Introduction
Food allergy is an increasing problem in developed countries. IgE-mediated food allergy affects 3%–10% of children1–3 and up to 10% of adults.4 5 Food allergy is an abnormal hypersensitivity reaction to certain proteins in food, which may involve an IgE or non-IgE immune response. The most frequent food allergens are cow’s milk, egg, wheat, soy, peanut, tree nut, fish and shellfish. The diagnostic algorithm for food allergy is based on the patient clinical history, a sequence of additional tests and, in indeterminate cases, oral food challenge (OFC).6 A supervised OFC is recommended as the reference diagnostic procedure and a double-blind, placebo-controlled food challenge (DBPCFC) is suggested if an open OFC is doubtful or in research phases of studies.7 The skin prick test (SPT),8 serum food-specific-IgE (sIgE),9 component specific-IgE10 and, more recently, basophil activation tests (BATs)11 are used to diagnose IgE-mediated allergy. Atopy patch testing12 may be positive in some non-IgE-mediated conditions.
Sesame seed allergy is less common, affecting 0.1%–0.9% of people.13–15 However, it can result in considerable morbidity, decreased quality of life and higher healthcare costs. Allergy to sesame is associated with severe, immediate IgE reactions, involving anaphylactic shock and an increased risk of death. In contrast to common allergens like milk and egg, the development of tolerance to sesame appears to be relatively rare and occurs in 20%–32% of adult patients.16–18 Seven sesame components are registered by The WHO/International Union of Immunological Societies Allergen Nomenclature Subcommittee: two 2S albumins (Ses i 1 and 2), one vicilin-like 7S globulin (Ses i 3), two oleosins (Ses i 4 and 5) and two 11S globulins (Ses i 6 and 7). The major antigen protein of sesame belongs to storage proteins, which are heat-stable and resistant to proteolytic digestion. Allergy to storage proteins is responsible for severe allergic reactions. In the diagnosis of sesame allergy, sIgE against component Ses i 1 is the most clinically relevant allergen component19 and can be assessed by commercial multiplex component assay. Recently, meta-analyses confirmed the moderate sensitivity (89%) and high specificity (93%) of BAT to sesame.20
In sesame allergy, allergen avoidance and emergency treatment are still therapeutic hallmarks.21 Avoiding sesame is troublesome because it is added to many products such as bread products, cereals, cookies and sweets. Additionally, there is an increasing tendency to include sesame in the diet in many countries, including Poland. Another problem is the possible inclusion of trace amounts of sesame in many products (so-called hidden allergens). In an Australian study, the prevalence of precautionary labelling statements for common food allergens on the packages of products was evaluated. The study found that 6.1% of products listed sesame as an ingredient while 27.5% of products had a precautionary statement for sesame.22 What’s more, Nguyen et al noted that 67.5% of 360 clinical reactions to sesame were caused by an unintentional ingestion of a packaged food product with only 43.8% of these using the term ‘sesame’ on the label.23 In a Canadian study, the parents of 115 children with confirmed allergies to sesame declared an annual accidental exposure rate of 15.9%.24 In a study of 42 children in Canada with multiple food allergies (to more than one allergen), Lemoine-Courcelles et al also reported that 25% considered avoiding sesame to be a greater financial, social and emotional burden compared to other food allergens.25 All the above data show how difficult and challenging it is to avoid an allergen in one’s diet.
This has led to an increasing interest in an alternative approach to managing food allergy, including allergen-specific immunotherapy. Currently considered allergen-specific immunotherapies for food allergy are oral immunotherapy (OIT), sublingual immunotherapy (SLIT), epicutaneous immunotherapy and subcutaneous immunotherapy (SCIT). These methods differ in terms of efficacy, safety profile and costs. OIT offers improved efficacy compared with SLIT, however, it can cause more severe adverse events. According to current research, OIT is considered safe and effective in milk, peanut and egg allergy.26 27 OIT aims to increase the threshold of food amounts that cause a reaction during therapy (desensitisation). The main goal of immunotherapy is to achieve the postdiscontinuation possibility of eating food without experiencing a reaction (tolerance or sustained unresponsiveness). To our knowledge, sesame immunotherapy has been conducted in three studies, including two open-label interventional studies and one real-world study. Nachshon et al demonstrated the high effectiveness of OIT in desensitising patients with sesame allergy aged 4 years or older.28 Chua et al confirmed the effectiveness of low-dose oral sesame immunotherapy in preschool children in a real-world study.29 Salari et al demonstrated a promising desensitisation strategy for adult patients using omalizumab as a pretreatment for immunotherapy. They enrolled 11 participants with a history of sesame anaphylaxis and conducted OIT with a high dose of sesame. All patients developed tolerance to 5000 mg of sesame protein, and the use of omalizumab improved the safety of the immunotherapy.30 The primary common outcome of these studies was desensitisation to sesame, defined as tolerance to doses between 2000 and 5000 mg of sesame protein.
