator: J. Faber 
 
Project leader: dr. T. Klok 
 
Principal Investigator: 
 
Dr. H.K. Brand 
 
Dr. A. Kamps 
 
Drs. D. Verhoeven 
 
 
 
 
 

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Inhoud 
1. 
INTRODUCTION AND RATIONALE 
9 
2. 
OBJECTIVES 
12 
3. 
STUDY DESIGN 
12 
4. 
STUDY POPULATION 
13 
4.1 
Population 
13 
4.2 
Inclusion criteria 
13 
4.3 
Exclusion criteria 
13 
4.4 
Sample size calculation 
14 
5. 
TREATMENT OF SUBJECTS 
14 
5.1 
Investigational treatment 
14 
5.2 
Use of co-intervention 
17 
5.3 
Escape medication 
17 
6. 
INVESTIGATIONAL PRODUCT 
18 
6.1 
Name and description of food  products 
18 
6.2 
Summary of findings from clinical studies 
19 
6.3 
Summary of known and potential risks and benefits 
19 
6.4 
Description and justification of route of administration and dosage 
19 
6.5 
Dosage, dosage modifications and method of administration 
19 
7. 
METHODS 
20 
7.1 
Study parameters/endpoints 
20 
7.1.1 
Main study endpoint 
20 
7.1.2 
Secondary study parameters/endpoints 
20 
7.1.3 
Other study parameters 
20 
7.2 
Randomisation, blinding and treatment allocation 
21 
7.3 
Study procedures 
22 
7.4 
Withdrawal of individual subjects 
25 
7.5 
Replacement of individual subjects after withdrawal 
26 
7.6 
Follow-up of subjects withdrawn from treatment 
26 
7.7 
Premature termination of the study 
26 
8. 
SAFETY REPORTING 
27 
8.1 
Temporary halt for reasons of subject safety 
27 
8.2 
AEs, SAEs and SUSARs 
27 
8.2.1 
Adverse events (AEs) 
27 
8.2.2 
Serious adverse events (SAEs) 
27 
8.3 
Follow-up of adverse events 
27 
8.4 
Data Safety Monitoring Board (DSMB) 
28 
9. 
STATISTICAL ANALYSIS 
29 
9.1 
Primary study parameter: tolerance induction 
29 
9.2 
Secondary study parameter(s) 
30 
10. 
ETHICAL CONSIDERATIONS 
31 
10.1 
Regulation statement 
31 
10.2 
Recruitment and consent 
31 

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10.3 
Objection by minors 
31 
10.4 
Benefits and risks assessment, group relatedness 
31 
10.5 
Compensation for injury 
31 
11. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
33 
11.1 
Handling and storage of data and documents 
33 
11.2 
Monitoring and Quality Assurance 
34 
11.3 
Amendments 
35 
11.4 
Annual progress report 
35 
11.5 
Temporary halt and (prematurely) end of study report 
35 
11.6 
Public disclosure and publication policy 
35 
12. 
STRUCTURED RISK ANALYSIS 
36 
12.1 
Potential issues of concern 
36 
12.2 
Synthesis 
38 
13. 
REFERENCES 
39 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
ABR 
General Assessment and Registration form (ABR form), the application form that is 
required for submission to the accredited Ethics Committee; in Dutch: Algemeen 
Beoordelings- en Registratieformulier (ABR-formulier) 
AE 
Adverse Event 
AR 
Adverse Reaction 
CV 
Curriculum Vitae 
DSMB 
Data Safety Monitoring Board 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
IB 
Investigator’s Brochure 
IC 
Informed Consent 
(s)IgE 
(specific) Immunoglobulin E 
METC  
Medical research ethics committee (MREC); in Dutch: medisch-ethische 
toetsingscommissie (METC) 
OIT 
Oral Immunotherapy 
(S)AE 
(Serious) Adverse Event  
Sponsor The sponsor is the party that commissions the organisation or performance of the 
research, for example a pharmaceutical 
company, academic hospital, scientific organisation or investigator. A party that 
provides funding for a study but does not commission it is not regarded as the 
sponsor, but referred to as a subsidising party. 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
UAVG 
Dutch Act on Implementation of the General Data Protection Regulation; in Dutch: 
Uitvoeringswet AVG 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
wetenschappelijk Onderzoek met Mensen 
 
 

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SUMMARY 
 
Rationale: Recent studies suggest that oral immunotherapy is associated with long-term tolerance 
development in food allergic children, but only when started early in life. Currently, no randomized 
controlled trials are performed for different kinds of food allergies in these young children. 
Hypothesis: Early low-dose oral immunotherapy in young children with an established food allergy 
will induce long-term tolerance within one year in at least 50% more children compared to the 
percentage of children who achieve spontaneous tolerance in the routine care group (strict 
avoidance of the allergen). 
Primary objective: What is the clinical- and cost-effectiveness of early low-dose oral immunotherapy 
aimed at long-term tolerance induction in children under the age of 30 months with an established 
food allergy  compared to routine care? 
Secundary objective: What is the effect of early low-dose oral immunotherapy in children under the 
age of 30 months with an established food allergy on (allergy specific) quality of life of parents and 
children compared to routine care? 
Study design: randomized controlled superiority trial  
Study population: Children between 9 and 30 months old with an IgE-mediated food allergy to 
peanut, tree nuts, cow9s milk and/or hen9s egg as proven by an oral food challenge. Intervention: 1-
year low-dose oral immunotherapy (daily 300 mg allergenic protein) compared to strict avoidance in 
the control group. 
Main study parameters/endpoints: Sustained unresponsiveness, defined as passing an exit oral food 
challenge at 4 weeks after discontinuation of the 12 months oral immunotherapy, and   
uncomplicated consumption of a full dose of the specific food at home, after 6 months unrestricted 
introduction of the specific food into the diet.  
Nature and extent of the burden and risks associated with participation, benefit and group 
relatedness:  
Burden: in all children participating in the study, oral food challenges are performed, and two blood 
samples are obtained (both will completely or partially be part of routine diagnostic allergy care). 
Parents have to fill in 4 questionnaires each 6 months. Children whose allergy is assigned to the 
intervention group, have to visit the hospital for an additional 1 to 6 times during the build-up phase 
of the treatment and an additional blood sample is obtained after 6 months of therapy. Parents have 
to take care of daily ingestion of the allergenic food by their child at home. 
Risks: the main risk of oral immunotherapy is the occurrence of allergic side-effects. Because a food 
allergy by definition is characterized by an allergic reaction in case of an accidental ingestion, parents 
have to be prepared for the risk of allergic reactions already. Inducing long-term tolerance, the main 

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goal of this treatment, would prevent a life-long risk of allergic reactions caused by accidental 
ingestions. 
Group relatedness: current scientific knowledge suggests that only in food-allergic infants oral 
immunotherapy may be associated with long-term tolerance in contradiction to school-aged 
children. 

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1. INTRODUCTION AND RATIONALE 
 
