Pragmatic Low‐Dose Oral Immunotherapy for Preschool Children With Peanut Allergy: A Randomised Controlled Trial

ABSTRACT

Introduction

Peanut allergy is the most common childhood‐onset, persistent food allergy. Peanut oral immunotherapy (OIT) is a potential treatment, but few studies prospectively examine the outcome of peanut OIT in young children using parent‐measured doses compared to standard care (peanut avoidance).

Objective

To determine the efficacy, safety and tolerability of a pragmatic peanut OIT protocol (parent‐measured doses with low maintenance dose) compared to avoidance.

Methods

In this unblinded randomised controlled trial (1:1 ratio), children 1–4 years old were assigned to receive peanut OIT (maintenance dose 360 mg) or avoidance for 12 months. The primary outcome was desensitisation, defined as the ability to tolerate at least 600 mg peanut protein during an end‐of‐treatment oral food challenge (EOT OFC), with secondary outcomes frequency and severity of adverse events, change in quality of life and change in immunological markers of peanut allergy.

Results

A total of 54 children were randomised, with 23/27 in the peanut OIT and 25/27 in the avoidance group undergoing open peanut challenge after 12 months. An eliciting dose of ≥ 600 mg peanut protein was tolerated by 74% (20/27) of OIT compared to 11% (3/27) of avoidance participants. 41% of OIT (11/27) and 7% of avoidance (2/27) participants passed the end‐of‐treatment challenge. The OIT group reported significantly better quality of life than the avoidance group after 12 months (Food Allergy Quality of Life Questionnaire‐Parent Form mean difference −0.5, p = 0.041). There were 79 treatment‐related adverse events reported by 21 participants in the OIT group (median 2 per participant, range 0–13).

Conclusion

Peanut OIT using parent‐measured doses and a low maintenance dose of 360 mg is effective at inducing desensitisation after 12 months in 1‐ to 4‐year‐old children. In this cohort, peanut OIT is associated with improved quality of life compared to avoidance and appears to have an acceptable safety profile.

Trial Registration

Australian New Zealand Clinical Trials Registry: ACTRN12621001001886 (registered 30 July 2021)

This randomised controlled trial of peanut oral immunotherapy (pOIT) in preschool children found that 12 months of low dose pOIT was effective at inducing desensitisation in 74% of children receiving pOIT (vs 11% of children avoiding peanut) and was associated with better quality of life than avoidance.

Abbreviations

AE

adverse event

EOS

end of study

EOT

end of treatment

FAQL‐PB

Food Allergy Quality of Life‐Parental Burden

FAQLQ‐PF

Food Allergy Quality of Life Questionnaire‐Parent Form

FASE‐P

Food Allergy Self‐Efficacy for Parents

ITT

intention to treat

OFC

oral food challenge

OIT

oral immunotherapy

pOIT

peanut oral immunotherapy

PTAH

peanut (Arachis hypogaea) allergen powder‐dnfp

QoL

quality of life

RCT

randomised controlled trial

sIgE

specific immunoglobulin E

SPT

skin prick test

TI

treatment initiation

trAE

treatment‐related adverse event

Summary.

• Low‐dose peanut OIT is effective and improves quality of life compared to avoidance in preschool‐aged children.

• Parents can safely measure OIT doses using powdered peanut butter, without need for pharmacy compounding.

• Pragmatic criteria can identify patients suitable for oral immunotherapy without requiring pre‐treatment peanut challenge.

1. Introduction

Food allergy is common, affecting an estimated one in ten Australian infants [1]. Up to 3% of 1‐year‐olds have a peanut allergy that usually persists to later in life, making peanut the most prevalent food allergy in school‐aged children [1, 2, 3, 4]. The burden of peanut allergy, including risk of potentially life‐threatening anaphylaxis [5], results in reduced quality of life (QoL) [6, 7] that worsens on reaching school age [8] due to dietary, social and emotional impact [9].

The prevalence of allergies in children continues to rise [10] and evidence‐based guidelines for infant feeding and allergy prevention have not reduced the incidence of peanut allergy in Australia [11]. Therefore, effective treatments for peanut allergy that can be implemented at scale are needed.

