Title: The Grown Up Peanut Immunotherapy (GUPI) study: a single arm phase II efficacy study of oral immunotherapy (OIT) in adults with peanut allergy
Funder: Department of Health and Social Care

Abstract: Peanut allergy is a common, mostly lifelong disorder associated with a significant risk of severe allergic reactions that can be fatal. Onset is commonly in childhood, but may also occur in adulthood. Constant vigilance and fear of reactions affects quality of life. Reactions in adults can be more severe than in children (odds ratios 8.9 for reduced consciousness; 3.7 for pharyngeal oedema; 2.0 for acute bronchospasm; see reference 1). There is no preventative treatment for peanut allergy in adults: management is reliant on avoidance and timely treatment of acute reactions. A number of phase II trials have shown efficacy of peanut oral immunotherapy (OIT) in children. Peanut OIT involves feeding peanut protein in gradually increasing doses ( updosing ) to induce desensitisation and immunomodulation. There is currently no evidence to suggest this approach is effective and safe in adults. Peanut OIT in children, especially during initial updosing, is associated with systemic and local reactions. There is a need to evaluate this approach in adults specifically, for several reasons. For example, other forms of immunotherapy (e.g. with pollen) are effective in adults but potential for immunomodulation by food OIT could significantly decline with age e.g. in one peanut OIT trial the final tolerated dose of peanut was inversely associated with participant age. Secondly, adults might have more severe reactions to peanut and therefore safety of OIT cannot be inferred from current paediatric trials. Thirdly, Ara h 2 sensitised adults show greater sensitisation to the minor Ara h 8 allergen. Ara h 8 may cause local oral allergy symptoms and it is unknown how this may affect peanut OIT outcomes. In this 3 year project we aim to evaluate whether adults with peanut allergy can be safely and effectively treated by peanut OIT in a real life NHS allergy service setting. On the advice of the Research Design Service we propose a Simons minimax two-stage clinical trial design to assess feasibility, efficacy and safety of peanut OIT in adults aged 18-40 years. Participants will undergo updosing at 2-weekly intervals from 0.8 mg peanut protein (in defatted peanut flour) up to maximum 2 g daily maintenance dose. The primary endpoint will be tolerance of 1.4g peanut protein during double-blind placebo controlled food challenge. A placebo group is not considered necessary because the expected response rate without intervention is 0%. Secondary endpoints will also include health related quality of life (HRQoL) and behavioural parameters. For the intervention to be worthwhile, we propose that a response rate of 50% or greater is required. Conversely, if the response rate is 20% or less peanut OIT would unlikely be adopted in an NHS setting. We will test the null hypothesis that true response is less than or equal to 20% (inadequate response level) against the alternative hypothesis that the response is greater than 50% (sufficiently promising response rate) with 90% power. To achieve the primary endpoint, a minimum of 7 of 21 participants must respond to peanut OIT. To minimise the number of participants if OIT is ineffective, and in accordance with the Simon s minimax two-stage design, an interim analysis will be conducted after the first 12 participants. For a 30% difference in response rate (20% v 50%), at least 2 of 12 participants will need to have responded for the trial to continue. An additional 9 patients will then be accrued and a second comparison will be made on the final sample size. A total of 25 participants will be enrolled to allow for a 20% drop out rate before the final double-blind placebo controlled food challenge.

Lay abstract: Peanut allergy is one of the most important food allergies in the UK and is usually a lifelong condition. Constant fear of severe or fatal reactions affects quality of life. An estimated 1 in 50 children in the UK are now peanut allergic and around 80% will become adults with a long term peanut allergy. Recent USA and UK studies have shown that allergic children can be desensitised to peanut. This involves eating a tiny amount of peanut daily, which is gradually increased over time. A downside is that this process can trigger allergic reactions, especially in the early stages as the peanut doses are being increased, so these steps are always done in a day hospital. Most children are able to eventually tolerate enough peanut (typically more than 10 peanuts) to protect them from accidental reactions. However, this treatment has NEVER been properly tested in adults. Without evidence that it is safe and works, allergy specialists cannot consider using peanut desensitisation to treat adults. Why might adults and children be different? Firstly, there is evidence suggesting nut reactions in adults are worse. Secondly, the immune system becomes less flexible with age, so it is possible that this approach might not work. Our aim is to test if peanut immunotherapy is effective and safe in adults. If so, this approach might benefit future patients in NHS allergy services. We have held discussion groups with patients, who agreed that this could be a life-changing treatment for them. We will test peanut desensitisation in 25 adults in the Adult Allergy Service at Guy s Hospital in a 3 year project. Each participant will undergo gradual desensitisation by eating peanut protein over several months. After this, each participant with undergo a test exposure to peanut to measure desensitisation and establish if they are protected.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM