Enrollment and Characteristics of the Participants

A total of 628 participants completed the primary trial (314 participants in the peanut-avoidance group and 314 in the peanut-consumption group) and had peanut-allergy outcomes that could be evaluated; these participants were eligible to enroll in the follow-up study. From May 26, 2011, to May 29, 2014, we enrolled 556 of these participants (88.5%; 282 participants in the peanut-avoidance group and 274 in the peanut-consumption group) in the follow-up study. Of these, 550 participants (280 in the peanut-avoidance group and 270 in the peanut-consumption group) had a peanut-allergy outcome that could be evaluated in the follow-up study and were included in the intention-to-treat analysis (Fig. S1 in the Supplementary Appendix).

The mean age of the participants at enrollment was 61.3 months. Of the 64 participants in the primary trial who had peanut allergy, 63 enrolled in the follow-up study. Additional characteristics of the participants in the primary trial who enrolled in the follow-up study and those who did not enroll are provided in Table S1A and S1B in the Supplementary Appendix.

Determination of Peanut Allergy

Among the 550 participants in the intention-to-treat population, determination of peanut allergy was made by means of an oral peanut challenge in 515 (93.6%). Among the 41 participants who did not undergo an oral challenge, we determined on the basis of a diagnostic algorithm that 28 participants had a peanut allergy and 7 were tolerant (Fig. S2 in the Supplementary Appendix). A determination could not be made for 6 participants. Further details regarding these participants who did not have primary-outcome data (and were not included in the intention-to-treat population) are shown in Table S2A and S2B in the Supplementary Appendix.

Adherence

A total of 223 of 282 participants who had been assigned to the peanut-avoidance group in the primary trial (79.1%) and 127 of 274 who had been assigned to the peanut-consumption group in the primary trial (46.4%) reported complete peanut avoidance during the follow-up period (Table S3 in the Supplementary Appendix). A total of 32 participants in the peanut-avoidance group (11.3%) and 63 in the peanut-consumption group (23.0%) reported consuming some peanut but still met the per-protocol definition; 8 participants in the peanut-avoidance group (2.8%) and 65 in the peanut-consumption group (23.7%) consumed too much peanut to meet the per-protocol definition.

Dust samples from participants’ beds were obtained at month 72 from 180 of 282 participants (63.8%) in the peanut-avoidance group and from 171 of 274 (62.4%) in the peanut-consumption group. In the peanut-avoidance group as a whole (those who met the per-protocol criteria for the follow-up study and those who did not), the median concentration of peanut protein in bed dust was 4.1 μg per gram at 60 months, as compared with 4.6 μg per gram at 72 months (Fig. S3 in the Supplementary Appendix). In the peanut-consumption group as a whole, the median concentration declined from 95.2 μg per gram at 60 months to 10.5 μg per gram at 72 months (Fig. S3 in the Supplementary Appendix). Participants in the peanut-consumption group who met the per-protocol criteria for the follow-up study had a greater decline in the concentration than did those in the peanut-consumption group as a whole and also a greater decline than those participants in the peanut-consumption group who did not meet the per-protocol criteria — from 75.9 μg per gram to 6.3 μg per gram, which is a level similar to the concentration in the peanut-avoidance group at 60 months.

Evidence for Unresponsiveness to Peanut

Figure 1. Figure 1. Primary Outcome. The prevalence of peanut allergy at 72 months of age is shown among participants who had a negative result on the skin-prick test (SPT) at the baseline visit in the primary trial, among those who had a positive result at the baseline visit, and in both groups combined. In the primary trial, participants at high risk for allergy had been randomly assigned to consume peanuts beginning in the first 11 months of life (peanut-consumption group) or avoid peanuts (peanut-avoidance group). Panel A shows the prevalence of peanut allergy at 60 months of age among only the participants in the primary trial who enrolled in the follow-up study. Panel B shows the prevalence of peanut allergy at 72 months of age among participants in the follow-up study who were included in the intention-to-treat analysis (i.e., all enrolled participants in the follow-up study who had a peanut-allergy outcome that could be evaluated). Panel C shows the prevalence of peanut allergy at 72 months of age among participants who met the per-protocol criteria in both the primary trial and the follow-up study. The main per-protocol criterion in the primary trial was adequate adherence to the randomized assignment to consume or avoid peanuts; the main per-protocol criterion in the follow-up study was adequate adherence to avoidance of peanut protein over a period of 12 months.

At 72 months, among the 550 participants in the intention-to-treat population, 18.6% of the participants in the peanut-avoidance group (52 of 280 participants) and 4.8% of those in the peanut-consumption group (13 of 270) had peanut allergy (P<0.001) (Figure 1). The findings remained significant in analyses that used worst-case imputation or that excluded participants who did not undergo an oral challenge (P<0.001) (Fig. S4 in the Supplementary Appendix). In the peanut-consumption group, the percentage of participants with peanut allergy was 3.6% (10 of 274 participants) at 60 months and 4.8% (13 of 270) at 72 months (P=0.25).

