Study Population

At screening, the median age of participants was 7.8 months (interquartile range, 6.3 to 9.1); the mean (±SD) age was 7.8±1.7 months. More male infants were randomly assigned to avoidance than to consumption (64.8% of the avoidance group vs. 55.2% of the consumption group were male infants). The groups were otherwise evenly balanced. Additional information on the baseline characteristics of the participants is presented in Table S2 in the Supplementary Appendix. The study had a 98.4% retention rate; 10 participants were withdrawn voluntarily by a parent or guardian or were lost to follow-up (Figure 1).

Peanut Consumption and Allergy in High-Risk Children

Among the 542 infants in the group with a negative result on the initial skin-prick test, 530 (97.8%) could be evaluated for the primary outcome and were included in the intention-to-treat analysis (Figure 1). At 60 months of age, 13.7% of the avoidance group and 1.9% of the consumption group were allergic to peanuts; this absolute difference in risk of 11.8 percentage points (95% confidence interval [CI], 3.4 to 20.3; P<0.001) represents an 86.1% relative reduction in the prevalence of peanut allergy (Figure 2).

All 98 children in the group with positive results on the initial skin-prick test were evaluated and were included in the intention-to-treat analysis. At 60 months of age, 35.3% of the avoidance group and 10.6% of the consumption group were allergic to peanuts; the absolute difference in risk of 24.7 percentage points (95% CI, 4.9 to 43.3; P=0.004) represents a 70.0% relative reduction in the prevalence of peanut allergy (Figure 2).

The per-protocol analysis included 500 infants from the group with negative results on the initial skin-prick test (94.3% of the 530 who could be evaluated) and 89 infants from the group with positive results on the test (90.8% of the 98 who could be evaluated) (Figure 1). The results in the per-protocol population were similar to those observed in the intention-to-treat population (Figure 2). The results of a worst-case imputation analysis in the intention-to-treat population were also consistent with the results of the main intention-to-treat analysis (Figure 2).

Primary prevention targets persons who are not sensitized to peanuts and secondary prevention targets those who are sensitized. In this study, 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) (Table S3 in the Supplementary Appendix). (Results of subgroup analyses according to race or ethnic group are provided in Table S12 in the Supplementary Appendix.)

Adherence

The median weekly consumption of peanut protein in the first 2 years of life in the avoidance group was 0 g, whereas the median in the consumption group was 7.7 g (interquartile range, 6.7 to 8.8). The results with respect to adherence were used to define the per-protocol population (Figure 1). Dust samples from participants' beds were obtained at month 60 from 423 of the 640 participants (66.1%) in the study population to provide an index of peanut exposure independent of parental reporting. The median level of peanut detected in the bed dust of participants in the avoidance group was 4.1 μg per gram of dust (interquartile range, 1.4 to 14.5), whereas the level in the consumption group was 91.1 μg per gram of dust (interquartile range, 27.2 to 362.0) (Fig. S2 in the Supplementary Appendix). For both measures of adherence, there were no significant differences between the cohort with negative results on the skin-prick test and the cohort with positive results (Tables S4 and S5 in the Supplementary Appendix).

Safety

No deaths occurred in the study. There were no significant differences in rates of hospitalization or serious adverse events between the avoidance group and the consumption group (Tables S6 and S7 in the Supplementary Appendix). Considering all adverse events, 99% of participants in each group reported at least one event, with more events recorded in the consumption group than in the avoidance group (4527 vs. 4287, P=0.02), according to a Poisson regression analysis (Table S8 in the Supplementary Appendix). With respect to adverse events for which frequencies differed between the two groups, we identified 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. The severity of the events was also similar in a comparison of participants with a peanut-specific IgE level below 0.1 kU per liter and those with a level of 0.1 kU per liter or higher (Table S9 in the Supplementary Appendix). (Additional data and discussion regarding adverse events are provided in the Results and Discussion sections in the Supplementary Appendix and in Table S9 and Fig. S3 in the Supplementary Appendix. All data on adverse events are also available in an interactive graphic at http://graphics.rhoworld.com/studies/leap/aes/explorer/.)