The immunotherapy protocols differed significantly between these studies, particularly in the schedule of the build-up phase, the size of the maintenance dose (ranging from 200 to 5000 mg) and the duration of the maintenance phase (ranging from 4 to 12 months). Several studies have shown that low-dose OIT is an effective and safe treatment option for other food allergies in children.31–33
More data is needed to recommend sesame immunotherapy as a viable treatment option. Efforts are being made to identify optimal dosing and therapy duration, to establish the most effective, safe and least demanding protocols for patients. A smaller amount of tahini is better accepted by paediatric patients. Therefore, successfully identifying the low effective dose of sesame is likely to improve patient compliance with the immunotherapy protocol. As Nachshon et al showed a relatively high rate of adverse events, it is expected that immunotherapy in the group which is administered with the 300 mg as opposed to 1200 mg dose of sesame protein will lead to fewer adverse symptoms such as epinephrine-treated reactions.28
We designed a randomised, single-centre, controlled trial to evaluate the effectiveness of OIT with low-dose sesame protein compared with standard treatment (elimination diet) in patients with sesame allergy. We will also report adverse events, changes in immunological parameters and the changes in maximum tolerated doses of sesame protein in each group.
Methods
Study aims
The primary objective of this study is to compare the efficacy and safety of the sesame immunotherapy protocol with a low maintenance dose of 300 mg of sesame protein compared with the control group.
Other outcomes include changes in SPT for sesame and laboratory data including specific IgE for sesame extract and components (Ses i 1), BAT and IgG4 for sesame before and after immunotherapy in both groups.
Trial design
The study is a randomised, open-label, parallel-group trial with an allocation ratio of 2:1. group 1 (experimental) will receive a gradually increasing dose of tahini until they reach the maintenance dose of 300 mg of sesame protein, and group 2 (control) will receive a recommendation to continue avoiding sesame consumption and to use emergency treatment in case of accidental exposure.
Study setting
39 participants will be enrolled by the Paediatric Hospital of the Medical University of Warsaw, Poland. Participants will be recruited from patients of our allergy department. We will also inform allergy specialists working in ambulatory settings about our research via direct contact or social media so they can refer patients to our department. The OFCs and updosing visits will be performed at the hospital by experienced staff. The doses of tahini that will be tolerated during hospitalisation will be administered later at home by parents.
Recruitment
Any patient with sensitisation or allergy to sesame hospitalised at the Allergology Clinic of the Medical University of Warsaw for any reason will be invited to participate in the sesame OIT study. In addition, information posters about the research project will be prepared for patients and specialists and placed in selected allergy outpatient clinics. Interested patients will be able to contact researchers and, after obtaining all the required information and consent, they will be enrolled into the study.
Eligibility criteria
Inclusion criteria
The inclusion criteria will be as follows:
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Age between 3 and 17 years.
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IgE-mediated sesame allergy confirmed with positive SPTs with sesame allergens (diameter of the weal of at least 3 mm) and/or specific IgE level greater than 0.35 kilo units of Allergen per litre (kUA/L).
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Allergic reaction to sesame protein during OFC.
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Signed informed consent by parent/legal guardian and patient (if aged >16 years old).
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Patient’s and caregivers’ cooperation with the researcher.
Exclusion criteria
The exclusion criteria will include the following:
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No confirmed sesame allergy.
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Negative OFC with sesame protein (maximum dose 4000 mg).
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Severe asthma, uncontrolled mild/moderate asthma: forced expiratory volume at one second (FEV1)<80% (under 5th percentile), FEV1/forced vital capacity <75% (under 5th percentile), hospitalisation due to asthma exacerbation within last 12 months.
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Current oral/sublingual/SCIT with other allergens in the first year of immunotherapy.
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Eosinophilic oesophagitis.
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A history of severe recurrent anaphylaxis episodes.
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Chronic diseases requiring continuous treatment, including heart disease, epilepsy, metabolic diseases, diabetes.
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Medication:
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Oral, daily steroid therapy lasting longer than 1 month within the last 12 months.
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At least two courses of oral steroid therapy (at least 7 days) within the last 12 months.
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Oral steroid therapy lasting longer than 7 days within the last 3 months.
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Any biological treatment.
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Therapy with β-blockers, ACE inhibitors, calcium channel inhibitors.
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Pregnancy.
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No consent to participate in the study.
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Lack of patient or caregiver cooperation.
Study procedure
In the first step of the study, a complete medical history will be obtained from each patient including inclusion and exclusion criteria, previous reactions to sesame, comorbidities and current treatment. Subsequently, the recruiter will explain the study procedures, risks and benefits and supply the patient with a leaflet containing the study’s description. After that, written informed consent will be obtained from the participant’s caregivers as well as from the participants themselves if they are 16 years of age or older. At the baseline and the end of the study SPT, blood analysis and OFC will be performed.34–36
The study procedures and time points are shown in table 1.
Procedures carried out during study
SPT and specific immunoglobulin E tests
SPT with both commercial and native sesame (raw sesame paste-tahini, a commercial product containing 200 mg protein/g—Quality Food Tahini Premium) will be performed on the volar surface of the forearm. Histamine 10 mg/mL (Diater, Spain) and saline (0.9% NaCl) will be used as positive and negative controls. A positive SPT result will be defined as a diameter of the weal of at least 3 mm. The immunological profile will be monitored during the protocol before each OFC. The blood sample will be analysed for sesame-specific IgE to extract, Ses i 1 and IgG4 levels (ImmunoCAP), commercially available IgE component levels towards Ses i 1 using multiplex Alex Allergy Explorer (Macro Array Diagnostics, Austria) and BAT (The Bühlmann Flow Cast, USA) for sesame.
Open OFC
In each patient, an OFC with sesame protein using the PRACTALL protocol for interpretation of the results will be performed with 30 min intervals between doses.37 The gold standard for diagnosing a food allergy is DBPCFC. However, open challenges have previously been carried out in the paediatric population and are widely used in clinical practice. The food challenge protocol is shown in table 2. The source of sesame protein will be tahini (a commercially available product—Quality Food Tahini Premium), as a recently published study showed that tahini can be more allergenic (22 of the 40 patients who had a negative OFC result with sesame experienced reactions during OFSs with tahini).38 When an allergic reaction is observed, the procedure will be stopped, and the patient will be enrolled into OIT. The last dose of tahini that caused the allergic reaction will be considered the eliciting dose.
Oral food challenge with sesame protein
Experimental group
OIT procedure
OIT consists of two phases: the build-up phase and the maintenance phase. The minimum duration of OIT is 3 months for those participants who immediately enter the maintenance phase and the maximum duration is 17 months. The participants will be randomised (2:1) to the experimental group (which will receive sesame OIT with a maintenance dose of 300 mg) and the control group, respectively.
It was decided that blinding would not be used in this study. Firstly, the distinctive smell and taste of tahini would have made effective blinding difficult to achieve. Secondly, participants in this study are likely to be allergic to a number of other foods as well. We decided to use standard treatment for the control group, as the use of a placebo is connected with many burdens such as time consumption, costs for parents and stress for families.
OIT: build-up phase
The first dose of OIT depends on the eliciting dose (see table 3). A detailed description of dose escalation during the build-up phase is shown in table 4.
The selection of first OIT dose
The build-up phase procedure
The first dose and escalating dose will be administered under medical supervision during hospitalisation (day-patient procedure) in 2-week intervals. After 2 hours of observation, if the patient tolerates the dose, they will be instructed to consume this dose daily at home. The participants will be reminded to take the doses approximately at the same time every day and not to ingest the tahini on an empty stomach and to avoid both exercise and sleep 2 hours after administration. In case of adverse effects, the highest previously tolerated dose will be continued for 2–4 weeks after which another attempt to increase the dose will be made. If the participant misses one or two doses, they are able to continue taking tahini at home. The omission of three or more doses requires contact with the doctor conducting the study to administer the current dose in a hospital setting. During the build-up visit, the following assessments will be conducted:
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Vital signs.
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Physical examination.
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Review of the daily symptoms diary.
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Adherence to treatment.
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Spirometry in patients with asthma.
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SCORAD in patients with atopic dermatitis.
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Allergic rhinitis symptoms questionnaire.
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Assessment of symptoms of eosinophilic oesophagitis.
The maximum duration of this phase is 14 months. Participants who do not reach the maintenance dose after 14 months will be advised to continue the highest tolerated dose and their subsequent treatment will be personalised. For the purposes of our analysis, they will be considered non-responders.
OIT: maintenance phase
The participants will receive sesame OIT with a maintenance dose of 300 mg. After achieving tolerance to the maximal dose, immunotherapy will be continued daily for 3 months (12±3 weeks).
At the end of OIT, a final OFC and evaluation of desensitisation to sesame protein will be performed. Confirmation of the total desensitisation to sesame will be the tolerance to a single dose of 4000 mg of sesame protein. During the intervention period, any adverse reaction will be recorded in the symptoms diary (online supplemental appendix A). All participants will be trained on how to manage in cases of adverse reactions including on the correct use of an autoinjector with epinephrine. Additionally, they will receive a personal action plan (online supplemental appendix B). They will also be able to contact researchers by phone at all times. Withdrawal of consent for participation in the study will be possible at any moment, with no consequences and without any obligation to give reasons for the decision. In case of the occurrence of severe adverse events (anaphylaxis grade V according to the World Allergy Organization (WAO), requiring the administration of two doses of epinephrine or treatment at the intensive care unit), or if any exclusion criteria manifest during the intervention, the patient will be withdrawn from the study.39
Supplemental material
Supplemental material
Control group
In the control group, standard treatment will be recommended, which is a restrictive elimination diet and the use of emergency treatment, including epinephrine, in case of incidental exposure. After 12 months of observation (±2 months), the final OFC will be performed. If the result of the challenge is negative, the patient will be advised to introduce sesame into the diet and if not, each patient will have the opportunity to start immunotherapy.
Clinical endpoints
Study outcomes.
Primary outcome
The proportion of participants who tolerated the single dose of 4000 mg of sesame protein (full desensitisation) in the experimental versus control group during final OFC.
Secondary outcome
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Quantity and severity of adverse events caused by sesame digestion (intentional or accidental), assessed and compared between groups, categorised based on the WAO systemic allergic reaction grading system.
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Changes in immunological measures (sIgE, sIgG4, BAT) compared between groups at baseline and the end of treatment.
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Correlation between the change in sesame SPT weal size at baseline to end of treatment, compared between groups.
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Change in the maximum tolerated dose of sesame in the OFC before and at the end of treatment, compared between groups.
Randomisation
Participants will be randomised into two study arms: an experimental group (low-dose sesame immunotherapy) and control group, with an allocation ratio of 2:1.
Permuted block randomisation with random block constellation was selected as a method for performing the randomisation, which is a method dedicated to studies with a small sample size, where it is harder to attain a ‘natural’ equality between the study groups. This method is based on iterative block randomisation, where the block size in each iteration is drawn at random, in this case from a set.
A list containing the randomisation codes for participants of this study was prepared independently using the package randomizeR (V.2.0.0) in R programming language (V.4.1.0). The list of codes will be placed by an independent person in sealed envelopes numbered 1–39. After enrolling the patient and assigning them a consecutive number from 1 to 39, the appropriate envelope with the code will be unsealed.
Statistical methods
The study sample size will be 39 participants, randomly allocated in a 2:1 ratio to experimental (n=26) and control group (n=13).
Allowing for a 15% drop-out rate, the number of patients in each group provides 80% power to detect the difference between 60% of fully desensitised patients in the experimental group and 5% in the control group, with 0.05 two-sided significance. Previous research showed a high efficacy of sesame immunotherapy (78.3%–88.4%) compared with 0% of controls. The 2:1 randomisation was intended to allow treatment for the largest possible group and to encourage participation in the study.