Oral immunotherapy (OIT) is a potential treatment for peanut allergy that involves daily ingestion of increasing amounts of peanut protein until a target maintenance is reached. Peanut OIT (pOIT) has been proven to be effective at inducing desensitisation in randomised controlled trials (RCTs) of the pharmaceutical product peanut (Arachis hypogaea) allergen powder‐dnfp (PTAH, trade name Palforzia), initially in 4‐ to 17‐year‐olds [12] and recently in younger children [13], or pharmacy‐compounded defatted peanut flour [14, 15, 16, 17, 18] provided in precisely quantitated individual daily doses for at least the duration of the dose escalation period.

While pOIT results in desensitisation, it is associated with an overall increase in the frequency of allergic reactions compared to placebo during clinical trials [19]. There is also a significant treatment burden for children receiving OIT and their families, with regular health professional visits during dose escalation in addition to daily home OIT doses. As a result, OIT is not routinely recommended by 2023 Australian expert guidelines due to uncertainty around efficacy, safety and other patient‐important outcomes that should be addressed in clinical trials [20].

The impact of pOIT on QoL is unclear [19, 21]. Increasing an individual's peanut eliciting dose, that is the amount of peanut protein that is required to provoke an allergic reaction, has been modelled to significantly reduce the likelihood of peanut allergic reactions from accidental consumption [22]. This may lead to reduced food‐related anxiety and improved patient empowerment; however, these benefits could be offset by the burden and side effects of treatment.

Theoretical concerns have been raised about potential variability of food products being used in OIT protocols; however, consensus guidelines [21, 23] supported by published data [19, 24] recommend OIT can be offered using food products while following standardised, evidence‐based protocols.

Administering OIT using readily available food products with doses prepared and administered by parents, rather than compounded by pharmacy or dispensed by health professionals, may improve access to OIT by reducing costs of treatment. However, research is needed to further investigate the efficacy, safety and tolerability of this approach.

In clinical practice, the alternative to pOIT is peanut avoidance. The pragmatic question facing clinicians and families of children with peanut allergy is whether pOIT, which requires significant changes to daily routines and carries a risk of side effects, is preferable to peanut avoidance. There is scant data from RCTs on patient‐reported outcomes of pOIT compared to the real‐world standard care of peanut avoidance in preschool‐aged children with peanut allergy.

We therefore investigated the efficacy, safety and patient‐reported outcomes of a pragmatic, food‐based pOIT protocol compared to peanut avoidance in an open‐label, randomised controlled trial in 1‐ to 4‐year‐old children.

2. Methods

Early Peanut Immunotherapy in Children (EPIC) is a two‐armed, open‐label, randomised controlled superiority trial of 12 months of pOIT compared to peanut avoidance at inducing desensitisation conducted at a single tertiary paediatric hospital (Perth Children's Hospital, Western Australia, Australia) [25].

2.1. Participants

Eligible participants were 1‐ to 4‐year‐old children with confirmed or highly probable peanut allergy. Potential participants were referred from public and private allergy clinics or responded to general community recruitment materials.

Confirmed peanut allergy was defined as peanut skin prick test (SPT; ALK USA peanut extract; HollisterStier Quintips lancet) mean wheal diameter ≥ 3 mm and/or peanut specific IgE (sIgE; ImmunoCAP, Phadia AB, Sweden) > 0.35 kU/L, and allergic reaction to open peanut oral food challenge (OFC) with eliciting dose ≤ 2500 mg peanut protein (cumulative dose 4530 mg) at screening that met pre‐specified criteria [26].

Highly probable peanut allergy was defined as either (i) unequivocal past clinical history of allergic reaction to peanut, and at least 1 of peanut SPT mean wheal diameter ≥ 8 mm, peanut sIgE > 15 kU/L or Ara h 2 sIgE > 1 kU/L at screening or (ii) equivocal or no clinical history of allergic reaction to peanut, with at least two of peanut SPT ≥ 8 mm, peanut sIgE > 15 kU/L or Ara h 2 sIgE > 1 kU/L at screening.

Children with a medical history that may increase their risk of severe adverse events during pOIT or OFC, including a history of life‐threatening anaphylaxis to peanut, uncontrolled asthma or other severe cardiovascular or respiratory disease, were excluded.

Written informed consent was obtained from participants' parent or guardian. The trial was approved by the Child and Adolescent Health Service Human Research Ethics Committee (RGS0000004384).

