Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up +

Outcome measures and effect size

Results

Comments

Du Toit 2015

Randomized Trial of Peanut Consumption

in Infants at Risk for Peanut Allergy (LEAP trial)

Type of study:

RCT

Setting: open label, single centre

Country: UK

Funding: National Institute of Allergy and Infectious

Diseases and others

Inclusion criteria:

Age 4-11 months, severe eczema and/or egg allergy.

Exclusion criteria:

Skin prick test >4mm

N total at baseline:

Skin prick test (SPT) neg: n=542 (n=530 in PP analysis)

>avoidance: 270 (263 ITT, 245 PP)

>consumption: 272 (266 ITT, 255 PP analysis)

SPT pos: n=98

>avoidance: 51 (51 ITT, 50 PP)

>consumption: 47

(41 ITT, 39 PP)

Groups comparable at baseline?

Neg SPT group larger.

Important prognostic factors:

For example

age:

mean 7.8+/-1.7 months

Sex:

64.8% of the avoidance

group vs. 55.2% of the consumption group were

male infants.

2 cohorts based on pre-existing sensitivity to peanut extract based on skin-prick test (1-4mm diameter).

In each cohort, pt were randomly assigned to group with dietary peanut consumption or group (I) with avoidance of peanut consumption ©

Cohort negative skin prick test:

Consumption group: 2g peanut protein single dose, when pos test results incremental doses up to 3.9g.

When no reaction: 6g peanut protein per week in 2-3 meals until 60 months.

>when reaction: avoidance but included in ITT analyses.

Avoidance group: -

Pt in whom peanut allergy was unlikely: 5g peanut protein single dose.

Cohort pos skin prick test 1-4mm:

Consumption group: 2g peanut protein single dose, when pos test results incremental doses up to 3.9g.

When no reaction: 6g peanut protein per week in 2-3 meals until 60 months.

>when reaction: avoidance but included in ITT analyses.

Avoidance group:

‑

Length of follow-up: until 60 months of age

Loss-to-follow-up:

SPT-neg:

>avoidance: 18

>consumption: 11

(in ITT, not in PP)

Due to inadequate adherence.

SPT-pos:

>avoidance: 1 (not in PP)

>consumption: 2 (not in PP)

Incomplete outcome data:

SPT-neg:

>avoidance: 7

>consumption: 5

(not in ITT)

SPT-pos:

>avoidance: 0

>consumption: 6

(in ITT due to pos baseline reaction)

10 participants

were withdrawn voluntarily by a parent or

guardian or were lost to follow-up

11pt with inconclusive data/unavailable data: other data were used to determine whether pt should be considered to have allergy.

Outcome measures and effect size n (%):

Primary: proportion of pt with peanut allergy at 60 months of age.

Peanut-specific IgG4:IgE ratio

Measures at baseline, 12, 30, 60 months.

The per-protocol population included participants

who adhered adequately to the assigned

regimen (consumption or avoidance of peanuts)

until 2 years of age (Fig. 1). Analyses of immune markers, including wheal size after skin-prick tests, were performed in the per-protocol population,

with data pooled from participants who had negative results on the initial skin-prick test and those who had positive results.

Among the 530 infants in the intention-to-treat population who initially had negative

results on the skin-prick test, the prevalence of peanut allergy at 60 months of

age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001).

Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = 0.004).

Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titers of peanut-specific IgE antibody.

A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy.

The intervention was effective in reducing the prevalence of peanut allergy in terms of both primary

prevention (prevalence of 6.0% in the avoidance group vs. 1.0% in the consumption group, P = 0.008) and secondary prevention (33.1% vs. 6.8%, P<0.001)

no large differences in ITT vs per protocol analyses.

Safety:

More events in consumption group.

In five categories of interest

in which the frequencies were higher in the consumption

group: upper respiratory tract infection, viral skin infection, gastroenteritis, urticaria,

and conjunctivitis. Events in these

categories were generally mild or moderate and did not differ significantly in severity between

groups.