Data handling, verification and analysis will be performed by an independent statistician. Sensitivity analysis will be used to assess the influence of outliers.
Primary endpoint
Fisher’s exact test will be used to compare the experimental and control groups in terms of proportions of patients who tolerated the single dose of 4000 mg of sesame.
The effect size will be estimated as relative risk and 95% CI. Sensitivity analysis will be performed. In addition, a sensitivity analysis will be performed to assess how different values of basal concomitant variables affect the effect size.
Secondary endpoints
Adverse events
The quantity and severity of adverse events will be summarised using descriptive statistics. Adverse events will be recorded from participants’ diaries and visit reports. Patients will be asked to record any concerns or adverse events. Causality will be assessed by study doctors using the following categories: unrelated, possibly related and related. The severity of an adverse event will be assessed and categorised into an allergic or a non-allergic reaction. The severity of the allergic reaction will be categorised based on the WAO systemic allergic reaction grading system.
Laboratory data
Differences in sesame serum IgE levels and IgG4 levels, compared between groups at the end of treatment, will be investigated using Student’s t-test for equality of means, provided the assumptions are fulfilled. In case of violation of one or more assumptions, appropriate non-parametric alternatives will be used. For comparison between the end of study and baseline, the Wilcoxon signed-rank test will be conducted. Relevant descriptive statistics, such as the medians and IQR for data, will be provided.
Basophil activation test
BAT results obtained from the patients’ blood will be compared between groups at the end of treatment and summarised using descriptive statistics.
Skin prick tests
Change in SPT reactivity to sesame protein from baseline to end of treatment and compared between groups, similarly to IgE and IgG4 results will be tested using Student’s t-test or, in case assumptions are violated, suitable alternatives. As for the comparison between the end of study and baseline, again the Wilcoxon signed-rank test will be conducted. Relevant descriptive statistics, such as the medians and IQR, for data will again be provided.
Desensitisation dose
The change in the maximum tolerated dose of sesame in OFC before and at the end of treatment, compared between groups, cannot reasonably be expected to be normally distributed. Hence, the results will be investigated using a Mann-Whitney U test, as well as using suitable descriptive statistics.
Patient and public involvement
None.
Monitoring
The research will be carried out in accordance with the protocol. No modifications in the protocol are planned, including exclusion and inclusion criteria and intervention. In the event of unexpected circumstances, any changes in the protocol and reports of severe adverse events will be documented at ClinicalTrials.gov and submitted to the ethics committee. An independent data monitoring committee (DMC) will be established prior to the commencement of the study. The DMC will receive data after recruitment reaches 50% to evaluate the study’s progress, including adverse events. We will continue with the study until the required number of participants is reached. If we fail to recruit an appropriate number of participants, we will conclude the study after 3 years.
Harms
During the OIT procedure, adverse reactions from mild to severe can occur. Patients will be monitored for local and systemic reactions as well as symptoms of new-onset eosinophilic oesophagitis. In OIT studies, most reactions were classified as mild, however, reports of moderate and severe reactions also exist.40 Nachshon et al reported the administration of epinephrine to 11.7% of patients during OIT (milk, peanut, egg, sesame, tree nuts).41 The Food and Drug Administration has since approved the first drug for treating peanut allergy in children, which can be used in ambulatory treatment. Adverse reactions that will be diagnosed during hospitalisation will be treated immediately by a professional team. All participants will be trained to manage adverse reactions including epinephrine use. In case of emergencies, they will also be able to contact a physician by phone during the study period. In case of severe adverse events, the decision regarding the continuation or discontinuation of the trial will be made by the study group in agreement with the ethics committee. All adverse events also will be noted in the CRFs. The study is insured using funds from the Medical University of Warsaw, which will ensure compensation in the case of severe complications.
Data collection and handling
Identification numbers will be given to all participants. Data will be collected and recorded electronically onto CRFs. Data collection and processing will be performed by using the SAS System (SAS 9.4 System). The electronic database will be protected by a password and accessible by the involved researchers only. The data will include prerandomisation and baseline characteristics (gender, age, the first reaction with sesame and concomitant diseases) and items recorded before and at the end of OIT (weal of SPT, specific IgE for extract and main recombinant fractions, and IgG4 for sesame). Personal data will be stored according to Polish law and will not be shared with any outside party.
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