Many babies and toddlers with moderate to severe eczema develop a food allergy. While the eczema 
will disappear in more than half of the children, the food allergy may persist, causing lifelong dietary 
restrictions. The current lack of curative treatment options is therefore a substantial unmet need for 
these parents, and for children later on in life.1 
Scientific research on treatment of food allergy has been focused on oral immunotherapy, because 
other treatment options have not proven significant profits. For oral immunotherapy, there is vast 
evidence that the therapy results in desensitisation of food-allergic children.2 Desensitization is 
defined as a temporarily desensitisation while on therapy. Meaning that only during ongoing 
treatment the frequency and severity of allergic reactions could be decreased, with acute cessation 
of this effect after discontinuation of the therapy.3 A second possible outcome of oral 
immunotherapy is curation of the food allergy, also named 8tolerance induction9 or 8sustained 
unresponsiveness9. Sustained unresponsiveness is typically tested 2 to 8 weeks after discontinuation 
of the therapy by an oral food challenge using a full-dosage of the allergenic food. In many studies on 
oral immunotherapy for food allergy performed in adults and children > 4 years of age, this outcome 
is only achieved in a minority of patients.32 
New promising perspectives have arisen during the past few years, suggesting that starting the 
therapy in the first years of life may increase the chance on curation of the food allergy. In babies 
with a high risk on development of food allergy, early introduction of high-allergenic food products 
has proven to prevent the development of food allergies to a very large extend.4 5 This high 
effectiveness of early oral ingestion of food allergens to prevent the development of food allergy, has 
proven that food tolerance development in young children originates in the intestinal immune 
system. The next step to benefit from this strong tolerogenic capacity of the intestinal immune 
system early in life is to start oral immunotherapy at a very young age in children with food allergy. 
Results of the first studies on oral immunotherapy started before the age of 4 years, suggest that 
curation of food allergy is achievable in a high rate of babies and toddlers. 
The first study on oral immunotherapy in young peanut-allergic children has shown very promising 
results, with more than 90% of children becoming tolerant for peanut. In this study, 37 children 
under the age of 3 years were included and randomized between high-dose (n=17) and low-dose 
(n=20) oral immunotherapy. A control group (n=154) was included in a cooperating hospital. No 
differences in effectiveness and immunological outcomes were observed between the two treatment 
arms. Sustained unresponsiveness was assessed after 4 weeks of discontinuation of the therapy and 
a survey five years later assessing regular consumption of peanut by the study participants. Long-
term tolerance was achieved in 84% of the children receiving oral immunotherapy compared to an 
estimated spontaneous tolerance development between 4% and 31% in the control group.6  
A recently published study on oral immunotherapy for peanut allergy is a randomized controlled 
study including 146 children between 12 and 48 months old with severe peanut allergy. The 
intervention consisted of two years of oral immunotherapy. Sustained unresponsiveness was the 
major outcome and was assessed after 6 months of withdrawal of the therapy. Long-term tolerance 
was achieved in 29 % of the children in the intervention group versus spontaneous tolerance 
development in 4 % of the children in de control group. The outcome appeared to be strongly related 
to the age of inclusion and the level of antibodies to peanut. Children who started the therapy before 

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the age of 24 months with a moderate level of peanut-specific antibodies, had the highest chance of 
achieving long term tolerance (up to 80%!). Unfortunately, only a minority of study participants 
started the therapy at such a young age, preventing from strong conclusions on this subgroup. 
However, the study suggests that starting oral immunotherapy after the age of 36 months is too late 
to achieve long-term tolerance in a significant proportion of the children, while starting the therapy 
at a very young age has very promising perspectives.7 
In a large Canadian study, peanut-sensitized children from 9 to 71 months old received 1 year of oral 
immunotherapy. In this study, OIT was not discontinued to assess sustained unresponsiveness. 
According to the per-protocol analysis, 92 of 117 patients (78.6%) who did the follow-up oral food 
challenge were able to tolerate the food without allergic symptoms. It can be concluded that at least 
21,4% of the children were still allergic after the therapy. The amount of children with no response to 
the therapy may be attributed to the higher age of these children.8  
In the current feasibility study of the Deventer hospital, 62 children with a single or multiple food 
allergy completed the 1-year low-dose oral immunotherapy and were tested for sustained 
unresponsiveness after 4 weeks of discontinuation of the therapy. Of these 62 children, 16 were 
treated for a peanut allergy, 28 for a nut allergy and 16 for a hen9s egg allergy. Only 3 children 
treated for peanut allergy, 1 treated for cow9s milk allergy and 1 treated for hazelnut allergy showed 
signs of an allergic reaction during the exit oral food challenge, while all other children passed the 
test, which is a unique and remarkable finding. Long-term introduction into the diet has been 
assessed in 12 children. They all introduced the specific allergen into their diet. Two children have 
experienced mild allergic symptoms in the first year after completing the therapy. One child, who 
was treated for cashew nut allergy, experienced an itchy mouth after 6 months of no allergen intake, 
the other child, who was treated for hen9s egg allergy, still experiences contact allergy, an itchy 
mouth and stomach pain after ingesting ½ hen9s egg. All other children are eating the specific 
allergen weekly or monthly without signs of an allergic reaction. 
Taken together, the current feasibility study on oral immunotherapy in the Deventer hospital shows 
the same high rate of tolerance development in young food allergic children as previous studies. And 
not only for peanut allergy, but also for tree nuts and hen9s egg allergy. This strongly contradicts to 
natural tolerance development rates for peanut and cashew nut allergy and to the inability to 
achieve long-term tolerance by oral immunotherapy in children > 4 years of age and adults. 
Apparently, the capacity of the intestinal immune system to contribute to tolerance development for 
foods only applies to young children. The age-related difference in clinical efficacy of oral 
immunotherapy correlates in time with recognition of conformational versus linear IgE epitopes, the 
latter being associated with persistent allergies and mainly developing after 30 months of life.9 
The window of opportunity for a curative treatment therefore seems to be limited, oral 
immunotherapy probably needs to be started as young as possible and at least before the age of 2 or 
3 years if aimed at curation. 
Because a food allergy is caused by an increased susceptibility of the dermal immune system, many 
children have a food allergy for more than 1 food product. In most children this is limited to 3 or 4 
products. Because of the need to start at a young age, oral immunotherapy for the different 
allergens should be started simultaneously. In children with multiple food allergy, an allergy for cow9s 
milk or hen9s egg is common. Particular in severe allergic children, the rate of persisting allergy to 

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cow9s milk allergy or hen9s egg is high. Oral immunotherapy for these allergens should therefore be 
involved in the treatment of those severe allergic children.  
In less allergic children, spontaneous tolerance development for cow9s milk or hen9s egg allergy is 
more common. Children with a persistent cow9s milk or hen9s egg allergy, however, are confronted 
with major dietary restrictions, because a lot of food products contain these allergens. For these 
children is waiting for spontaneous tolerance development also losing a chance for successful 
treatment. It remains to be questioned, however, whether oral immunotherapy for cow9s milk and 
hen9s egg allergy is cost-effective in less allergic children.  
 
In conclusion: oral immunotherapy is a highly promising treatment for young children with food 
allergy. It may prevent the food allergy from becoming a lifelong burden, which causes a substantial 
decrease in quality of life. Worldwide, scientific research to this promising treatment has still been 
performed to a limited extend, probably because of the vulnerability of young children, fear of the 
unknown and the risk of allergic reactions inherent to the therapy. However, since studies have 
shown that oral immunotherapy can be performed with low-doses of normal food products, with a 
lower risk of severe allergic reactions, and because of the recent findings about the safety and 
feasibility of the therapy (https://www.dz.nl/patient/afdelingen/kinderallergie-
behandelcentrum/orka-studie), it is time to proceed with new studies on this promising treatment. A 
large randomized controlled trial on the clinical efficacy and cost effectiveness is needed to clarify 
whether all food allergic children should be offered this therapy. Oral immunotherapy is suspected to 
be cost-effective by saving life-long medication prescriptions and emergency care visits, and above 
all, a much better quality of life. 
 
Hypothesis 
1a) Early low-dose oral immunotherapy in young children with an established food allergy to peanut 
and/or nuts will induce long-term tolerance in at least 60% of the children after a treatment duration 
of one year compared to 20% in the routine care group (strict avoidance of the allergen). 
1b) Early low-dose oral immunotherapy in young children with an established food allergy to cow9s 
milk or hen9s egg will induce long-term tolerance in respectively at least 75% and 65% of the children 
after a treatment duration of one year compared to respectively 50% and 35% in the routine care 
group (strict avoidance of the allergen). 
1c) Early low-dose oral immunotherapy in young children with an established food allergy is expected 
to be cost-effective compared to routine care (strict avoidance of the allergen). 
2) Early low-dose oral immunotherapy in young children with an established food allergy will increase 
(allergy specific) quality of life for both parents and children compared to the routine care group 
(strict avoidance of the allergen). 

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2. OBJECTIVES 
 
Primary Objective 
What is the clinical- and cost-effectiveness of early low-dose oral immunotherapy in children under 
the age of 30 months with an established food allergy on the induction of long-term tolerance 
compared to routine care (strict avoidance of the allergen) for each allergen?  
 
Secondary Objective(s) 
What is the effect of early low dose oral immunotherapy in children under the age of 30 months with 
an established food allergy on (allergy specific) quality of life of parents and children compared to 
routine care (strict avoidance of the allergen)? 
 