2.2. Randomisation

Participants were randomised 1:1 to pOIT or avoidance in blocks of 2, stratified by confirmed versus highly probable peanut allergy (as per inclusion criteria) and age (1–2 or 3–4 years old at enrolment). Randomisation occurred after confirmation of eligibility. This pragmatic study was unblinded with no placebo.

2.3. Intervention

2.3.1. Peanut OIT

The interventional product was defatted peanut flour available for retail purchase as powdered peanut butter (50% protein by weight; Peanut Butter & Co Pure Peanut Powder, New York, USA). Additional equipment was provided for families to measure doses including metal measuring spoons, 70‐mL specimen jar with lid and 20‐ and 5‐mL syringes.

The pOIT protocol comprised three phases, treatment initiation (TI), up‐dosing and maintenance, as previously reported [25]. In brief, up to four increasing doses from 1 mg to a maximum of 15 mg peanut protein were given during TI. Participants continued the maximum tolerated dose at home daily for 2 weeks, until their first up‐dosing visit. Dose increments are summarised in Table 1.

TABLE 1.

Peanut OIT dosing schedule.

Treatment phase	Dose level	Defatted peanut flour dose	Equivalent peanut protein	Interval prior to dose increase
Treatment initiation (single day if tolerated)	1	2 mg	1 mg	N/A
	2	6 mg	3 mg	20 min
	3	20 mg	10 mg	20 min
	4	1/64 tsp	15 mg	2 weeks
Up‐dosing	5	1/32 tsp	30 mg	2 weeks
	6	1/16 tsp	60 mg	2 weeks
	7	1/8 tsp	120 mg	2 weeks
	8	3/16 tsp	180 mg	2 weeks
	9	1/4 tsp	240 mg	2 weeks
Maintenance	10	3/8 tsp	360 mg	Until 52 weeks total treatment

Doses ≤ 10 mg were prepared as a suspension of peanut flour in water, with the required dose drawn up using the 5‐mL syringe. Doses ≥ 15 mg were measured using measuring spoons only and mixed with a food of the family's choice.

Outpatient up‐dosing visits occurred every 2 weeks under nurse supervision. If the increased dose was tolerated, it was continued daily at home until the next scheduled visit. If an allergic reaction occurred at the up‐dosing visit, the previously tolerated dose was continued for a further 2 weeks. Up‐dosing visits continued until the target maintenance of 3/8 teaspoon peanut flour (approximately 360 mg peanut protein) was reached, with maintenance continued to complete a total of 12 months of OIT from TI.

Dose modifications were made according to pre‐specified criteria for moderate to severe treatment‐related allergic reactions, intercurrent illnesses or extended periods of missed doses. Specifically, the next OIT dose was reduced by half following any episode of anaphylaxis or if five or more consecutive days of OIT doses were missed, and participants were advised to withhold OIT doses during infections associated with fever, diarrhoea, vomiting, frequent cough and/or wheeze.

2.3.2. Control (Peanut Avoidance)

Participants in the avoidance arm continued strict peanut avoidance for 12 months from randomisation.

2.4. Study Procedures

The schedules of procedures have been previously reported [25] (see also Tables S1 and S2). All participants underwent baseline assessments including medical history, physical examination, eczema assessment, SPT with two commercial peanut extracts (ALK USA and Immunotek), peanut and Ara h 2 sIgE and biospecimen storage.

Peanut and Ara h 2 sIgE and peanut SPT were also performed at the end of treatment (EOT), prior to the EOT OFC. Some participants did not have SPT with ALK peanut extract performed at EOT due to a voluntary market recall of the ALK extract during the trial.

Open peanut OFC was performed at screening for eligible participants who did not meet criteria for highly probable peanut allergy, and in all randomised participants at EOT. Dose increments of 10, 30, 100, 300, 600, 1000 and 2500 mg peanut protein were given at 20‐min intervals.

Positive challenges were defined by an allergic reaction meeting PRACTALL consensus stopping criteria [26] and assessed for severity according to published guidelines [27]. The eliciting dose (ED) was defined as the amount of peanut protein in the OFC dose given that resulted in the onset of a reaction meeting stopping criteria.

