Study of induction of Tolerance to Oral Peanut: a randomized controlled trial of desensitisation using peanut oral immunotherapy in children (STOP II)

我们建议研究一种治疗花生过敏的新方法，这种方法有可能大大改善患者的护理。花生过敏是致命的食物过敏反应的最常见原因，人口研究显示它影响2%的儿童，这意味着成千上万的英国儿童处于危险之中。自发性消退很罕见，患者有发生过敏反应和死亡的风险。食物选择受限带来的永久恐惧和不便，以及需要随时携带紧急肾上腺素注射剂，导致生活质量显著下降。除了建议患者避免吃花生外，这种情况没有治疗方法。按照目前的做法，每年有高达55%的儿童发生意外反应，其中相当多的儿童严重死亡。显然需要开发一种新的疾病修饰治疗。这是一项基于成功的试点研究的新疗法的确定性研究。这种治疗方法可以在整个NHS中广泛使用，对患者有相当大的好处。我们将招募104名花生过敏受试者，并使用减少偏倚的方法将他们分配到治疗组和对照组。对照组将被建议在5个月的等待期内避免花生（即目前的标准做法）。对于治疗组，我们将在5个月内小心地通过口腔给予增加量的花生粉。在医院每2周增加一次剂量，在家中每天服用相同剂量。然后受试者接受一段时间的维持治疗，最高剂量为6周（appox. 5花生）。主要的结果测量是每组中对花生激发试验没有反应的受试者的比例（即过敏被“治愈”的比例）。之后，为了保持高道德标准并鼓励良好的依从性，在等待期后，对照组中的受试者也将接受治疗。其他结果将是干预前后生活质量评分的变化。将对血液实验室检查进行分析，以确定干预机制，确定预测成功治疗的生物标志物，并确定治疗可能成功的个体。初步研究证明，迄今为止完成方案的所有18名受试者均获得成功。它还表明，每日家庭治疗耐受性良好，未发生严重反应。参与的家庭说，这种疗法改变了他们的生活，反映在生活质量评分的提高上。上个月初步结果的发布引起了媒体的巨大积极关注，全球600多篇电视、广播和报纸文章报道了该研究。伦理方面的考虑包括最初的口服激发会引起令人不快的过敏反应的风险。然而，我们已经采取了许多预防措施，以确保这种情况不会发生（在我们的试点研究中得到证实）。这种风险被入组研究将为受试者带来显著益处的可能性所平衡，受试者在治疗后可能能够吃花生。我们已获得当地研究伦理委员会的许可，可以进行设计相似的初步研究。我们的团队非常适合进行这项研究。帕梅拉·尤恩博士和安德鲁·克拉克博士在临床和实验室政府资助的研究方面有着良好的记录。克拉克博士构思、发起、设计和实施了试点研究，并领导了目前的提案。我们的团队拥有必要的专业知识深度和广度，所有人都致力于完成成功的试点研究。统计设计和分析由剑桥医学统计研究所的创始主任Chris Palmer博士提供。研究结果将在科学会议、同行评审期刊和患者支持团体中传播。主要费用用于工作人员，包括一名全职临床研究员，负责进行口腔挑战和向上提升

We propose to study a new treatment for peanut allergy with the potential for major improvement in patient care. Peanut allergy is the commonest cause of fatal food-allergic reactions, population studies show it affects 2% of children, meaning tens of thousands of UK children are at risk. Spontaneous resolution is rare and patients are at risk of anaphylaxis and death. The perpetual fear and inconvenience surrounding restricted food choices and the requirement to carry emergency adrenaline injections at all times causes a significant reduction in quality of life. There is no treatment for this condition except to advise patients to avoid peanuts. With current practice up to 55% of children have accidental reactions every year, a significant number are severe and deaths occur. There is a clear need to develop a novel disease-modifying treatment. This is a definitive study of a new treatment based on a successful pilot study. This treatment could be made widely available across the NHS with considerable benefit for patients. We will recruit 104 peanut allergic subjects and allocate them to treatment and control groups using methods to reduce bias.The control group will be advised to avoid peanuts during a 5 month waiting period (i.e. the current standard practice).For the treatment group we will carefully administer increasing amounts of peanut flour by mouth over 5 months. Doses are increased every 2 weeks in hospital and the same doses taken daily at home. Subjects then receive a period of maintenance treatment with the highest dose for six weeks (appox. 5 peanuts). The main outcome measure is the proportion of subjects in each group who do not react to a peanut challenge test (i.e. the proportion iwhose allergy is 'cured'). Afterwards, to maintain a high ethical standard and encourage good compliance, after the waiting period, subjects in the control arm will also be offered the treatment. Other outcomes will be the change in quality of life score before and after intervention. Blood laboratory tests will be analysed throughout to define the mechanism of intervention, identify biomarkers which predict successful treatment and identify individuals in whom treatment is likely to be successful. The pilot study demonstrated success in all 18 subjects who have completed the protocol to date. It also showed that the daily home treatment is well tolerated and no severe reactions occurred. The families involved say the therapy has transformed their lives,reflected by increased quality of life scores. Publication of the initial results last month attracted enormous positive media attention and the study was covered by over 600 television, radio and newspaper articles world wide. Ethical considerations include the risk that the initial oral challenge will induce a unpleasant allergic reaction. However, we have taken many precautions to ensure that this does not occur (confirmed in our pilot study). This risk is balanced by the likelihood that enrolment in the study will confer a significant benefit to subjects, who may be able to eat peanut after treatment. We have obtained permission from the Local Research Ethics Committee to perform our pilot study which was of similar design. Our team is well placed to perform this research. Dr Pamela Ewan and Dr Andrew Clark have an excellent track record on delivering in clinical and laboratory Government funded research. Dr Clark conceived, initiated, designed and implemented the pilot study and led the current proposal. Our team have the necessary depth and breadth of expertise, all of whom have worked to complete the successful pilot study. Statistical design and analysis is provided by Dr Chris Palmer, Founding Director of the Institute of Medical Statistics in Cambridge. Results will be disseminated at scientific conferences, peer reviewed journals and via patient support groups. Major costs are for staff, consisting of a full time Clinical Fellow to perform the oral challenges and updo