3. STUDY DESIGN 
 
Multicenter, randomized controlled superiority trial, performed in the Netherlands. Blinding is not 
possible, because general available food products are used. The risk of bias caused by the open-label 
character of the study is assessed as small, because the primary end-point on effectiveness is 
assessed by an oral food challenge with objective allergy symptoms as stop criteria (the test is only 
stopped and assessed as positive when objective signs of an allergic reaction occur, according to 
national and international guidelines).  
The main risk is (self)selection bias, causing a difference in chance of spontaneous tolerance 
development, despite randomization. This may be caused by withdrawal of children by their parents 
who are disappointed about being randomized to the control group, with parents of children at a 
higher risk of a persisting allergy being more disappointed. The levels of allergy specific IgE and IgG4 
are the strongest predictors of tolerance development10, therefore these immunologic parameters 
will be assessed to check differences between the intervention and control group and added as 
confounding factors in a multivariate analyses.  

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4. STUDY POPULATION 
 
4.1 Population 
Children between 9 and 30 months of age with an IgE-mediated food allergy to peanut, tree nuts (i.e. 
hazelnut, cashewnut and walnut), cow9s milk and/or hen9s egg as proven by an oral food challenge 
are eligible for inclusion. Patients with different (combinations of) food allergies will be included, 
until the sample size for each allergen is achieved. The population will range from children with a 
mild allergy for 1 allergen to children with a severe food allergy characterized by multiple food 
allergies (mostly 3 to 5), low threshold levels and/or anaphylactic reactions. Consecutive children 
with a (suspected) food allergy referred to one of the participating paediatric allergy centres will be 
enrolled. Contraindications at the discretion of the including physician are language barriers and 
doubts about the capability of the family to perform the daily maintenance therapy at home 
according to the protocol in order to guarantee the safety of the child.   
 
Enrolment of the intended number of patients is assessed as achievable based on: 
- High parental motivation to participate in a study on oral immunotherapy with their young child 
as shown in a qualitative study and by the fact that in the current safety and feasibility study in our 
hospital, patients were participating with a travel distance of up to 2 hours from our hospital.   
- The high number of patients diagnosed with food allergy by the four cooperating paediatric 
allergy centres. An indication of these numbers are the number of oral food challenges performed in 
these allergy centres, ranging from 400 up to 1200 oral food challenges per year in each . The 
majority of these oral food challenges are performed in pre-school aged children. 
- Due to the screening of infants with a high-risk of food allergy, the number of infants diagnosed 
with a food allergy in these 4 centres largely exceeds the intended number of inclusions. 
 
4.2 Inclusion criteria 
In order to be eligible for participation in this study, a subject must meet all of the following 
criteria:  
- 
9 to 30 months of age at inclusion. 
- 
An IgE-mediated food allergy to peanut, cashew, hazelnut, walnut, cow9s milk and/or 
hen9s egg as proven by sensitization to the specific allergen (sIgE > 0.35kU/l) and a 
positive oral food challenge.  
- 
The 8primary allergen9 as described in section 7.2 is identified. 
- 
The fore-mentioned allergens are introduced into the diet of the child,the child is tolerant 
for the specific allergen(s) or the child is sensitized to these allergens (sIgE > 0.35kU/l or a 
positive skin prick test ≥ 3mm).Informed consent is given by parent(s) or guardian(s). 
 
 
4.3 Exclusion criteria 
A potential subject who meets any of the following criteria will be excluded from participation in 
this study: 
- 
(suspected) eosinophilic oesophagitis 
- 
uncontrolled asthma/ viral wheeze. 

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- 
The inability of parents to follow instructions, recognize allergic reactions or administer 
emergency medication. 
- 
Participation in any other intervention study at the time of the OIT study, with the 
exception of studies on guided early introduction of highly allergenic foods. 
 
4.4 Sample size calculation 
We estimate that a sample size of 500 children (250 intervention group and 250 control group) will 
be needed to provide 450 food specific immunotherapies, which was the minimum necessary for 
90% power to detect an effect size of 50% induced food-specific tolerance development in children 
with a persisting allergy. This calculation was based on a two-sided significance level of 0.05 and the 
following assumptions: (1) providing a mean of 1.5 food-specific oral immunotherapy per patient, (2)  
spontaneous tolerance development rates as estimated on different levels of evidence (scientific 
literature and expert opinion), (3) the need to include 5% more children because of a mismatch of 
multiple-food allergies to the allergies needed for inclusion, and (4) loss to follow-up for no more 
than 10% of the participants. 
 
Table 1. Power calculation per individual allergen 
 
spontaneous tolerance 
development after 12 
months follow-up 
Spontaneous + 50% 
induced tolerance 
development 
Sample size 
intervention + control 
group based on alpha 
of 0.05 and a power of 
90% 
Cow9s milk 
50 
75 
77 + 77 
Hen9s egg 
35 
65 
56 + 56 
peanut 
20 
60 
29 + 29 
Cashew 
20 
60 
29 + 29 
hazelnut 
20 
60 
29 + 29 
Walnut 
20 
60 
29 + 29 
total 249 + 249 allergies (in 
200 + 200 children) 
 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational treatment 
Early low-dose oral immunotherapy will be executed by the daily intake of small amounts of 
generally available food products the child is allergic to (e.g. peanut butter). After confirming the 
diagnosis by an oral food challenge, children will start with the build-up phase of the therapy. The 
starting dose is 30% of the threshold level as determined by the oral food challenge (table 2). This 
dose is administered in the clinic, preferable within 4 weeks after the initial oral food challenge. 
After this initial dose, patients ingest the same amount of food on a daily basis at home. In 
patients with threshold levels below 1000 mg protein,  increasing doses of the allergen are 
administered in the clinic with an interval of at least 2 weeks over 1 to 15 visits to achieve the 
maintenance dose of 300 mg allergenic protein (Table 2). Between clinic visits, patients ingest the 
last administered dose of food on a daily basis at home. On average, 4 visits are required to 
achieve the maintenance dose of 300 mg protein per day (approximately half of the children have 

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threshold levels above the 300 mg protein). During the maintenance phase, this dose of 300 mg 
protein will be administered daily by parents at home for a period of one year. Oral food 
challenges and build-up visits for dose escalation are performed by trained health care providers 
who will be supervised by an allergologist, because of the risk of allergic reactions.  
 
Build-up schemes will be personalized based on threshold levels and the shared decision of 
parents and health care providers to build-up with a regular regimen (one build-up step per 
hospital visit) or a rush regimen (up to 5 build-up steps per hospital visit, Table 3).  
 
Table 2. Regular build-up scheme depending on threshold levels 
Threshold 
level 
0.001g = 
1mg 
0.003g = 
3mg 
0.010g = 
10mg 
0.030g = 
30mg 
0.1g = 
100mg 
0.3g =     
300mg 
1g =        
1000mg 
3g =      
3000mg 
Step 1 
0.3 mg 
1 mg 
3.3 mg 
10 mg 
33 mg 
100 mg 
300 mg 
300 mg 
Step 2 
0.6 mg 
2 mg 
6.6 mg 
20 mg 
66 mg 
125 mg 
 
 
Step 3 
1.2 mg 
4 mg 
13.2 mg 
40 mg 
75 mg 
160 mg 
 
 
Step 4 
2.4 mg 
8 mg 
26.4 mg 
75 mg 
100 mg 
200 mg 
 
 
Step 5 
4.8 mg 
16 mg 
52.8 mg 
100 mg 
125 mg 
250 mg 
 
 
Step 6 
9.6 mg 
32 mg 
75 mg 
125 mg 
160 mg 
300 mg 
 
 
Step 7 
19.2 mg 
64 mg 
100 mg 
160 mg 
200 mg 
 
 
 
Step 8 
38 mg 
75 mg 
125 mg 
200 mg 
250 mg 
 
 
 
Step 9 
75 mg 
100 mg 
160 mg 
250 mg 
300 mg 
 
 
 
Step 10 
100 mg 
125 mg 
200 mg 
300 mg 
 
 
 
 
Step 11 
125 mg 
160 mg 
250 mg 
 
 
 
 
 
Step 12 
160 mg 
200 mg 
300 mg 
 
 
 
 
 
Step 13 
200 mg 
250 mg 
 
 
 
 
 
 
Step 14 
250 mg 
300 mg 
 
 
 
 
 
 
Step 15 
300 mg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 3. Examples of rush build-up schemes for 2 threshold levels 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Threshold 
level 
0.003g = 
3mg 
 0.1g = 100mg 
Dag 1 
Step 1 
1 mg 
Step 1 
33mg 
Dag 2 
Step 2 
2 mg 
Step 2 
65mg 
 
