Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study

Abstract

Background: Dietary avoidance is recommended for peanut allergies. We evaluated the sustained effects of peanut allergy oral immunotherapy (OIT) in a randomised long-term study in adults and children.

Methods: In this randomised, double-blind, placebo-controlled, phase 2 study, we enrolled participants at the Sean N Parker Center for Allergy and Asthma Research at Stanford University (Stanford, CA, USA) with peanut allergy aged 7-55 years with a positive result from a double-blind, placebo-controlled, food challenge (DBPCFC; ≤500 mg of peanut protein), a positive skin-prick test (SPT) result (≥5 mm wheal diameter above the negative control), and peanut-specific immunoglobulin (Ig)E concentration of more than 4 kU/L. Participants were randomly assigned (2·4:1·4:1) in a two-by-two block design via a computerised system to be built up and maintained on 4000 mg peanut protein through to week 104 then discontinued on peanut (peanut-0 group), to be built up and maintained on 4000 mg peanut protein through to week 104 then to ingest 300 mg peanut protein daily (peanut-300 group) for 52 weeks, or to receive oat flour (placebo group). DBPCFCs to 4000 mg peanut protein were done at baseline and weeks 104, 117, 130, 143, and 156. The pharmacist assigned treatment on the basis of a randomised computer list. Peanut or placebo (oat) flour was administered orally and participants and the study team were masked throughout by use of oat flour that was similar in look and feel to the peanut flour and nose clips, as tolerated, to mask taste. The statistician was also masked. The primary endpoint was the proportion of participants who passed DBPCFCs to a cumulative dose of 4000 mg at both 104 and 117 weeks. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT02103270.

Findings: Between April 15, 2014, and March 2, 2016, of 152 individuals assessed, we enrolled 120 participants, who were randomly assigned to the peanut-0 (n=60), peanut-300 (n=35), and placebo groups (n=25). 21 (35%) of peanut-0 group participants and one (4%) placebo group participant passed the 4000 mg challenge at both 104 and 117 weeks (odds ratio [OR] 12·7, 95% CI 1·8-554·8; p=0·0024). Over the entire study, the most common adverse events were mild gastrointestinal symptoms, which were seen in 90 of 120 patients (50/60 in the peanut-0 group, 29/35 in the peanut-300 group, and 11/25 in the placebo group) and skin disorders, which were seen in 50/120 patients (26/60 in the peanut-0 group, 15/35 in the peanut-300 group, and 9/25 in the placebo group). Adverse events decreased over time in all groups. Two participants in the peanut groups had serious adverse events during the 3-year study. In the peanut-0 group, in which eight (13%) of 60 participants passed DBPCFCs at week 156, higher baseline peanut-specific IgG4 to IgE ratio and lower Ara h 2 IgE and basophil activation responses were associated with sustained unresponsiveness. No treatment-related deaths occurred.

Interpretation: Our study suggests that peanut OIT could desensitise individuals with peanut allergy to 4000 mg peanut protein but discontinuation, or even reduction to 300 mg daily, could increase the likelihood of regaining clinical reactivity to peanut. Since baseline blood tests correlated with week 117 treatment outcomes, this study might aid in optimal patient selection for this therapy.

Funding: National Institute of Allergy and Infectious Diseases.

Figure 1.

Trial profile: ITT: intention-to-treat. DBPCFC: double-blind, placebo-controlled food challenge.

Figure 2.

Percentage of participants who tolerated cumulative peanut challenge dose of 900 mg, 1900 mg and 4 g by DBPCFC week and treatment arm for the ITT population. Number on the top of each bar is the number of participants. P-values based on Fisher’s exact test between peanut-0 (orange bar) and peanut-300 (blue bar), or, highlighted by brackets, comparisons between placebo and peanut-0. Although not noted in the figure, all comparisons between placebo and peanut-300 had P < 0.05. Further detailed percentages are provided below each panel. Peanut-0 = oral immunotherapy with peanut discontinuation arm; Peanut-300 = oral immunotherapy with peanut continuation arm (300 mg).

Figure 3.

Time until challenge failure. Drop in risk at the pre-104 time point refers to participants who did not reach the week 104 challenge (i.e., drop outs). Participants who passed the last performed challenge but did not complete the next challenge, or dropped out prior to the week 104 challenge, were censored at their last cumulative tolerated dose (denoted by the vertical tick in the Kaplan-Meier curve). Colored bands represent the 95% confidence intervals. Peanut-0 = peanut oral immunotherapy with peanut discontinuation arm; Peanut-300 = oral immunotherapy with peanut continuation arm (300 mg).

Figure 4.

Baseline basophil %CD63^high area under the curve by treatment arm and week 117 outcome (red = failure, green = success). Baseline CD63^high area under the curve by treatment arm and week 117 outcome for per-protocol participants. P-values were calculated using the Mann-Whitney U test. Peanut-0 = oral immunotherapy with discontinuation arm; Peanut-300 = oral immunotherapy with peanut continuation arm (300 mg).

Figure 5.

Hazard of study failure among baseline characteristics using dose and time to failure. Each characteristic was fit to a Cox proportional hazards model adjusting for treatment arm. An estimate above 1 (gray line) denotes a higher risk of treatment failure, while an estimate below 1 denotes a lower risk of study failure. Q-value is the FDR-adjusted P-value. Characteristics with significant Q-values are highlighted in red. BMI: body mass index.