Following completion of the EOT OFC, participants in the OIT group who elected to continue peanut consumption (rather than revert to avoidance) were advised to resume daily consumption of the same amount of powdered peanut butter as they were taking during OIT maintenance (3/8th teaspoon) from the following day, regardless of OFC outcome. Participants in the avoidance group were advised to continue peanut avoidance if they had a positive EOT OFC, or to introduce peanut‐containing foods to their diet regularly if they had a negative EOT OFC. Ongoing clinical follow‐up was arranged through the Immunology Department at Perth Children's Hospital.

2.5. Questionnaires

Patient‐reported outcomes (parent proxy) were assessed using instruments validated in general population samples of children with food allergy and their parents (but not specifically those undergoing OIT or other food allergy treatment), including the Food Allergy Quality of Life Questionnaire–Parent Form (FAQLQ‐PF) [28], Food Allergy Quality of Life–Parental Burden (FAQL‐PB) [29] and Food Allergy Self‐Efficacy for Parents (FASE‐P) [30]. The same parent was asked to complete the questionnaires throughout the study.

The FAQLQ‐PF and FAQL‐PB are disease‐specific health‐related QoL for children with food allergy [31] and their parents [29]. The FAQLQ‐PF has been used for longitudinal monitoring of QoL in children receiving immunotherapy for peanut allergy [32]. The FASE‐P is a validated questionnaire to assess parental confidence in managing food allergy [30].

Questionnaires were administered at screening, Week 12, Week 24 and at the end of study (EOS, 4 weeks after the EOT OFC).

2.6. Monitoring and Adverse Event Assessment

Parents of pOIT participants completed a web‐based daily electronic diary, developed using Research Electronic Data Capture software [33, 34] (REDCap, Vanderbilt University, USA), to assess adherence, parent‐reported adverse events (AEs), accidental peanut consumption and hospital admissions.

Parent‐reported AEs via the electronic diary were assessed and graded by study clinicians for severity (using the consensus severity grading system published by Dribin et al.) [27] and relatedness to pOIT. Parent‐reported events that were not medically significant were not classified as AEs. Any history of adverse events not recorded in the electronic diary was also elicited by staff at study visits.

2.7. Outcomes

The primary outcome was the proportion of participants with an ED > 600 mg peanut protein at EOT in pOIT versus avoidance, as assessed by open peanut OFC at EOT (defined as 12 months after Treatment Initiation in the pOIT group and 12 months after randomisation in the avoidance group).

Secondary outcomes were the proportion of participants reporting, severity of and frequency of treatment‐related AEs (trAEs); change in child and parent QoL (FAQLQ‐PF, FAQLQ‐PB) and parent food allergy self‐efficacy (FASE‐P) from baseline to EOS in pOIT versus avoidance; change in peanut sIgE and skin prick test size from baseline to EOT; and the proportions in each group with ED at EOT of ≥ 300 and ≥ 600 mg, and with negative OFC (no reaction to 2500 mg final dose).

2.8. Sample Size

Sample size of 50 randomised 1:1 to pOIT or avoidance was based on Fisher's exact test with power of 0.85 and alpha 0.05 to detect a difference in proportion achieving the primary outcome of 66% in pOIT and 25% in control. Participants who enrolled prior to the target sample size being reached remained eligible for randomisation. Baseline assumptions were derived from published registry data of preschool pOIT outcomes [35] and a phase III RCT of pOIT in 4– to 17‐year‐olds [12]. The estimated 25% response rate in controls includes participants with naturally high (> 600 mg) reaction threshold, spontaneous resolution of allergy or misclassification at baseline of a non‐allergic participant as having ‘highly probable’ peanut allergy.

2.9. Statistical Analysis

Tolerated dose is reported as frequency and proportions, with differences between OIT and control groups compared using a chi‐square test or Fisher's Exact test (if expected cell counts < 5), followed by logistic regression producing odds ratios and their corresponding 95% confidence intervals. Adverse events are described using frequencies and proportions and counts, with rates determined per 100 visits or 100 days, depending on the treatment phase.

Between‐group differences for secondary outcomes were analysed using regression models, adjusting for baseline score. Outcomes with baseline, Week 12 and EOT measures (QoL and sIgE) were analysed using linear mixed models to account for the within subject repeated measures. Due to skewed distributions, IgE was reported using medians and interquartile ranges and then log transformed for the linear mixed model. Peanut SPT, with baseline and EOT measures, was skewed with scores of zero and therefore not log transformed. The best model fit (determined by examining residuals) was found using a generalised linear model with a Gaussian family, a log link and robust standard errors.