Step 3 
3 mg 
Step 3 
78mg 
 
Step 4 
4 mg 
Step 4 
95mg 
 
 
Step 5 
115mg 
 
 
Step 6 
135mg 
Dag 3 
Step 5 
6 mg 
Step 7 
170mg 
 
Step 6 
10 mg 
Step  
200mg 
 
Step 7 
15 mg 
Step 9 
230mg 
 
 
Step 10 
260mg 
 
 
Step 11 
300mg 
Dag 4 
Step 8 
25 mg 
 
 
Step 9 
37,5 mg 
 
 
Step 10 
60 mg 
 
Dag 5 
Step 11 
90 mg 
 
 
Step 12 
135 mg 
 
 
Step 13 
200 mg 
 
Dag 6 
Step 14 
250 mg 
 
 
Step 15 
300 mg 
 

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5.2 Use of co-intervention  
Desloratadine 1.25 – 2.5 mg per dose 
Levocetirizine 1.25 – 2.5 mg per dose 
Cetirizine 1.5 – 5 mg per dose 
5.3 Escape medication  
Applicable for the intervention group and the control group 
Epinephrine autoinjector, 0.15mg per dose 
Desloratadine 1.25 – 2.5 mg per dose 
(Levo)cetirizine 1.25 – 2.5 mg per dose  
Cetirizine 1.5 – 5 mg per dose 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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6. INVESTIGATIONAL PRODUCT  
 
It can be discussed if this chapter is applicable for the current study. Food products are used during 
the therapy, therefore some would argue that this is research on an investigational product. However, 
the food products are freely available, widely used food products, and regularly part of a normal 
infant9s diet. This is apparently a strong argument as most studies on oral immunotherapy using 
standard food products are not labelled as studies on investigational medicinal products.2 Our 
previous feasibility study on oral immunotherapy was also not labelled as such. Therefore, we 
consider this study on oral immunotherapy not as a study with an investigational product. However, 
because of the young age of the children involved, we will discuss some aspects of oral 
immunotherapy based on freely available food products in this chapter and provide a risk analysis in 
chapter 11. 
  
6.1 Name and description of food  products 
Table 4. Examples of free available food products to be used in the ORKA-NL study  
Allergen 
Food product, example 1  
Food product, example 2  
Food product, example 3  
Hen’s 
egg 
Boiled hen9s egg (10 minutes)  
(300 mg protein = 2,4 grams)   
Hen9s egg pancake (2 eggs 
in 10 pancakes) 
(300 mg protein = 19,6 
grams)   
X 
Peanut 
100% peanut butter  
(300 mg protein = 1,1 grams)   
Ground unsalted peanut 
(300 mg protein = 1,2 
grams)   
Defatted peanut flour 
(300 mg protein = 0,6 
grams)   
Hazelnut 
Terrasana pure hazelnut 
spread   
(300 mg protein = 2,2 grams)   
Ground unsalted hazelnut 
(300 mg protein = 1,9 
grams)   
Hazelnut flour 
(300 mg protein = 2,0 
grams)   
Cashew 
nut 
Terrasana cashew nut spread 
(300 mg protein = 1,5 grams)   
Ground unsalted cashew 
nut 
(300 mg protein = 1,5 
grams)   
Cashew nut flour 
(300 mg protein = 1,7 
grams)   
Walnut 
Terrasana walnut spread 
(300 mg protein = 1,3 grams)   
Ground unsalted walnut 
(300 mg protein = 2,0 
grams)   
Walnut flour 
(300 mg protein = 2,1 
grams)   
Cow’s 
milk 
Semi-skimmed Cow9s milk 
(300 mg protein = 8,8 
grams/ml)   
Low-fat yoghurt 
(300 mg protein = 6,4 
grams)   
Danoontje 
(300 mg protein = 4,8 
grams)   
 
 

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6.2 Summary of findings from clinical studies 
Having a food allergy is associated with a lifelong risk of (severe) allergic reactions due to 
accidental ingestions. This risk probably outweighs the risk of mild allergic reactions during 
immunotherapy. In addition, the allergic reactions during oral immunotherapy are predictable, 
because they are associated with the moment of administration of the food product, which will 
be at home or in the hospital. This contrasts with the accidental ingestions later on in life, which 
frequently don9t occur at home. 
 
6.3 Summary of known and potential risks and benefits 
Benefits: 
 
Desensitization, starting within weeks after starting the therapy, will diminish the risk of 
allergic reactions caused by accidental ingestion of (small amounts of) the allergen. 
 
Increased chance on long-term tolerance induction (curation). 
Risks: 
 
Increased risk of mild and moderate allergic side effects 
 
Slightly increased risk of severe allergic side effects 
 
Slightly increased risk of eosinophilic esophagitis or eosinophilic intestinal diseases, which 
are expected to recover after stopping the therapy 
 
6.4 Description and justification of route of administration and dosage 
Different routes of administration have been studied for immunotherapy for food allergy, 
including oral, epicutaneous and sublingual route of administration. Only oral 
administration is associated with long-term tolerance development in young children. 
While for a long period of time it was usual to provide high dose oral immunotherapy (3000 
to 4500mg allergenic protein), recent studies have shown that a daily ingestion of 300 mg 
allergenic protein is sufficient to induce tolerance.6 This low-dose immunotherapy favours 
the achievability of the therapy in young children and may reduce the risk of side effects. 
 
6.5 Dosage, dosage modifications and method of administration 
Maintenance therapy consists of daily ingestion of 300 mg allergenic protein for 1 year. 
Children with threshold levels below 1000 mg of allergenic protein as established by an oral 
food challenge, have to start the therapy with a lower dosage, followed by a build-up phase 
until the maintenance dose is achieved. Build-up schemes are personalised based on 
threshold levels, the choice for a regular or a rush build-up scheme and adapted in case of 
allergic side effects. In case of illness or other circumstances increasing the risk of allergic 
side effects, parents will provide half of the dose as used in the previous days or even stop 
the therapy for a few days. Parents will receive written information about such dosage 
modifications. 
  
 
 

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7. METHODS 
 
7.1 Study parameters/endpoints 
7.1.1 Main study endpoint 
Intervention group: Sustained unresponsiveness defined as both  
1. Passing an exit oral food challenge# performed at 4 weeks after discontinuation of the 
1-year oral immunotherapy 
2. uncomplicated (i.e. without any allergic symptoms) consumption of a full dose of the 
specific food (e.g. a glass of milk or a sandwich with peanut butter with a minimum of 
4.4 gram allergenic protein) at home, after 6 months unrestricted introduction of the 
specific food into the diet of the participant following the exit oral food challenge.  
Control group: Spontaneous tolerance development defined as both 
1. Passing an exit oral food challenge 12 to 18 months* after inclusion 
2. Uncomplicated (i.e. without any allergic symptoms) consumption of a full dose of the 
specific food (e.g. a glass of milk or a sandwich with peanut butter with a minimum of 
4.4 gram allergenic protein) at home, after 6 months unrestricted introduction of the 
specific food into the diet of the participant following the exit oral food challenge. 
# Challenge results are considered positive, and dosing is stopped when objective symptoms 
occur, following the recommendations of the 8PRACTALL consensus report9.11 
* Since the chance of natural tolerance development possibly increases during a longer 
follow-up time, it is important to achieve a comparable follow-up time for allergies assigned 
to the intervention group and allergies assigned to the control group. The follow-up time for 
allergies assigned to the intervention group depend on the threshold level, because this 
determines the duration of the build-up phase. Therefore, the follow-up time for allergies 
assigned to the control group will be adjusted to the threshold level.  
 
7.1.2 Secondary study parameters/endpoints 
 
Quality of life (Food Allergy Quality of Life Questionnaire - parental form (FAQLQ-
PF13), The 17-item Food Allergy Quality of Life– Parental Burden (FAQL-PB), the 
CarerQol-7D15, the EQ-5D-Y.111213 
 
Health care resource use (measured by collecting data from medical records and by 
using parts of the iMTA Medical Consumption Questionnaire (iMCQ)14 
 
Productivity loss will be estimated through additional questions concerning 
parental absence from their work due to their child9s disease and treatment 
 
Allergy-related immune parameters including food specific IgE and IgG4 (blood 
samples)10 
 
Safety, as measured by the frequency of treatment-related (serious) adverse events 
 
Therapy adherence, as assessed by monthly reports of a smartphone medication 
adherence app 
 
7.1.3 Other study parameters 
 
Medical history of the patient (concomitant atopic diseases such as eczema, 
medical prescription history, food allergy history)    

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 
Threshold level and severity of the allergy as determined by the entry oral food 
challenge 
 
Age of the patient at inclusion 
 
Data of skin prick tests, if performed. 
 