Among the

57 participants (9 randomly assigned to consumption

and 48 to avoidance) who had a positive response to the oral food challenge at 60 months, 14 had respiratory or cardiovascular signs and 9 received intramuscular epinephrine owing to

concerns about the severity of the allergic reaction

The peanut-specific IgG4:IgE ratio was calculated,

since it has been reported that this ratio may

additionally reflect immune modulation.

Participants randomly assigned to peanut consumption

who had a positive response to the oral

food challenge administered at baseline were instructed

not to eat peanuts but were included in the intention-to-

treat analysis. Only participants who adequately adhered

to treatment were included in the per-protocol

analysis.

Worst-case imputation performed.

Du Toit 2016

Effect of Avoidance on Peanut Allergy

after Early Peanut Consumption

Type of study:

RCT

Setting:

Single centre

Country: UK

Funding: National Institute of Allergy and Infectious

Diseases and others;

Inclusion criteria:

See du Toit 2016

All patient from the LEAP trial were instructed to avoid peanuts for 12 months.

N total at baseline: 556 (of 628 ITT group)

Avoidance: 282

Consumption: 274

N=550 in ITT analysis.

Important prognostic factors:

For example

age:

mean 61.3 months.

N=63 with peanut allergy from first trial.

All patient from the LEAP trial were instructed to avoid peanuts for 12 months.

Per protocol population:

Adherence was defined as

fulfilling all three of the following criteria: consumption

of 2 g or less of peanut on no more than 6 occasions (maximum of once per month);

consumption of 1 g of peanut or less on no more

than 12 occasions (maximum of twice per month);

and a cumulative ingestion of no more than 18

g of peanut.

Length of follow-up: 12 months (from age 60 months to 72 months)

Loss-to-follow-up:

Intervention:

Control:

Incomplete outcome data:

N=6

For 41 pt who did not undergo oral challenge, allergy/tolerance was determined on the basis of a diagnostic algorithm.

Outcome measures and effect size n (%):

Primary: percentage of participants with peanut allergy after 12 months of peanut avoidance.

The rate of adherence to avoidance

in the follow-up study was high (90.4% in the peanut-avoidance group and 69.3% in the peanut-consumption group). Peanut allergy at 72 months was significantly more

prevalent among participants in the peanut-avoidance group than among those in the peanut-consumption group (18.6% [52 of 280 participants] vs. 4.8% [13 of 270], P<0.001). Three new cases of allergy developed in each group, but after 12 months of avoidance there was no significant increase in the prevalence of allergy among participants in the consumption group (3.6% [10 of 274 participants] at 60 months and 4.8% [13 of 270] at 72 months, P = 0.25). Fewer participants in the peanut-consumption group than in the peanut-avoidance group had high levels of Ara h2 (a component

of peanut protein)–specific IgE and peanut-specific IgE; in addition, participants in the peanut-consumption group continued to have a higher level of peanut-specific IgG4 and a higher peanut-specific IgG4:IgE ratio.

More participants in the peanut-avoidance

group than in the peanut-consumption group

reported adverse events during the follow-up study (252 of 282 participants [89.4%] vs. 221 of

274 [80.7%]). Eczema, lower respiratory tract infection,

myopia, and gastroenteritis were reported more frequently among participants in the peanut-

avoidance group than among those in the peanut-consumption group

12-month period of peanut avoidance was not associated with an increase in the prevalence of peanut allergy.

Follow up study du Toit 2015.

Fleischer 2015

Consensus communication on early peanut introduction

and the prevention of peanut allergy in high-risk infants

Type of study:

Consensus reaction on du Toit 2015

Setting:

European academy of allergy and clinical immunology, National Institute of Allergy and Infectious Diseases (US).

-

Length of follow-up:-

this communication’s guidance is limited to integrating the findings learned in the LEAP trial to

other similar high-risk children in more diverse settings

around the world. However, multiple guidelines have not recommended delaying allergen introduction in the general to

low-risk populations.

