Title: A randomised controlled double-blind trial assessing desensitisation to cow's milk, following partially or extensively hydrolysed formulae feeding regimens, in children with allergy to cow's milk (The DREAM study)
Funder: Medical Research Council

Abstract: Around 2-7% of babies in the UK have allergy to cow’s milk (CMA). Many of these babies get well after 1-2 years, but others remain allergic for many years, or even as adults. Parents must avoid giving dairy to allergic children, and, if they cannot breast-feed, they must use special formulas. However, cow’s milk is everywhere, so avoiding it is difficult and accidental reactions – even severe ones – are common. For this reason parents and doctors agree that better solutions are needed. The DREAM study will investigate a new way to manage milk allergy in 6-12 month old babies. We will compare two different formulas: the one that is now indicated for CMA and another one that we believe will help them overcome their allergy faster. The ‘test’ formula is one that is already used for infants with “colics”. About half of the allergic infants can have this formula directly, without a problem. Those that cannot have it from the start, will be ‘trained’ to have it, by slowly increasing the amount they eat._x000D_ _x000D_ We know that people with allergies can overcome their problem if they get very small and slowly increasing amounts, under strict doctor supervision. This is known as “oral immunotherapy” (OIT). This study will use this idea in many new ways: 1) we will offer this to young babies at a time the immune system is more easy to change; 2) we will feed most of the babies freely and not only in small doses; and 3) we will use a formula which is safer than normal cow’s milk (which is typically used for OIT). We believe that in this way we can help babies get rid of their allergy sooner. It will also be safer and cheaper than the way we treat allergy right now._x000D_ _x000D_ At the start of the study, we will use allergy tests to find allergic babies who have a smaller chance to get rid of their allergy soon (they have ‘severe’ allergy). Babies who don’t react to the ‘test’ formula (pHF) will be randomly given either pHF or the normal care formula (eHF). This will be ‘blinded’ feeding, meaning that the study team and the families will not know which formula each infant is having, so that they are not influenced. Babies who react at the start to the ‘test’ formula will be treated with OIT in order to be able to have it, as much as they can. At the end of the study, all children will be given cow’s milk at the hospital to see if they are still allergic or not. During the study we will get some blood, stools and some other samples to run tests in the future, to help us understand allergy better._x000D_ _x000D_ There will be 12 NHS centres taking part in DREAM. We will be including babies for 3 years and each baby will be in the study for one year. Parents of patients have helped in designing and preparing the study, and will help us run it until the end. The patient charity “Anaphylaxis Campaign” is a partner of the study and plays a very important role. If this research shows that the ‘test’ formula (pHF) works, we will be able to start using it in normal everyday care very soon, because it is already on the market.

Lay abstract: DREAM is a UK-wide, multicenter, randomized, double-blind, routine-care-controlled, parallel-group Trial which will assess a new treatment for IgE-mediated (immediate) cow’s milk allergy (CMA). DREAM will evaluate the efficacy and safety of free-feeding allergic infants with commercially available, partially hydrolyzed milk formula (pHF). We hypothesise that pHF will facilitate CMA resolution faster than routine care (extensively Hydrolyzed Formulae - eHF) and will also induce tolerance where CMA would have otherwise persisted._x000D_ Immediate CMA is one of the most frequent food allergies in children, with prevalence in infancy of 1.8%-7.5% and with a significant impact on QOL and health expenditure. There is no satisfactory treatment and management consists of cow’s milk (CM) avoidance, feeding with ‘hypoallergenic’ formulas (eHFs), emergency management of accidental reactions, and waiting for CMA to resolve naturally (spontaneously). Feeding with processed CM products is also supported, but this is an empiric approach. The only potentially curative approach is Oral ImmunoTherapy (OIT) i.e. exposing patients to strictly-controlled increasing doses of CM, but this is not used in clinical practice due to risk of reactions._x000D_ In the recent literature, a novel paradigm suggests that allergy may be treated via early allergen exposure. To evaluate whether exposure to the processed CM proteins in pHF can facilitate CMA resolution we will initially stratify infants by pHF reactivity, and those who do not react to pHF will be randomised into blinded pHF/eHF free-feeding for a year; those who react will be randomised to be desensitized to pHF or eHF via a short OIT regimen before being fed freely. At the end, a double-blind, placebo-controlled food challenge to CM (DBPCFC), the gold standard rule of diagnosis will determine whether CMA has resolved._x000D_ Numerous trials have shown that early feeding with normal/processed (baked) CM facilitates tolerance. We propose three important breakthroughs: 1. targeting young (6-12-month-old) infants, when the immune system is more amenable to manipulation; 2. free-feeding, in contrast to strict OIT dosing schedules; and 3. using a formula with reduced allergenicity to improve safety. Tissue samples will be stored for future research into tolerance development through antigen-dependent epigenetic modification of key regulatory genes, the influence of microbiome maturation and the effect of key immune-active cytokines._x000D_ Trial duration is 5 years, recruitment duration is 3 years and each patient will participate for 1 year. The Trial team includes five UK academic partners, a UK-wide Charity (Anaphylaxis Campaign) and the Liverpool Clinical Trials Unit. The sponsor is the Manchester University NHS Foundation Trust and there will be 12 UK recruitment centres. Nutricia-Danone will provide the pHF and eHF formulas. Extensive early PPI activities have involved the patients/public in identifying and prioritizing the research question, in designing the study and in developing the grant proposal; robust PPI has also been planned for the Trial’s delivery. Dissemination will be conducted through the network of Anaphylaxis Campaign, the partners’ institutions and the industry, and the impact is expected to be substantial from several perspectives (including clinical, scientific, socioeconomic, financial, and industrial aspects).

Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: INFLAMMATORY AND IMMUNE SYSTEM