 
7.2 Randomisation, blinding and treatment allocation 
Randomization will be performed per participant. Castor EDC (Castor, Amsterdam, Ciwit BV 
the N. Castor electronic data capture 2017) will be used to randomize the children to oral 
immunotherapy (intervention group) or routine care (control group). In Castor, block 
randomisation will be used with computer generated variable block sizes. The sizes of the 
blocks will vary depending on the size of the group to be included which is different for the 
six allergens. The block sizes are unknown to the investigators of the different sites. An 
allocation ratio of 1:1,stratification per centre and stratification for each of the six allergens 
will be used.  
Children with a multiple food allergy are included and randomized for their 8primary allergy9. 
The next sequence will be used to determine the 8primary allergy9: cow9s milk, hen9s egg, 
walnut, hazelnut, cashewnut, peanut. The first allergy in this sequence, which is present in 
the participant will be the 8primary allergy9. The sequence of allergies is based on the ratio of 
the prevalence and the number of participants to be included for that specific allergy. The 
sequence for determining the primary allergen can be adjusted when inclusion for a 
particular allergen is lagging behind or when performing additional OFC9s to determine the 
primary allergy is too burdensome for the child as assessed by the health care professional. 
Children randomized to the intervention group will receive treatment for all of their food 
allergies. In children with multiple-food allergy (>4 allergies), treatment of all allergies is only 
performed if feasibleIn multiple-sensitized children randomized to the control group, the 
diagnostic process will be individualized based on standard allergy care practice. Oral food 
challenges for food products not being the primary allergen are not required to prevent a 
high burden for children in the control group, with an imbalance between benefits and 
burden of participation for these young children. Food products, for which a patient shows 
sensitization (sIgE > 0.35kU/l  or a positive skin prick test ≥ 3mm) without confirmed evidence 
based on an OFC but with a strong suspicion of a food allergy, are included as secondary 
allergens. Based on the clinical history and sIgE levels, a decision will be made regarding 
whether all secondary allergens should be provoked during the exit OFC. The aim is to 
provoke as many secondary allergens as possible during the exit OFC to evaluate 
spontaneous tolerance development.  
Blinding is not possible, because general available food products will be used. The risk of bias 
caused by the open-label character of the study, such as detection bias, is assessed as small, 
because the primary end-point on effectiveness is assessed by an oral food challenge with 
objective allergy symptoms as stop criteria (the test is only stopped and assessed as positive 
when objective signs of an allergic reaction occur, according to national and international 
guidelines). 
Because parents are aware of the assignment to the intervention group or the control group, 
the risk of performance bias is increased as discussed in more detail on page 12. 

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7.3 Study procedures 
Early low-dose oral immunotherapy will be executed by the daily intake of small amounts of 
generally available food products the child is allergic to (e.g. peanut butter). After confirming 
the diagnosis by an oral food challenge, children will start with the build-up phase of the 
therapy (see Figure 1). To build-up, doses of the allergen are administered in the clinic with 
at least a 2-week interval over 1 to 11 visits to 300 mg protein maintenance. Between clinic 
visits, patients ingest the same amount of food on a daily basis at home. On average, 4 visits 
are required to achieve the maintenance dose of 300 mg protein per day. During the 
maintenance phase, this dose will be administered daily by parents at home for a period of 
one year. Oral food challenges and build-up visits for increasing the dose are performed by 
trained health care providers and supervised by a paediatric allergologist, because of the risk 
of allergic reactions.  
 
In clinics not familiar with providing oral immunotherapy for food allergy, paediatric 
allergologists will be trained in providing this new therapy, e.g. how to adjust the build-up 
scheme in case of side-effects. These paediatric allergologists are provided with all standard 
operating procedures and instructions needed to provide high quality of care.  
Parents will receive a personal and extended instruction about the daily administration of the 
allergenic food to their child, together with written action plans containing instructions on 
how to manage at-home reactions, when to adjust the doses (e.g., during a viral illness), and 
when to administer medication including epinephrine. Parents will receive a precision scale 
and they will be instructed to use the smartphone medication adherence app to increase 
therapy adherence and to assess daily adherence to the protocol by monthly reports that will 
be generated by the app and send to the study investigator. 
After one year, the OIT is stopped for 4 weeks, after which an exit oral food challenge is 
performed. In case of a negative food challenge, parents will be advised to introduce the 
food in the child9s diet without limitations. Six months later, intake of the allergenic food will 
be assessed by a telephone survey. In case of a multiple food allergy, the above mentioned 
procedure will be performed in parallel. 
Children whose allergy was assigned to the control group receive standard care which is 
defined as strictly avoidance of the specific allergenic food. The standard care for children 
with an allergy to cow9s milk and hen9s egg has gradually changed in recent years. The 
parents are offered the possibility to introduce highly heated cow9s milk (baked milk) or hen9s 
egg (baked egg) into the diet. These food products can be introduced at home (often guided 
by the dietitian) or during an OFC. The introduction of baked milk and egg have two 
advantages: 1) it imposes fewer restrictions on the food products that can be consumed and 
2) there is scientific evidence that the introduction of highly heated food products can 
expedite natural tolerance development. Currently, there is no evidence that the 
introduction of baked milk and egg influence the course of a persistent cow9s milk or hen9s 
egg allergy. As a result, the development of natural tolerance remains consistent in both 
groups.  
 

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At 12 to 18 months after inclusion, the allergic state of the child will be assessed, including an 
oral food challenge when indicated. In case children pass the exit oral food challenge without 
symptoms, 6 months later the consumption of the allergenic food will be assessed by a 
telephone survey. 
In case of a positive oral food challenge, the primary end point has been reached. A 
telephone survey will be performed 6 months later, to confirm ongoing avoidance of the 
specific food. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1 
 
 

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Procedures 
Allergy-related immune parameters including food specific IgE and IgG4: 
Baseline  
(screening) 
Visite 1 
In-/exclusie criteria 
Informed Consent 
Patiëntkarakteristieken 
Relevante medische VG* 
Medicatie 
Bloedafname 
Vragenlijsten 
Ingangs 
provocatie en 
randomisatie 
Visite 2 (V2) 
Eerste dosis 
dagbehandelin
Visite 3 (V3) 
Ong. 2 weken 
Maximale 
dosering 
6 maand 
controle 
Visite X (VX) 
Patiëntkarakteristieken 
Relevante medische VG* 
Medicatie 
Bloedafname 
Vragenlijsten 
12 maand     
Stop OIT 
Visite X (VX) 
Patiëntkarakteristieken 
Relevante medische VG* 
Medicatie 
Bloedafname 
Vragenlijsten 
Eind       
provocatie 
Visite X (VX) 
4 weken 
2 weken 
2 weken 
2 weken 
2 weken 
2 weken 
Opbouwschema OIT (duur en aantal visites afhankelijk van drempelwaarde) 
Onderhoudsdosering OIT 
Visite X(VX) 
Visite X (VX) Visite X (VX) Visite X (VX) Visite X (VX) 
n=500 
*VG = voorgeschiedenis; 
#SPT = Skin Prick Test (huidpriktest); 
$TC = 
Eind       
provocatie 
Visite X (VX) 
18 maand 
evaluatie 
TC
$ 
6 maand 
18 maand 
evaluatie 
TC
$ 
Vragenlijsten 
Vragenlijsten 
n=250  
interventiegroe
n=250  
controlegroep 
6 maand 
controle 
TC
$/Visite X (VX) 
Patiëntkarakteristieken 
Vragenlijsten 
Patiëntkarakteristieken 
Bloedafname 
Vragenlijsten 
12 maand      

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 
Capillary or venous blood sampling (maximal 5 ml) during diagnostic work-up/ entry 
oral food challenge, after 6 months of oral immunotherapy (only in the intervention 
group) and after 12 months of follow-up (both intervention and control group). 
 
Assessment of sensitization (sIgE in blood or a skin prick test) one year after 
diagnosing the food allergy is part of routine care for food allergic infants. For 
participants receiving routine care the blood sampling will be part of standard 
diagnostic work-up and follow-up care, when the assessment of sensitization by 
blood tests is the standard practice of the participating allergy centre. For children 
who receive care in allergy centres using skin prick tests as the standard method to 
assess sensitization, blood tests will be additionally performed. 
 