The LEAP study demonstrates that early peanut introduction

can be successfully carried out in a high-risk population (such

as the population defined in the LEAP trial). However, without

intervention by healthcare providers, there is the potential that such high-risk infants will remain at risk for delayed introduction of solids and allergenic foods into their diet, because of the widespread belief that such foods may exacerbate eczema.

Consensus reaction du Toit 2015

Greenhawt 2017

LEAPing through the looking glass: secondary analysis of

the effect of skin test size and age of introduction on

peanut tolerance after early peanut introduction

Type of study:

Secondary analysis on LEAP trial data

Setting:

Single centre data from LEAP trial

Country: UK

Funding:

Inclusion criteria:

All 640 individuals

from the LEAP study included in the dataset with complete

data available for nrolment and 60-month oral food challenge

(OFC) outcomes to determine ultimately if the subject was peanut tolerant or peanut allergic were included for analysis.

N total at baseline: 640

Intervention:

Control:

Secondary analysis was conducted on the publically available LEAP

dataset, exploring relationships between peanut tolerance, baseline peanut/egg

sensitization, eczema severity/duration, age of introduction, gender, and race.

Length of follow-up:

60 months

Loss-to-follow-up:

-

Outcome measures and effect size n (%):

relationship between peanut wheal size and challenge outcome, maintaining the

trial stratification of negative (0 mm) peanut skin tests (n = 542) vs a combined group of all infants with ‘positive’ (1–4 mm) peanut skin tests (n = 98), which assumes homogeneity

of wheal size from 1 to 4 mm and clinical significance

of 1 and 2 mm sensitization, despite an established convention

of clinical significance at 3 mm or greater.

Multiple regression model to explore influence of peanut skin test and sIgE, egg skin test an dsIgE, age, eczema severity and duration, race, gender on odds of successful peanut OFC at month 60.

In univariate subgroup analysis, nearly 70% of those with a 3- to 4-mm wheal had successful peanut OFC irrespective of their randomization arm, and the overall occurrence of unsuccessful OFC was lower in both the 1–2 and 3–4 mm subgroups among the early introduction arm compared with the avoidance arm.

The subgroup effects

strongly support early peanut introduction and better highlight

that the true value of the prerandomization peanut skin

test wheal size and eczema severity was of most importance

in predicting OFC outcome among the avoidance group.

This distinctly highlights worse and divergent outcomes for

those children randomized to avoid peanut at each incremental

peanut wheal size (or SCORAD score) vs those who had

early introduction.

The highest predicted probability of peanut tolerance

occurred with peanut introduction between 6 and 11 months

of life, which withstood sensitivity analysis. Arguably, the

probability of tolerance is not lower than 85% with introduction

at 4 and 5 months even in the most conservative model,

which would be supportive of a policy suggesting peanut

should be introduced starting as early as 4–6 months of life.

However, peanut introduction between 6 and 11 months of life

was consistently associated with better outcome (~95% probability

of tolerance, with a very narrow 95% CI) in all models.

Data of Du Toit 2015

Same limitations as in initial trial

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up +

Outcome measures and effect size

Results

Comments

Bellach 2017

Randomized placebo-controlled trial of hen’s egg

consumption for primary prevention in infants (HEAP study)

Type of study:

Randomized placebo-controlled trial

Setting: the Department for

Pediatric Allergology and Immunology, Charité Berlin, Germany

Country: Germany

Source of funding: Supported by FAAN (Food Allergy & Anaphylaxis Network), and pina e.V. (Prevention

and Information Network for Allergy/Asthma, Germany).

Inclusion criteria: a gestational age of ≥34 weeks and a birth weight of ≥2.5 kg. age 4-6 months. Not sensitized against hen’s egg (hen’s egg–specific IgE levels of <0.35 kUA/L)

Exclusion criteria: if the child’s mother was <18 years or if parents had insufficient

language skills.

N total at baseline: 383

Intervention: 184

Control: 199

23 infants with hens egg specific IgE underwent double blind placebo controlled food challenge.

Important prognostic factors1:

For example

age:

I: 21.9 weeks

C: 22.3 weeks

Sex:

I: 56,2% M

C: 57,1% M

Groups comparable at baseline? Yes

Egg white powder.

(The verum powder contained pasteurized egg white equal in its allergenicity to raw hen’s egg and manufactured by Ovobest (Neuenkirchen-Vörden, ermany))

1½ MS contained 2.5 g of hen’s egg protein, which is equivalent to one third of an egg.

The study powder was administered orally 3 times a week by mixing the allocated study powder with solid baby food using a 10-mL measuring spoon (MS), starting with ½ MS in the first week and 1 MS in the second week and continuing with 1½ MS from the third week of intervention until 12 months of age.

Rice powder.

(The placebo powder contained rice manufactured by Milupa (Friedrichsdorf, Germany))

Parents in both groups were instructed to follow an egg-free diet for their child, including avoidance of egg-containing products.

We performed an analysis of all randomized

participants who could be assessed for the primary outcome irrespective of

whether some of these patients might have switched or discontinued treatment

before the final visit (modified intent-to-treat analysis).

The per-protocol population included participants who could be assessed for the primary outcome and who adhered to the assigned regimen

Length of follow-up:

Age 12 months

Loss-to-follow-up:

Intervention:

Control:

Incomplete outcome data:

I: 42

C: 43

ITT:

I: 142

C: 156

PP:

I: 124

C: 152

Outcome measures and effect size (include 95%CI and p-value if available):

The primary outcome was defined as hen’s egg sensitization (specific IgE >0.35 kUA/L in serum) at 12 months of age. The secondary outcome was

defined as hen’s egg allergy confirmed by clinical reactions to pasteurized

hen’s egg on oral food challenge tests.

Oral food challenges

were conducted in all children newly sensitized against hen’s egg: as

titrated DBPCFCs in the placebo group, as described above, and as open challenges with one dose containing 7.5 g of hen’s egg protein

in the verum group.

Among 406 screened infants, 23 (5.7%) had hen’s egg–specific IgE before randomization. Seventeen of 23 underwent subsequent double-blind, placebo-controlled food

challenges, and 16 were confirmed as allergic, including 11 with

anaphylactic reactions. Of the 383 nonsensitized infants (56.7%

male), 184 were randomized to verum and 199 to placebo.At 12 months of age, 5.6% of the children in the verum group were

hen’s egg sensitized versus 2.6% in the placebo group (primary

outcome; relative risk, 2.20; 95% CI, 0.68-7.14; P 5.24), and

2.1% were confirmed to have hen’s egg allergy versus 0.6% in the placebo group (relative risk, 3.30; 95% CI, 0.35-31.32; P 5.35).

We found no evidence that consumption of hen’s egg starting at 4 to 6 months of age prevents hen’s egg sensitization or allergy. In contrast, it might result in frequent allergic reactions in the community considering that many 4- to 6-month-old infants were already allergic to hen’s egg.

The trial was

stopped early because of the allergic reactions at first exposure to

the study powder in the verum group despite screening for pre-existing hen’s egg–specific IgE along with the high rate of

hen’s egg sensitization and allergy at the screening visit.

High prevalence of hen egg’s sensitization.

Two third of the allergic infants had anaphylactic reaction.

General population.

Natsume 2017

Two-step egg introduction for prevention of egg allergy in

high-risk infants with eczema (PETIT): a randomised,

double-blind, placebo-controlled trial

Type of study:

randomised, double-blind, placebo-controlled trial

Setting: 2 centres

Country: Japan

Funding: The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Inclusion criteria:

Infants 4-5months of age with atopic dermatitis meeting

Hanifi n-Rajkas’ diagnostic criteria

Exclusion criteria:

Being born before 37 weeks of gestational age, experience of

ingestion of hen’s eggs or egg products, history of immediate allergic reaction to hen’s eggs, history of non-immediate

allergic reaction to a particular type of food, and complications of any severe disease