Statistical significance was set at p < 0.05. All statistical analysis was performed using Stata v18.1 (StataCorp, College Station, Texas, USA).

3. Results

The trial profile is summarised in Figure 1. Recruitment of participants occurred between September 2021 and September 2022. Seventy‐three were enrolled in screening; 19 were ineligible and 54 participants were randomised to pOIT (n = 27) or avoidance (n = 27) and included in the intention‐to‐treat (ITT) analysis. Of these, 23/27 in the pOIT and 25/27 in the avoidance group attended the EOT OFC visit. Participant baseline characteristics are summarised in Table 2.

FIGURE 1.

Trial profile. EOT, end of treatment; ITT, intention to treat; OFC, oral food challenge; OIT, oral immunotherapy; SV1, screening visit 1.

TABLE 2.

Baseline participant demographic and characteristics.

	Control (n = 27)	OIT (n = 27)
Age: mean years (SD)	2.6 (1.2)	2.7 (1.3)
Age group
< 3	17 (63.0%)	17 (63.0%)
≥ 3–4	10 (37.0%)	10 (37.0%)
Sex
Male	15 (55.6%)	16 (59.3%)
Female	12 (44.4%)	11 (40.7%)
Eczema—yes: n (%)	24 (88.9%)	25 (92.6%)
Bronchiolitis/wheezing episodes—yes: n (%)	13 (48.1%)	9 (33.3%)
Other food allergy—yes: n (%)	13 (48.1%)	18 (66.7%)
Tree nut allergy—yes: n (%)	4 (16.0%)	12 (44.4%)
Eligibility based on confirmed peanut allergy (positive OFC during screening)	7 (25.9%)	7 (25.9%)
Eligibility based on highly probable peanut allergy criteria	20 (74.1%)	20 (74.1%)
Baseline peanut sIgE: median kU/L (IQR)	2.3 (0.7, 5.7)	4.7 (1.6, 12.9)
Baseline Ara h 2 sIgE: median kU/L (IQR)	2.2 (0.6, 6.5)	3.6 (0.7, 11.2)
Baseline SPT peanut (ALK): median mm (IQR)	8 (6, 9)	8 (6, 9.5)

A total of 7643 participant daily eDiary entries were completed (missing entries = 1527). OIT doses were taken on 6891 of 7643 days (90.2%) where eDiary data were available. The most common reasons provided for missed doses were intercurrent illness (240 of 752 recorded missed doses, 31.6%), followed by parents either choosing to miss a dose for convenience (such as travel or other commitments) that day (177 of 752 missed doses, 23.5%) or forgetting to administer a dose (156 of 752 missed doses, 20.8%).

Three participants (2 OIT, 1 control) withdrew after randomisation but prior to undertaking any further study procedures. An additional two participants (1 OIT, 1 control) did not attend the EOT OFC visit, and one participant discontinued OIT but attended the EOT OFC. The reasons for withdrawal/discontinuation are summarised in Table 3.

TABLE 3.

Summary of withdrawn participants.

Participant ID	Group	Withdrawal timepoint	Reason for withdrawal
37	OIT	Prior to OIT initiation	Parent started new job, unable to adhere to visit requirements for OIT
44	OIT	Prior to OIT initiation	Recurrent tonsillitis, awaiting surgery
50	OIT	Up‐dosing phase (180 mg dose)	Parental decision, previous episode of anaphylaxis to OIT dose
57	OIT	Up‐dosing phase (60 mg dose)	Parental choice due to burden of visits and anxiety related to doses. Attended EOT OFC
36	Control	Immediately after randomisation	To pursue OIT outside trial after being randomised to avoidance
69	Control	9 months post‐randomisation	Family moved overseas

3.1. Efficacy

The primary outcome of ED > 600 mg was met by 20 of 27 (74%) pOIT and 3 of 27 (11%) control participants by ITT analysis (risk difference 63% [95% CI 43–83, p < 0.001], odds ratio 22.9 [95% CI 5.2–100.1, p < 0.001] for OIT compared to controls).

The comparison of various eliciting dose thresholds for the OIT and control groups by ITT and per protocol is shown in Table 4, with the proportion of participants tolerating each EOT OFC dose level shown in Figure 2.