Questionnaires to be completed by parents: 
 
At start of the study, and after 6, 12 and 18 months follow-up: Quality of life (Food 
Allergy Quality of Life Questionnaire - parental form (FAQLQ-PF13), The 17-item 
Food Allergy Quality of Life– Parental Burden (FAQL-PB), the CarerQol-7D15 and the 
EQ-5D-Y. 
 
At 6, 12 and 18 months of follow-up: parts of the iMTA Medical Consumption 
Questionnaire (iMCQ) and additional questions concerning parental absence from 
work due to their child9s disease and treatment 
 
Adherence  
 
Parents have to install a smartphone medication adherence app to register daily 
use of the therapy and have to send monthly reports (digital)  
 
Oral food challenges 
 
Oral food challenges are performed in all participants, as part of the standard 
diagnostic work-up at the study entry. The exit oral food challenge is standard care 
for children receiving oral immunotherapy (a high chance of tolerance is an 
indication for a test). In participants receiving routine care, the exit oral food 
challenge would be part of standard care in approximately 65% of the children, for 
35% of the children in the control group, the exit oral food challenge is a study 
procedure. 
 
7.4 Withdrawal of individual subjects 
Subjects can leave the study at any time for any reason if they wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons. 
 

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7.5 Replacement of individual subjects after withdrawal 
If achievable, taking health care costs into account, the individual allergy centres have the 
option to replace individual subjects after withdrawal. If the loss to follow-up exceeds 10% 
of inclusion for specific allergies, replacement of subjects is recommended. 
7.5.1 Specific criteria for withdrawal (if applicable) 
- 
Only withdrawal for OIT for the 8primary allergen9 (see 7.2) will be defined as withdrawal 
of the subject providing the option to replace a patient for that specific allergen. After 
withdrawal for the primary allergen, the patient may complete OIT for other allergens if 
applicable and the data will be used for analysis. 
Failure to provide OIT because of child factors (such as food aversion) or medical factors 
(such as ongoing side effects), will not be defined as withdrawal but as treatment failure. 
In patients with multiple allergies, failure to provide OIT for a specific allergen does not 
imply the stop of OIT for other allergens. 
 
7.6 Follow-up of subjects withdrawn from treatment 
After withdrawal from treatment, follow-up will be continued to assess tolerance 
development, unless parents refuse follow-up. 
 
7.7 Premature termination of the study 
 Taking into account the findings on safety parameters of the current feasibility study 
performed in the Deventer Ziekenhuis, reasons for premature termination of the study are 
not to be expected.  
 
 

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8. SAFETY REPORTING 
 
8.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the study if 
there is sufficient ground that continuation of the study will jeopardise subject health or safety.  
The sponsor will notify the accredited METC without undue delay of a temporary halt including 
the reason for such an action. The study will be suspended pending a further positive decision by 
the accredited METC. The investigator will take care that all subjects are kept informed.  
 
8.2 AEs, SAEs and SUSARs 
8.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, considered related or possible related to oral immunotherapy. All such adverse events 
reported spontaneously by the subject or observed by the investigator or his staff will be 
recorded. 
 
8.2.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients9 hospitalisation; 
- 
results in persistent or significant disability or incapacity; or 
- 
any other important medical event that did not result in any of the outcomes listed 
above due to medical or surgical intervention but could have been based upon 
appropriate judgement by the investigator. 
An elective hospital admission will not be considered as a serious adverse event. 
 
The investigator will report all SAEs to the sponsor without undue delay after obtaining 
knowledge of the events, except for the following SAEs:   
- 
anaphylaxis as provoked by an oral food challenge (which will be reported in the 
annual progress report) 
 
The sponsor will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 7 days of first knowledge for SAEs that result in 
death or are life threatening followed by a period of maximum of 8 days to complete the 
initial preliminary report. All other SAEs will be reported within a period of maximum 15 days 
after the sponsor has first knowledge of the serious adverse events. 
 
8.3 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
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8.4 Data Safety Monitoring Board (DSMB) 
A DSMB is established to perform ongoing safety surveillance. The DSMB will assess all (serious) 
adverse events periodically, every 6 months after start of the study. The DSMB may advice the 
study team to increase the safety for participants. The task and responsibility of the DSMB is 
described in more detail in the DSMB charter. The advice(s) of the DSMB will only be sent to the 
sponsor of the study, who will discuss the advice with the investigators of all participating 
centers. Should the sponsor decide not to fully implement the advice of the DSMB, the sponsor 
will send the advice to the reviewing METC, including a note to substantiate why (part of) the 
advice of the DSMB will not be followed. 
 
The DSMB consists of three  members. Two are experienced paediatric-allergists, the third 
member who will also be the chair of the Board is a dermatologist providing food allergy care to 
adults and is experienced in performing food allergy studies. These members have no conflict of 
interest with the sponsor of the study. 
(1) Dr. T.T.M. Le, Dermatoloog, afdeling Dermatologie/Allergologie, Universitair Medisch 
Centrum Utrecht 
(2) Dr. E.C. Koffeman, kinderarts-allergoloog, Rijnstate Allergiecentrum, Arnhem 
(3) Dr. I.F.A. Bocca-Tjeertes, kinderarts-allergoloog, afdeling inderlongziekten/allergologie, 
Universitair Medisch Centrum Groningen  
 
 
 

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9. STATISTICAL ANALYSIS 
 
The statistical analyses will be performed with SPSS (version 26.0). Continuous data will be 
presented as means ± SD (normal distribution) or medians with IQR (non-normal distribution), 
categorical data will be presented as frequencies with percentages. As primary analysis, an 
intention to treat analysis will be performed. A per-protocol analysis will also be performed, 
based on parental information regarding actual administration of the allergen to their child. 
 
9.1 Primary study parameter: tolerance induction 
Differences in the primary parameter 8clinical effectiveness9 will be analysed separately for each 
of the six allergens using univariate logistic regression analyses, followed by multiple logistic 
regression analyses in which we will adjust for potentially confounding factors, including but not 
limited to: age and level of sIgE at start of the therapy, threshold level and severity of the allergic 
reaction as assessed during the entry oral food challenge, number of allergies and study. For the 
multivariate logistic regression analyses, a minimum of 10 events per variable will be necessary 
to avoid bias. Results will be presented as odds ratios (OR) with 95% confidence intervals. Besides 
eyeballing, patterns of missing data will be analysed in SPSS with missing data analyses as well. 
Based on the pattern of missing data, the recommended approach for dealing with these missing 
data in a RCT will be chosen. 
 
A trial-based cost-effectiveness analysis will be performed to compare early low-dose oral 
immunotherapy with usual care for the treatment of children between 9 and 30 months of age 
with an IgE-mediated food allergy. The analysis will be performed from a societal perspective, 
including cost inside and outside the healthcare sector. The main outcomes of this cost-
effectiveness analysis will be total quality-adjusted life years (QALYs) and costs for both 
strategies, which will be compared through an incremental cost-effectiveness ratio (incremental 
costs/ incremental QALYs). To obtain quality of life estimates of the included patients, the Food 
Allergy Quality of Life Questionnaire-Parent Form (FAQLQ-PF) and the EQ-5D-Y,12 will be 
completed by the patients9 parents at the different measurement moments. Since the FAQLQ-PF 
is not a preference-based instrument, it will be mapped to utility values (which are needed to 
calculate QALYs) through the AQoL-6D instrument which is a preference-based instrument. 
13Additionally, the impact of caring for the patients on the parents9 quality of life will be 
measured through the CarerQol -7D and Food Allergy Quality of Life-Parental Burden 
Questionnaire. 16,17 This disease-specific instrument will also be used because it is expected that 
the CarerQoL-7D does not capture all aspect of the children9s disease which may have an impact 
on their parents9 quality of life. Health care resource use due to the patients9 allergy and 
treatment will be measured by collecting data from medical records and by using parts of the 
iMTA Medical Consumption Questionnaire, which will be filled in by the patients9 parents to 
assess the productivity loss of parents due to caring for the patients, questions concerning their 
absence from work will be added to the iMCQ16. For this trial-based economic evaluation, the 
measurement moments for both quality of life and resource use are at the start of the study, and 
at 6, 12, and 18 months follow up. The uncertainty surrounding the cost-effectiveness results of 
the trial-based economic evaluation will be assessed through bootstrapping. The time horizon of 
the cost-effectiveness analysis will be two years (study duration). The outcomes of the trial-based 
analysis will be extrapolated (via a health economic model) using literature and external sources, 

