Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study
Sustained outcomes in oral immunotherapy for peanut allergy (POISED study): a large, randomised, double-blind, placebo-controlled, phase 2 study
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DOI：
10.1016/s0140-6736(19)31793-3
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发表时间：
2019-10-19
期刊：
影响因子：
168.9
通讯作者：
Nadeau, Kari C.
中科院分区：
文献类型：
--
作者：
Chinthrajah, R. Sharon;Purington, Natasha;Nadeau, Kari C.
背景对于花生过敏者建议避免饮食。我们在成人和儿童的一项随机长期研究中评估了花生过敏口服免疫疗法（OIT）的持续效果。方法在这项随机、双盲、安慰剂对照的2期研究中，我们招募了斯坦福大学肖恩N帕克过敏和哮喘研究中心的参与者（斯坦福大学，加利福尼亚州，美国）7-55岁花生过敏患者，双盲、安慰剂对照食物挑战结果呈阳性（DBPCFC; =阴性对照上方5 mm风团直径），花生特异性免疫球蛋白（IG）E浓度大于4 kU/L。参与者通过计算机化系统以2 × 2区组设计随机分配（2.4：1.4：1），以建立并维持4000 mg花生蛋白直到第104周，然后停止花生（花生-0组），以建立并维持4000 mg花生蛋白直到第104周，然后每天摄入300 mg花生蛋白（花生-300组）52周，或接受燕麦粉（安慰剂组）。在基线和第104、117、130、143和156周进行DBPCFC至4000 mg花生蛋白。药剂师根据随机计算机列表分配治疗。口服花生或安慰剂（燕麦）粉，并通过使用外观和感觉与花生粉相似的燕麦粉和鼻夹（如耐受）来掩盖味道，来掩盖参与者和研究小组。统计学家也设盲。主要终点是在104周和117周时通过DBPCFC的参与者比例，累积剂量为4000 mg。在意向治疗人群中进行主要疗效分析。在意向治疗人群中评估安全性。在2014年4月15日至2016年3月2日期间，在评估的152名个体中，我们招募了120名参与者，他们被随机分配到花生-0（n=60），花生-300（n=35）和安慰剂组（n=25）。ClinicalTrials.gov 21名（35%）花生-0组参与者和1名（4%）安慰剂组参与者在104周和117周时通过了4000 mg挑战（比值比[OR] 12.7，95% CI 1.8-554.8; p=0.0024）。在整个研究中，最常见的不良事件是轻度胃肠道症状，120名患者中有90名出现这种症状（花生-0组50/60，花生-300组29/35，安慰剂组11/25）和皮肤病，120例患者中有50例（花生-0组26/60，花生-300组15/35，安慰剂组9/25）。所有组的不良事件均随时间推移而减少。在3年的研究中，花生组的两名参与者发生了严重的不良事件。在花生-0组中，60名参与者中有8名（13%）在第156周通过了DBPCFC，较高的基线花生特异性IgG 4与IgE比率和较低的Ara h 2 IgE和嗜碱性粒细胞活化反应与持续的无反应性相关。解释我们的研究表明，花生OIT可以脱敏与花生过敏的个人4000毫克花生蛋白，但停止，甚至减少到每天300毫克，可能会增加恢复花生的临床反应的可能性。由于基线血液检查与第117周的治疗结果相关，因此该研究可能有助于选择最佳患者进行该治疗。版权所有（C）2019 Elsevier Ltd.保留所有权利。
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; = 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.