N total at baseline: 147

Intervention: 73

Control: 74

Infants were randomly assigned

(block size of four; stratified by institution and sex) to early introduction of egg or placebo (1:1)

Important prognostic factors:

SCORAD:

I: 27.5 (10.3-38.2)

C: 42 (22.1-52.3)

Egg white specific IgE:

I: 0.73 (0.17-5.55)

C: 4.46 (0.47-24.8)

More than 90% of participants received breastfeeding at

6 months of age.

orally 50 mg of heated egg powder (=25mg egg protein) and squash per day from 6 months to 9 months of age and 250 mg (=125mg egg protein) per day thereafter until 12 months of age

eczema was aggressively treated at entry and control without exacerbations was controlled. (topical corticosteroids and emollients)

On first dosage at 6 months and 9 months clinical oral food challenge (7g heated whole egg powder)

a powder consisting of squash, for which was matched colour and volume with the egg powder

Length of follow-up: from 6 to 12 months of age

Loss-to-follow-up:

Exclusion due to not following protocol, not meeting diagnostic criteria atopic dermatitis:

I: 11
C: 14

(primary analysis)

Incomplete outcome data:

Exclusion due to inadequate protocol adherence/allergy:

I: 24

C: 27

(per protocol)

Outcome measures and effect size n (%):

Primary: proportion of patients with hen’s egg allergy confirmed by open oral food challenge at 12 months of age.

SCORAD and POEM eczema severity.

Adverse events

Serum concentrations of IgE, IgG1, IgG4, IgA to egg white and ovomucoid and thymus and activation-regulated chemokine (TARC) concentration

In the primary analysis population, five (8%) of 60 participants had an egg allergy in the egg group compared with 23 (38%) of 61 in the placebo group (risk ratio 0·221 [0·090–0·543]; p=0·0001).

In the per-protocol analysis, two (4%) of 46 participants in the

egg group were diagnosed as having hen’s egg allergy

compared with 19 (38%) of 50 participants in the placebo group The risk difference was 33·7% (95% CI 19·0–48·3) and the risk ratio was

0·114 (0·028–0·464; p<0·0001).

The two participants who developed egg allergy in the egg group in the per-protocol analysis had a higher POEM score than did the other participants.

Adverse events:

Hospital admission: 6 in intervention group vs 0 in control group (p=0.022).

No participants withdrew because of

adverse reactions caused by the trial powder.

infants who showed acute signs of

angioedema of the lip or vomiting were able to continue taking the trial egg powder without developing the same symptom again.

Ovomucoid-specifi c IgE concentration at 12 months of

age in the egg group was lower than that in the placebo

group, whereas ovomucoid-specifi c IgG1, IgG4, and IgA

concentrations at 12 months of age were higher in the

egg group than in the placebo group.

Egg white-specific IgE and ovomucoid-specifi c IgE and IgG4 concentrations of participants with egg allergies in the placebo group were increased compared with those without egg allergies

POEM scores during the intervention were low

in both groups

Eczema was actively treated.

We stopped recruitment early at the

request of the IDSMC because the interim analysis of the

first 100 participants detected a significant difference between the two groups in the primary outcome.

>risk of selection bias

Difference in baseline characteristics: eczema severity and serum IgE >after sensitivity analyses no significant difference between subgroups in non-sensitized group

Palmer 2013

Early regular egg exposure in infants with eczema:

A randomized controlled trial

(STAR trial)

Type of study:

RCT

Setting: 2 centres

Country: Australia

Funding:

Inclusion criteria:

Singleton term infants with symptoms of moderate-to-severe eczema

(determined by using a standardized SCORAD20 score of >15) were recruited

at 4 months of age from 2 Australian centers

Exclusion criteria:

Commenced solids before 4 months of age or any previous known direct ingestion of egg

N total at baseline: 86

Intervention: 49

Control: 37

Groups comparable at baseline?