A total of 445 participants met the per-protocol criteria in both the primary trial and the follow-up study. At 72 months, 19.2% of the participants in the peanut-avoidance group had peanut allergy and 2.1% of those in the peanut-consumption group had peanut allergy (P<0.001) (Figure 1).

We also assessed the percentage of participants with peanut allergy according to the degree of peanut consumption during the follow-up study among participants who met the per-protocol criteria in the primary trial (Table S3 in the Supplementary Appendix). Among participants who reported no peanut consumption during the follow-up study, the percentage of those with allergy was 21.5% (48 of 223 participants) in the peanut-avoidance group and 2.4% (3 of 127) in the peanut-consumption group (P<0.001).

Safety

Overall, 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 (Table S4 in the Supplementary Appendix).

Immunologic Assessments

Figure 2. Figure 2. Immunologic Outcomes in the Peanut-Avoidance and Peanut-Consumption Groups, from Baseline to 72 Months of Age. Data are shown for participants who met the per-protocol criteria for both the primary trial and the follow-up study. Panel A shows the Ara h2–specific and peanut-specific IgE titers and wheal sizes on skin-prick testing for peanut. (Ara h2 is a component of peanut protein.) The level of Ara h2–specific IgE was assessed in all available participants who had a peanut-specific IgE level that was greater than or equal to 0.1 kU per liter at any visit (approximately 60% of the participants). Panel B shows peanut-specific IgG4 levels and IgG4:IgE ratios. The solid black lines show the group mean over the course of the study period. The thin red lines represent the trajectory among participants who had a peanut allergy at 72 months of age. Dots represent individual participants (blue indicates that the participant did not have peanut allergy, and red indicates allergy at 72 months). The gray shading represents the density of the distribution of the dots for participants who met the per-protocol criteria for both the primary trial and the follow-up study. The density of the distribution facilitates visual comparisons over time and between groups, which is not easily achievable with display of the individual dots alone, owing to a large amount of over-plotting. The log 10 of the ratio of peanut-specific IgG4:IgE was calculated after 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]).

As expected, participants with peanut allergy at 72 months had higher levels of Ara h2–specific IgE and peanut-specific IgE and larger wheal size on skin-prick testing with peanut extract than participants who did not have peanut allergy (Figure 2A; and Fig. S5A, S5B, and S5D in the Supplementary Appendix). The mean levels of Ara h2–specific IgE declined significantly in the peanut-consumption group from 30 months to 60 months during the primary trial (P<0.001) (Figure 2A, and Fig. S5A in the Supplementary Appendix) and remained low at 72 months in the follow-up study. In contrast, the mean levels of Ara h2–specific IgE in the peanut-avoidance group in the primary trial were stable over time and were significantly higher than the levels in the peanut-consumption group at 60 months and at 72 months (P<0.001) (Figure 2A, and Fig. S5A in the Supplementary Appendix). The mean wheal size on skin-prick testing remained smaller in the peanut-consumption group than in the peanut-avoidance group at month 72 (P<0.001) (Figure 2A, and Fig. S5B in the Supplementary Appendix).

After the yearlong period of peanut avoidance, the peanut-specific IgG4 levels continued to be higher in the peanut-consumption group than in the peanut-avoidance group (P<0.001) (Figure 2B, and Fig. S5C in the Supplementary Appendix), despite a decline that started before the participants in the peanut-consumption group stopped eating peanuts. The ratio of peanut-specific IgG4:IgE also continued to be significantly higher in participants in the peanut-consumption group than in those in the peanut-avoidance group (Figure 2B).

Immunologic Changes in Participants Whose Allergy Outcome Changed

Figure 3. Figure 3. Immunologic Outcomes According to Differing or Stable Allergy Status between Months 60 and 72. Participants were categorized as “stayed allergic,” “stayed tolerant,” “became allergic,” or “no longer allergic.” Shown are the Ara h2–specific IgE antibody levels, peanut-specific IgE level, wheal size on skin-prick testing for peanut, peanut-specific IgG4 level, and IgG4:IgE ratios at the five assessments during the primary trial and the follow-up study. Data are shown only for participants who met the per-protocol criteria in both the primary trial and the follow-up study. At month 72, a total of 46 participants in the peanut-avoidance group and 1 in the peanut-consumption group were determined by the investigators to be still allergic, 202 in the peanut-avoidance group and 186 in the peanut-consumption group were still not allergic, 3 in the peanut-avoidance group and 3 in the peanut-consumption group became allergic, and 4 in the peanut-avoidance group and 0 in the peanut-consumption group no longer had allergy. Lines represent population means. The log 10 of the ratio of peanut-specific IgG4:IgE was calculated after 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]).

New allergy developed in three participants in the peanut-consumption group (1.1%) and in three in the peanut-avoidance group (1.1%) between month 60 and month 72 (Figure 3). The ratio of peanut-specific IgG4:IgE declined between month 60 and month 72 in all six participants (Table S6A in the Supplementary Appendix).

In addition, four participants in the peanut-avoidance group who had peanut allergy at month 60 did not have an allergic status by month 72. Their wheal size on skin-prick testing declined, although other immunologic variables remained stable (Figure 3, and Table S6B in the Supplementary Appendix).