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if deemed necessary to obtain an accurate estimation of the (differences in) total costs and 
QALYs of immunotherapy and usual care. All analyses will be performed according to the Dutch 
guidelines for performing health economic evaluations.14 
 
9.2 Secondary study parameter(s)  
Quality of life as assessed by four questionnaires will be scored by adding up the scores on each 
item to yield a total score. In case of sufficient normally distributed data, or possibly after 
transformation, a mixed model repeated measurements analyses will be performed or a 
Wilcoxon signed rank test (depending on the distribution of the data). Allergy-related immune 
parameters (e.g. sIgE en sIgG4) will be analysed for the six different allergens separately on 
baseline and on 12 months after starting the maintenance phase. Differences between the 
intervention and the control group will be analysed using Student T-tests or Mann Whitney U test 
(depending on the distribution of the data). Adherence will be calculated as provided doses/ days 
on oral immunotherapy and presented as a percentage. Safety as measured by treatment-related 
(serious) adverse events will be presented as frequencies of number and severity.  
 
The full description of all analyses is described in the statistical plan, which will be final before the 
database lock. 

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10. ETHICAL CONSIDERATIONS 
 
10.1 Regulation statement 
The study will be conducted according to the principles of the Declaration of Helsinki (64th WMA 
General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the Medical Research 
Involving Human Subjects Act (WMO). 
 
10.2 Recruitment and consent 
Parents of (possible) eligible children will be informed about the study by a member of the 
Allergy Care Team providing allergy care to the child during outpatient clinic visits or during 
clinically performed oral food challenges. Oral and written information is provided to these 
parents. Parents will have at least 1 week to decide about participation and providing informed 
consent. 
 
10.3 Objection by minors 
The burden associated with participation will be minimised. Blood sampling by finger prick or 
vena punction is part of the therapy in children in the intervention group. In children in the 
control group, blood sampling can be part of the normal diagnostic work-up of a food-allergic 
child, but can also be an additional study-based procedure. If in the context of such research-
based procedure, a child objects to a procedure, the procedure will be discontinued. Ongoing 
participation in the study is encouraged, despite missing blood samples. Oral food challenges and 
a blood sample to assess the level of sIgE at entry of the study are mandatory because these are 
inclusion criteria. If a child objects to this procedure, the child is not eligible for inclusion. 
 
10.4 Benefits and risks assessment, group relatedness 
This study will include participants between 9 and 30 months of age, to study the effectiveness of 
oral immunotherapy when started at a young age. Current scientific knowledge has been 
showing that this therapy, when started in children older than 3 or 4 years of age, is not effective 
regarding the achievement of long-term tolerance, whether a superior outcome is presumed 
when the therapy is started at a young age (as described in the introduction section).  
Participants assigned to the intervention group may benefit by achieving long-term tolerance 
(curation of the allergy). These participants have an increased risk for mild allergic reactions 
related to the daily ingestion of the allergen, as shown by previous studies and the current 
feasibility study in the Deventer ziekenhuis. The risk for severe allergic reactions not responding 
to epinephrine is very low.  
Participants assigned to the control group have no benefit regarding an increased chance on 
tolerance induction, and no increased risk for allergic reactions. 
 
10.5 Compensation for injury 
The sponsor/investigator has a liability insurance which is in accordance with article 7 of the 
WMO. The sponsor also has an insurance which is in accordance with the legal requirements in 
the Netherlands (Article 7 WMO). This insurance provides cover for damage to research subjects 
through injury or death caused by the study. 

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The insurance applies to the damage that becomes apparent during the study or within 4 years 
after the end of the study. 
 

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11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents 
Castor data management system is used as a validated electronic case report form (eCRF) to 
collect clinical data for the study. Access and training for the ecRF will be made available to the 
participating sites. An explanation for missing (required) data should be displayed on the 
appropriate eCRF page. 
The sponsor/principle investigator will perform data validation according to standard operating 
procedures and as described in the data management plan (DMP). The investigators of the 
different sites are responsible for maintaining and entering complete and correct data and has to 
respond to questions/queries within agreed timelines. 
All information recorded in the eCRF must be traceable in the (medical) files of the subjects, 
except for the data from the electronic diaries (MediSafe app) and the different questionnaires 
(Castor data management system); these data are transferred directly to the database and are 
considered as source data. 
 
The sponsor/investigator will provide the researchers on the other sites with an Investigator Site 
File (ISF). The investigator is responsible for keeping this ISF up-to-date and will keep it available 
for review by the study monitor. 
 
The handling of personal data will comply with the EU General Data Protection Regulation and 
the Dutch Act on Implementation of the General Data Protection Regulation. (in Dutch: 
Uitvoeringswet AVG, UAVG). Accordingly, the researcher is responsible for treating study data 
confidentially and has to ensure that the subject's identity is not made public. All study data 
(including blood samples) are coded to maintain subject confidentiality (subjects' patient 
numbers do not include patient initials or birthdate). The Subject Identification Log that links the 
patient numbers to the subjects' identities must be stored locally on a password protected server 
or in the Investigator Site File that is only accessible to the local researcher, research coordinators 
of the sites and to regulatory authorities. 
 
Study documents may not be destroyed without prior written agreement between the 
sponsor/investigator and the researcher at the site. All documents related to the conduct of the 
study must be kept by the researcher for a period of 15 years. Moreover, blood samples are not 
destroyed immediately after use. They will be stored in order to be able to determine new 
biomarkers in the field of oral immunotherapy for food allergy during or in the period after the 
study. It can be stated on the consent form whether permission is provided for this. If consent is 
not provided by the parents, the child can simply participate in the current study and the blood 
will be destroyed. 
 
By the use of the principles of FAIR data we will achieve a maximum impact from our research, 
increasing the visibility, improving the reproducibility and reliability and reaching a broader 
public, enabling also new research questions to be answered. We will make our data findable by 
assigning a persistent identifier (DOI) and ensuring the registry in a 
searchable resource. Moreover, a trusted and well-suited repository will be used to publish our 
data (e.g. Yoda) and a personal persistent author identifier will be used in all our publications. 

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Metadata will be added as rich as possible (description of context, quality, condition and 
characteristics). Data will be made accessible by using a persistent 
identifier by which data can be retrieved. The repository that will be used allows us to share data 
and to collaborate with external parties. Publications are directly accessible via Open Access. To 
make the data interoperable README files will be used containing a description what data it 
includes. Moreover, controlled vocabularies and keywords and standard measurement units will 
be used. Wherever possible programming scripts will be added that were used to analyse the 
data. We will make our data reusable by ensuring that our data is well-documented to support a 
proper interpretation. We will provide information needed to make clear how, why and by whom 
the data have been created and processed. In addition, documentation will be provided on 
project level, file level as well as item level. 
 
11.2 Monitoring and Quality Assurance  
Prior to participation in this study, investigational sites will be evaluated for appropriate 
qualifications and ability to properly execute the study. Each investigational site 
must undergo proper training on the study protocol and ancillary study procedures/documents 
through participation in an initiation visit and/or Investigator meeting. Such training must take 
place before any subjects are enrolled at that site. Moreover, the study will only start if: 
 
the METC/local authorities have given their approval to conduct the study. 
 
essential documents are available, such as the ISF, CV of the investigator and of the 
research personnel on the site, and the Consortium agreement/ Clinical Trial Agreement. 
The sponsor/investigator or designee will make periodic visits to the investigational site to assess 
compliance with study procedures and regulatory requirements; to ensure that the safety, 
welfare and privacy of subjects are being protected; and to verify the accuracy and integrity of the 
study data. 
In addition, the study data will periodically be review to ensure that data are being 
appropriately collected and reported. Logic checks will be also programmed and run to identify 
errors and data discrepancies. Discrepancies will be reviewed with investigational site personnel, 
corrections will be made to the database, and a validated audit trail will be 
maintained. The database will be locked and audited before it is released for analysis. 
 