Yes

Important prognostic factors:

SCORAD:

I :33.8 (29.2-37.5)

C: 32.7 (25-39.5)

1 teaspoon (= 0.9 g of egg protein, which is quivalent to one sixth of an

egg) per day of pasteurized raw whole egg powder

until 8 months of age (4 months)

the study powder was administered orally by mixing

the powder with infant rice cereal.

Egg free diet

At 8 months of age: medically supervised

cooked egg exposure (2 teaspoons of mashed

hard-boiled whole egg (equivalent to one sixth of an egg))

At 12 months of age, all infants had a medically supervised pasteurized raw

egg challenge in which the infant was given half of a whole egg

teaspoon

(5 0.25 g of rice protein) per day of rice flour powder

the study powder was administered orally by mixing

the powder with infant rice cereal.

Egg free diet

Length of follow-up: telephone contact month 5,6,7,10 of age. Hospital visit at 8 and 12 months of age.

Loss-to-follow-up:

I: 7 withdrew consent

C: 2 withdrew consent

Incomplete outcome data:

9 had no skin prick test, 19 had OFC.

Any infant whose powder use was ceased was

still included in all follow-up assessments.

Outcome measures and effect size n (%):

The primary outcome was

IgE-mediated egg allergy at 12 months, as defined based on the results of an observed pasteurized raw egg challenge and skin

prick tests.

A high proportion (31% [15/49]) of infants randomized to receive egg had an allergic reaction to the egg powder and did not continue powder ingestion. At 4 months of age, before any known egg ingestion, 36% (24/67) of infants already had eggspecific IgE levels of greater than 0.35 kilounits of antibody

(kUA)/L. At 12 months, a lower (but not significant) proportion

of infants in the egg group (33%) were given a diagnosis of

IgE-mediated egg allergy compared with the control group

(51%; relative risk, 0.65; 95% CI, 0.38-1.11; P = .11).

No participating infants had a positive SPT response

to rice at 12 months of age.

Adverse events:

Serious AE: n=4

I: n=1 with food protein induced enterocolitis, n=1 anaphylaxis

C: n=2 anaphylaxis

First trial

Sample size not reached due to early study termination because of rate of allergic reactions/anaphylaxis.

Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up +

Outcome measures and effect size

Results

Comments

Perkin 2016

Randomized Trial of Introduction

of Allergenic Foods in Breast-Fed Infants (EAT trial)

Type of study:

RCT

Setting: single site

Country: UK

Funding:

Inclusion criteria:

Exclusion criteria:

N total at baseline: 1303

Intervention: 652

Control: 651

ITT groups:

I: 567

C: 595

The intention-to-treat analysis for the primary

outcome included all the participants who

had data that could be evaluated.

The per-protocol population included all participants

who adhered adequately to the assigned regimen.

Important prognostic factors:

For example

age:

median 3.4 months.

significantly higher rate of birth by cesarean section in the early-introduction

group than in the standard-introduction

group

76% of the participants in the standard-

introduction group did not have eczema at

3 months of age, and yet they accounted for 38% of the participants in the standard-introduction

group with food allergy to one or more of the

foods tested

Early introduction:

Skin prick test

Introduction 6 allergens (first cow’s milk, random others, last wheat).

>pos SPT: oral food challenge 2g protein of 1 allergen.

>neg SPT or neg OFC: continue 2g of the allergen twice weekly.

>pos OFC: avoid food but continue other allergens.

Breast feeding at least to 5 months of age.

consumption

of at least five of the early-introduction foods,

for at least 5 weeks between 3 and 6 months of

age, of at least 75% of the recommended dose

(i.e., 3 g per week of allergenic protein).

Standard introduction:

Exclusively breast fed to approximately 6 months of age; after 6 months of age introduction allergenic food according to parental discretion.

Breast feeding at least to 5 months of age

No consumption of peanut, egg, sesame, fish, wheat before 5 months of age and consumption of less than 300 mL formula milk between 3-6 months of age.

Length of follow-up:

Each month to 1 year of age, every 3 months to 3 years of age.