TABLE 4.

Comparison of eliciting dose thresholds for OIT and control groups by intention to treat and per protocol.

Eliciting dose	OIT (n = 27)	Control (n = 27)	p	OR (95% CI)	p
Intention to treat
> 100 mg	24 (88.9%)	12 (44.4%)	0.001	10 (2.4–41.4)	0.001
> 300 mg	22 (81.8%)	7 (25.9%)	< 0.001	12.6 (3.4–45.0)	< 0.001
> 600 mg a	20 (74.1%)	3 (11.1%)	< 0.001	22.9 (5.2–100.1)	< 0.001
No reaction at 2500 mg	11 (40.7%)	2 (7.4%)	0.009	8.6 (1.7–44.0)	0.010

Eliciting dose	OIT (n = 23)	Control (n = 24)	p	OR (95% CI)	p
Per protocol
> 100 mg	23 (100%)	12 (50.0%)	< 0.001	NR	NR
> 300 mg	22 (95.6%)	7 (29.2%)	< 0.001	53.4 (6.0–476.8)	< 0.001
> 600 mg a	20 (87.0%)	3 (12.5%)	< 0.001	46.7 (8.4–258.9)	< 0.001
No reaction at 2500 mg	11 (47.8%)	2 (8.3%)	0.003	10.1 (1.9–53.2)	0.006

Abbreviation: NR = no results as 100% in OIT group.

^a > 600 mg = primary outcome.

FIGURE 2.

Proportion of participants tolerating each dose level at end‐of‐treatment oral food challenge (per protocol analysis).

3.2. Patient‐Reported Outcomes

Participants in the pOIT group (via parent proxy) and their parents reported significantly better QoL compared to peanut avoidance at EOS, as assessed by mean difference in FAQLQ‐PF and FAQLQ‐PB (Table S3).

For the FAQLQ‐PF total score, the between‐group mean difference at EOS (adjusted for baseline) was −0.5 in OIT versus avoidance, p = 0.041 (where lower scores represent better QoL). The difference between groups was significant across all three domains of the FAQLF‐PF (emotional impact −0.4, p = 0.045; food‐related anxiety −1.0, p = 0.011; social and dietary limitations −0.6, p = 0.011).

There were also significant differences between pOIT and avoidance groups in the mean FAQL‐PB total score (−0.7, p = 0.003), and life limitations (−0.5, p = 0.036) and emotional stress (−0.8, p = 0.002) domains at EOS.

There was no significant difference in FAQLQ‐PF total scores or subdomains, or FAQL‐PB total score between groups at the Week 12 or Week 24 timepoints. There was no significant difference in FASE‐P scores between groups at any timepoint.

3.3. Safety

Overall, 21/25 participants in the OIT group who commenced treatment (excluding two participants who withdrew prior to receiving any OIT doses) reported at least one trAEs (total of 79 trAEs; median 2, range 0–13). A summary of the trAEs is presented in Table 5 and Table S4.

TABLE 5.

Number of participants reporting and rate of treatment‐related AEs by location where OIT dose was taken (supervised hospital visit or at home) and treatment phase.

Setting of dose	In hospital		At home
Treatment phase	Initiation	Up‐dosing	Up‐dosing	Maintenance
Participants with at least 1 AE	12/25 (48%)	8/25 (32%)	16/25 (64%)	7/23 a (30%)
Number of AEs	12	10	48	9
Number of visits/days on treatment	25 b	182 c	3079 d	5787 e
Rate of events	48 per 100 visits	5.5 per 100 visits	1.6 per 100 days	0.16 per 100 days
Total number of adrenaline‐treated AEs	5	0	2	1

^a n = 2 participants withdrew before reaching the maintenance phase.

^b Number of participants attending treatment initiation.

^c Total number of outpatient clinic up‐dosing visits.

^d Total number of participant days in up‐dosing phase (excluding up‐dosing clinic visit days).

^e Total number of participant days in maintenance phase.

There were trAEs during 12/25 TI and 10/182 up‐dosing visits. During at‐home dosing, there were 48 trAEs reported during the collective 3079 days that participants were in the up‐dosing phase, and nine trAEs during 5787 days in the maintenance phase (at‐home trAE rates of 1.7 per 100 days in up‐dosing and 0.16 per 100 days in maintenance). There were three at‐home trAEs treated with adrenaline (two during up‐dosing, one during maintenance).