Response to Oral Food Challenge

Seven participants who were randomly assigned to the consumption group had a positive response to the oral food challenge at baseline and did not consume peanuts. At month 60, four of these participants had a positive response to an oral food challenge and three had a negative response.

Nine participants who were randomly assigned to peanut consumption subsequently discontinued consumption (Table S10 and the Results section in the Supplementary Appendix). At month 60, six of these participants had a positive response to the oral food challenge and three had a negative response.

The 7 participants randomly assigned to consumption who had a positive response to the oral food challenge at baseline had symptoms that were predominantly cutaneous during the challenge. Six were treated with an antihistamine and 1 was treated with an oral glucocorticoid. 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 (Table S11 in the Supplementary Appendix).

Immunologic Assessments

Figure 3. Figure 3. Immunologic Outcomes for the Peanut-Avoidance and Peanut-Consumption Groups at Baseline (4 to <11 Months of Age) and at 12, 30, and 60 Months of Age. Panel A shows wheal sizes after the peanut-specific skin-prick test and the levels of peanut-specific IgE in participants in the avoidance and consumption groups who met the per-protocol criteria. The solid black lines show the group mean over the course of the study period; the mean wheal size after the peanut-specific skin-prick test differed significantly between the randomized groups at all time points after baseline (P=0.002 at 12 months and P<0.001 at 30 months and 60 months). The thin red lines represent the trajectory of the development of allergic responses among participants who were allergic at 60 months of age. Panel B shows the levels of peanut-specific IgG and IgG4 and the peanut-specific IgG4:IgE ratio over the course of the study period. The means of each of these measures differed significantly between the two study groups at all postbaseline time points (P<0.001). The log 10 of the ratio of peanut-specific IgG4:IgE was calculated after the peanut-specific IgG4 levels were converted from micrograms per liter to nanograms per milliliter and the peanut-specific IgE levels were converted from kilo unit per liter to nanograms per milliliter with the use of the formula IgG4÷(IgE×2.4).

Peanut-specific immunoglobulins were measured in serum samples at baseline (at which time participants were between 4 months and 11 months of age) and when the children were 12, 30, and 60 months of age. Figure 3A shows wheal size and level of peanut-specific IgE in participants who met the per-protocol criteria. A significant increase from baseline in wheal size was seen only in the peanut-avoidance group. Participants who were allergic to peanuts at month 60 showed a more pronounced increase in wheal size over time. These participants also had higher peanut-specific IgE levels. Although peanut-specific IgE levels increased over time in both the peanut-avoidance and peanut-consumption groups, there were fewer participants in the consumption group with very high IgE levels at 12, 30, and 60 months (Fig. S4 in the Supplementary Appendix).

Figure 3B shows the levels of peanut-specific IgG and IgG4 and the IgG4:IgE ratio. The levels of peanut-specific IgG and IgG4 were higher in the consumption group than in the avoidance group. Peanut-specific IgG4 levels increased over time in both groups, but these changes were significantly larger in the consumption group (P<0.001). The ratio of peanut-specific IgG4 to IgE increased up to 30 months of age in the consumption group but was relatively constant in the avoidance group. At month 60, the IgG4:IgE ratio in nearly all the participants with peanut allergy in the avoidance group fell below the mean ratio for the group.

Some participants in the per-protocol analysis who were allergic at month 60 had elevated levels of peanut-specific IgE as early as 12 months of age. At month 60, all the participants in the peanut-avoidance group who had peanut-specific IgE levels of more than 10.0 kU per liter were allergic to peanuts, regardless of their level of peanut-specific IgG4. All other allergic participants had levels of peanut-specific IgE between 0.1 and 10 kU per liter and levels of IgG4 that were less than 1000.0 μg per liter. (Fig. S5 in the Supplementary Appendix shows contour diagrams of the distribution of peanut-specific IgE in relation to peanut-specific IgG4 over time in participants who met the per-protocol criteria. Fig. S5 also shows that levels of peanut-specific IgE did not exceed 100.0 kU per liter in the peanut-consumption group. Peanut-specific IgG4 levels in this group rose early and continued to increase through 60 months of age.)