Loss-to-follow-up:

Intervention:

Control:

A total of 91.3% of the participants attended the

final clinic visit, 90.0% of whom attended within

the visit window (by 4 years of age). A total of

94.0% of the participants’ families completed the 3-year questionnaire.

Outcome measures and effect size n (%):

Prim outcome: food allergy 1 or more allergens between 1 year and 3 years of age.

Sec outcomes: allergy to individual foods, pos skin prick test, adherence, safety, dose variation

A food allergy developed in 74 participants. In 70 of these participants (39 in the standard-introduction group and 31 in the early-introduction group), based on double blind, placebo controlled food challenge, and in 4

(3 in the standard-introduction group and 1 in early-introduction group), diagnoses were made on the basis of an allergic reaction that resulted

in a wheal size of 5 mm or more in diameter on skin-prick testing.

A diagnosis of any food allergy was significantly associated with the presence of eczema at enrollment,

nonwhite race, and having siblings.

ITT:

The rate of the primary outcome was non-significantly lower in the early-introduction group than in the standard-introduction group

(5.6% [32 of 567 participants] and 7.1% [42 of 595], respectively), which represented a relative

risk of 0.80 (95% confidence interval [CI], 0.51 to 1.25; P = 0.32), with the point estimate representing

a 20% lower prevalence in the early-introduction group.

The prevalence of allergy

to more than one food was non-significantly lower in the early-introduction group than in the standard-introduction group (P = 0.17)

peanut allergy, egg allergy nonsignificant lower relative risk in early introduction group. For other early introduction foods, the prevalence of allergy was 0.7% or less in each group.

Per protocol:

In the per-protocol analysis, the rate of the primary outcome was significantly lower in the early-introduction group than in the standard introduction group (2.4% [5 of 208 participants] vs. 7.3% [38 of 524]).

Participants in the two trial groups who did not adhere to the protocol or whose adherence could not be evaluated had rates of allergy that

were similar to the rate among the participants in the standard-introduction group who adhered

to the protocol.

Skin prick test:

In the intention-to-treat

analyses, the risk of a positive skin-prick test to any food was 22% lower in the early-introduction group than in the standard-introduction

group at 12 months of age (P = 0.07) and 12% lower at 36 months of age (P = 0.47); both differences were nonsignificant.

Positive skin-prick tests

to wheat occurred significantly less frequently in the early-introduction group than in the standard-introduction group at 12 months (1.3% vs. 3.2%, P = 0.03) and at 36 months of age (1.4% vs. 3.2%, P = 0.04). The prevalence of positive skinprick

tests at 12 months and 36 months of age was nonsignificantly lower in the early-introduction group than in the standard-introduction group for every other food, with the exception of fish at 12 months of age, which had a higher prevalence in the early-introduction group.

In the per-protocol analyses, the early-introduction group had a significant 42% lower rate

of positive skin-prick tests to any food than the standard-introduction group at 12 months of age

(P = 0.01) and a significant 67% lower rate at 36 months of age (P = 0.002).

At 36 months of age, the effect was greater; the relative risk of a positive result on skin-prick testing was 67%

lower in the early-introduction group than in the standard-introduction group with respect to peanut (P = 0.007), 48% lower with respect to

egg (P = 0.10), 88% lower with respect to milk (P = 0.02), 100% lower with respect to both sesa

me (P = 0.04) and fish (P = 0.17), and 69% lower with respect to wheat (P = 0.12).

Adherence: 92.9%

Variations in the number of foods consumed, the weekly dose of each food consumed, and the

number of weeks during which this dose was consumed resulted in a rate of adherence in the early-introduction group that ranged from 6% to 81%. higher consumption was associated with a lower prevalence of allergy and sensitization to that food

Safety:

no cases of anaphylaxis with the introduction of foods at home in the early-introduction group.

Low per protocol adherence in early introduction group:

-Early introduction prevented the development of food allergy

-Reverse causality: infants with nascent food allergy were less likely to successfully consume the food because of aversive feeding behaviour

- bias leading to higher prevalence of atopy and food allergy among children outside per protocol analysis.