Study monitoring will take place at various times during the study by an independent 
person/monitor that is qualified to monitor under the responsibility of the sponsor/investigator 
as described in the monitoring plan. 
Monitoring includes both on- and off-site visits to check whether the rights and well-being of the 
subjects are protected, such as checking the presence of informed consent statements and the 
inclusion and exclusion criteria used. It also serves to verify that the data from the study reported 
is accurate and fully verifiable in the source documents. The third purpose is to verify that the 
conduct of the study is in accordance with the currently approved protocol(s), with GCP and with 
the relevant legal requirements. 
The researcher at the site has to permit study-related monitoring, audit, review by the METC and 
regulatory authorities (inspection) and thereby provide direct access to source data and source 
documents subject to the protection and safeguarding of the subject's privacy. 
 

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11.3 Amendments  
 
All substantial amendments are reported to the METC and the competent authority.  
Non-substantial amendments will not be reported to the accredited METC, but will be registered 
and filed by the sponsor.  
 
11.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
11.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a period 
of 8 weeks. The end of the study is defined as the last patient9s last telephone interview 6 months 
after the last exit oral food challenge.  
The sponsor will notify the METC immediately of a temporary halt of the study, including the 
reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC within 15 
days, including the reasons for the premature termination.  
Within one year after the end of the study, the investigator/sponsor will submit a final study 
report with the results of the study, including any publications/abstracts of the study, to the 
accredited METC.  
11.6 Public disclosure and publication policy 
The clinical trial will be registered in a public trial registry before the first patient is recruited. The 
results of this study will be disclosed unreservedly, preferably by submitting for publication to 
peer-reviewed scientific journals. If these journals do not consider the results for publication, the 
research results will be disclosed at least by publication in the trial register. Taken the basic 
principles into account of the rules of the Vancouver convention and the editors' statements of a 
number of authoritative biomedical scientific journals, one author of the 3 cooperating allergy 
centres will be involved in publication. 

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12. STRUCTURED RISK ANALYSIS  
 
12.1 Potential issues of concern 
a. Level of knowledge about mechanism of action 
Oral immunotherapy (OIT) involves daily consumption of a vast amount of allergenic food during a 
given time period. It can result in sustained unresponsiveness (absence of allergic symptoms 
when the food allergen is ingested after a period of therapy discontinuation). This clinical 
outcome has been associated with alterations in the allergen-specific immune response during 
the therapy. Various cell types are involved, including T-cells. Tregs are considered to be key 
contributors to tolerance induction and maintenance, by producing the anti-inflammatory IL-10. It 
is therefore likely that changes in allergen-specific T-cells are a main component to the clinical 
effectiveness of OIT. In mouse OIT-studies, Tregs are induced by allergenic exposure during OIT 
and have been associated with sustained unresponsiveness. Prolonged antigenic stimulation 
during the maintenance phase of OIT has also shown epigenetic modification of Tregs. Syed et al 
demonstrated an association between Foxp3 hypomethylation during Treg cell differentiation and 
sustained unresponsiveness 19. Mouse models showed suppression of IL-5, IL-13, IgE production 
and effector T-cell responses with induction of CD4+CD25+FoxP3+ Tregs in the lamina propria.20 
Although more research is needed, allergen specific T-cells and in particular allergen specific Tregs 
play a pivotal role in achieving long-term tolerance. 
 
b. Previous exposure of children to oral immunotherapy 
Studies on the safety and feasibility of low-dose oral immunotherapy in infants with a peanut or 
cow9s milk allergy have shown a high rate of mild allergic reactions.8,6,21 40% to 90% of 
participants are experiencing at least once a mild allergic reaction such as angioedema of the lips, 
facial urticaria or vomiting during their treatment. The rate of severe allergic reactions differs in 
these studies between 0,4% to 7%. Authors of these studies have regarded these rates of side-
effects as safe. Safety data for patients (aged 1 to 18 years of age) undergoing (e-)OIT (early-oral 
immunotherapy) for multiple foods (up to 12 food products) haven been published very recently. 
Allergic reactions occurred in 22 patients (49%) during up-dosing or in the first 3 months of 
maintenance therapy during clinical visits or with a home dosage. No patients reported reactions 
after the first 3 months of daily maintenance therapy. All allergic reactions in this study were of 
mild to moderate severity. The study suggests that OIT for multiple foods has a comparable safety 
profile.22 
Results from our current study on safety and feasibility of e-OIT started in children at an age 
between 9 and 24 months (https://www.trialregister.nl/trial/7663), show a similar pattern of 
frequent but mainly mild side effects of the oral immunotherapy; 61 % of the children 
experienced at least one mild allergic symptom. Patients undergoing e-OIT for multiple foods (2 to 
4 products) had a similar risk of adverse events. Only a few severe adverse events were reported 
by parents. Moreover, parents considered the therapy as safe and feasible to perform. These data 
were examined by the Data Safety Monitoring Board of the study and assessed as an acceptable 
safety profile in June 2021 (the Safety report is available on 
https://www.dz.nl/patient/afdelingen/kinderallergie-behandelcentrum/orka-studie). Low-dose 
OIT in young children displays at least a similar (and probably a more favorable) safety profile 

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than the same therapy in older children and adults. It is important to consider that high-dose OIT 
is recommended for older children and adults by a recent European guideline.2 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human cell 
material? 
The primary mechanism of long-term tolerance can be induced in mouse-models.23 
 
d. Selectivity of the mechanism to target tissue in human beings 
Allergen immunotherapy is a very specific therapy: changes of the immune-system are allergen 
specific, with no effect on tolerance for other allergens. This is widely proven, both for 
immunotherapy for inhalant allergens and food allergens. 
 
e. Analysis of potential effect 
A dose-finding study compared 2 maintenance doses of oral immunotherapy for peanut allergy in 
young children: 3000 mg vs 300 mg peanut protein.6 This study shows similar effectiveness 
regarding the achievement of long-term tolerance and a similar rate of side effects. In this study, 
oral immunotherapy will be provided by a maintenance dose of 300 mg. If this dose is accidentally 
increased, no major effect is to be expected on efficacy or side effects. A lower dose may affect 
the efficacy of the therapy. 
 
g. Study population 
Children between 9 to 30 months of age with an IgE-mediated food allergy. Many of these 
children also have eczema, because eczema is the main risk factor for developing a food allergy.  
 
h. Interaction with other products 
There are no interactions with other (food) products to be expected. 
 
i. Predictability of effect 
A higher level of food specific IgE at the start of the study is associated with a higher risk of a 
persisting allergy despite oral immunotherapy. A decrease of food specific IgE after 6 to 12 
months of therapy and an increase in food specific IgG4 are associated with long-term tolerance 
development. An accurate prediction of the individual outcome of oral immunotherapy based on 
IgE or IgG4 levels is not possible. 
The risk of allergic side effects is related to the threshold level: children with lower threshold 
levels are more at risk. The risk of developing eosinophilic esophagitis can not be predicted. 
 
j. Can effects be managed? 
Most allergic side-effects can be treated by antihistamines, anaphylaxis can be treated by 
administering epinephrine by an auto-injector.  
Eosinophilic esophagitis will disappear by stopping the oral immunotherapy. 
 

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12.2 Synthesis 
The main risk of oral immunotherapy is the occurrence of allergic side effects. High-dose oral 
immunotherapy has been studied widely in older children and is a recommended therapy 
(European guideline). Currently available evidence strongly suggests that low-dose oral 
immunotherapy in young children has a favourable safety profile.  
Allergic side-effects can be treated very well with appropriate medicines, when administered 
without delay. To ensure this timely treatment of allergic side-effects, procedings with a higher 
risk of severe allergic side-effects are performed in-hospital (including oral food challenges and 
up-dosing of the therapy). Additionally, to ensure appropriate treatment of allergic side-effects at 
home, parents are provided with a written self-management plan, antihistamines and the 
epinephrine auto-injector. Extensive instructions are provided to parents to reduce the risk of 
allergic side-effects at home, including instructions about lowering the dose or stopping the 
therapy for a few days in case of infectious diseases or other health problems.  
 
Having a food allergy is characterized by a lifelong risk of (severe) allergic reactions due to 
accidental ingestions. This risk probably outweighs the risk of mild and moderate allergic 
reactions during immunotherapy. In particular because the allergic reactions during oral 
immunotherapy are predictable, as they are associated with the moment of administering the 
food product, which will be at home or in the hospital. This contradicts to the accidental 
ingestions later on in life which frequently don9t occur at home. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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