Of all trAEs, 67/79 (85%) were Grade 1 or 2 (including two mild non‐allergic AEs deemed possibly related to treatment), 11/79 (11%) were Grade 3 (four during TI, two during hospital UP visits, five at home) and 1/79 (1%) was Grade 4 (during TI) [27]. There were no Grade 5 AEs.

3.4. Immunological Changes

The median peanut and Ara h 2 sIgE and peanut SPT wheal size at each timepoint is summarised in Figure 3. Peanut sIgE, Ara h 2 sIgE and skin prick test were all significantly lower at EOT in the OIT group compared to control, after adjusting for baseline results (Tables S5 and S6). In the OIT group, there was a significant increase in both peanut and Ara h 2 sIgE from baseline to Week 12 that subsequently returned to baseline by EOT, in contrast with the control group, who had a significant increase in peanut sIgE from baseline to EOT.

FIGURE 3.

Median peanut specific IgE (A), Ara h 2 specific IgE (B) and peanut skin prick test wheal diameter (C) with 95% confidence intervals at each timepoint for OIT and control groups.

4. Discussion

We have shown that our pragmatic food‐based low dose OIT protocol is effective at inducing desensitisation after 12 months and is associated with meaningful improvement in QoL compared to avoidance.

To our knowledge, this is the first randomised controlled trial to demonstrate that exclusively parent‐measured dosing of a routinely available food product can be considered an effective method for OIT based on objective and patient‐reported outcomes, with acceptable safety.

The proportion of participants achieving desensitisation to at least 600 mg peanut protein in our study is similar to that reported in Phase 3 trials of PTAH in children [12, 13], and the exposure‐adjusted incidence of adverse reactions is within the range reported in a meta‐analysis of safety of OIT [19]. Taken together, these findings suggest the variable composition of food products and parent‐measured doses did not have a meaningful impact on the efficacy or safety of pOIT in this cohort and align with the recently published results of an ongoing trial of peanut OIT using Bamba for the latter stages of dose escalation and maintenance [36].

We have demonstrated that pOIT with a desensitisation outcome is associated with a significantly better QoL than avoidance after 12 months in our cohort, with between‐group mean difference in FAQLQ‐PF total score of −0.5 in favour of OIT. This contrasts with a 2019 systematic review and meta‐analysis that found, with low‐certainty evidence, pOIT might not improve QoL compared to avoidance [19], and an analysis of HRQoL assessments from randomised trials of PTAH that did not find a significant difference between OIT and placebo groups at the end of treatment [37]. While a minimum clinically important difference (MCID) in FAQLQ for treatment trials has not been definitively determined, an MCID of −0.45 has been established for change in FAQLQ‐PF from pre‐ to post‐OFC [38], and has been suggested as representing a clinically meaningful change in participants receiving epicutaneous immunotherapy for peanut allergy [32].

The strengths of our study include the randomised design with a clinically relevant real‐world comparator of peanut avoidance as the control. Real‐world, uncontrolled observational studies of pOIT have been identified as being at high risk for confounding and bias [19] that is minimised by our randomised controlled trial design.

Our retention rate was high, with 87% of randomised participants attending the primary outcome assessment. The prospective and active collection of parent‐reported adverse events, subsequently assessed and verified by a study clinician, provides a robust data set for assessment of safety and tolerability of this approach to pOIT that would not be available if relying solely on retrospective parent recall of adverse reactions elicited at study appointments.

There are several limitations inherent to the pragmatic, real‐world design of this study.

The results of this trial are not generalisable to all children under 5 with peanut allergy, particularly those related to patient‐reported outcomes. The study population will invariably be biased towards families who are seeking interventional treatment, and who are willing and able to adhere to the requirements of OIT. Our data therefore support that providing OIT for families who want access to interventional treatment for their child's peanut allergy results in improved QoL compared to continuing peanut avoidance, but should not be extrapolated to conclude that OIT will improve QoL for all children with peanut allergy.

We did not undertake OFCs for all participants at baseline, with most participants being eligible according to our definition of highly probable peanut allergy. This was a deliberate feature of the study design in response to consumer and clinician feedback, who suggested OFCs should not be mandatory in patients with very high probability of peanut allergy based on history, SPT and sIgE. This preference was clearly demonstrated by our study cohort; all 40 participants with highly probable peanut allergy were offered the option of a baseline OFC prior to OIT, and all declined. It is possible, albeit unlikely, that some children who did not have peanut allergy were enrolled in the trial. To mitigate the risk of bias, we stratified randomisation according to whether participants were eligible based on a positive OFC or clinical history with high SPT and/or sIgE results. Notably, the only two control participants with negative OFC at EOT both had confirmed peanut allergy with positive OFC at baseline.

Participants did not require a low ED at baseline to be eligible for this trial. This decision was consistent with our aim to investigate the outcomes of pOIT as it would be implemented in clinical practice, where all children with peanut allergy (rather than those with a low ED at a particular point in time) may be considered for OIT. Phase 3 trials of PTAH have demonstrated the efficacy of pOIT to achieve an ED of > 600 mg in children with low ED at baseline [12, 13], however no such restriction on ED threshold is included in the licenced indication for this treatment [39].

The inclusion of participants with any confirmed or highly probable peanut allergy (rather than only those with low ED) may also provide some explanation for the relatively low median peanut sIgE in our cohort compared to Phase 3 trials of oral [13] or epicutaneous [40] immunotherapy in a similar age group, while the IMPACT trial of peanut OIT in 1–3 years old excluded participants with peanut sIgE < 5kU/L [16]. However, the comparatively low peanut sIgE in our cohort should not infer that a significant number of sensitised non‐allergic participants were enrolled. Ara h 2 sIgE is a more accurate diagnostic test for peanut allergy than whole peanut sIgE [41, 42], with Ara h 2 sIgE > 0.88 kU/L reported to have high specificity for peanut allergy in Australian infants [41]. In this context, the relatively high median Ara h 2 sIgE of study participants is consistent with a population of Australian peanut‐allergic preschool‐aged children.

We performed open peanut OFC at EOT. This was informed by consultation with consumers who preferred a single OFC visit, and a judgement by the investigators that the incremental scientific value of a double‐blind, placebo‐controlled food challenge outcome over an open OFC with objective stopping criteria did not justify the additional cost and burden on families given the substantial existing evidence demonstrating the efficacy of other approaches to pOIT in achieving desensitisation.

The intervention was open label, and there was no placebo control. Quality of life outcomes may therefore be biased in favour of pOIT due to a placebo effect, rather than any biological response. However, a significant difference in QoL between the pOIT and avoidance groups was only observed after the EOT peanut OFC was completed, suggesting that the outcome of OIT (i.e., achieving desensitisation) rather than simply the process of receiving OIT was a significant contributor to this improvement.

5. Conclusion

We found that in children 1–4 years old with peanut allergy, 12 months of pOIT was more effective at achieving desensitisation to at least 600 mg peanut protein and associated with better quality of life than peanut avoidance. A pragmatic protocol for pOIT relying on parent‐measured doses of a commercially available food product is feasible, acceptable to parents, and results in similarly low rates of adverse events as other reported trials of pOIT in this age group.

Author Contributions

M.O. and J.R.M. conceived the trial and wrote the study protocol, along with N.B. who wrote the statistical analysis plan for the study. I.R. assisted in planning the study intervention. M.O. oversaw the conduct of the entire trial as coordinating principal investigator. J.R.M. was responsible for study management. M.O., R.W., S.T., A.G. and S.B. were involved in conducting study procedures and data collection. N.B., B.M., S.M. and J.R.M. were involved in study database development, data cleaning and analysis. M.O. prepared the initial manuscript draft. All authors were involved in critical review of the manuscript and approval for submission.

Ethics Statement

The trial was approved by the Child and Adolescent Health Service Human Research Ethics Committee on 31 March 2021 (RGS0000004384). Written informed consent was obtained from participants' parent or guardian.

Conflicts of Interest

M.O. is a non‐remunerated Board Director and current President of the Australasian Society of Clinical Immunology and Allergy. Other authors have no conflicts of interest to declare.

Supporting information

Appendix S1: cea70126‐sup‐0001‐AppendixS1.docx.

Tables S1–S6: cea70126‐sup‐0002‐TablesS1‐S6.docx.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.