ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 66 OC6.3 | DOI: 10.1530/endoabs.66.OC6.3

Here's the POInT: a multicentre European Primary Oral Insulin Trial

Owen Bendor-Samuel1, Tabitha Wishlade2, Manu Vatish2, Anette-Gabriele Ziegler3,4,5, Ezio Bonifacio6, John A Todd7, Matthew Snape1,8 & GPPAD Study Group9

1Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK; 2Nuffield Department of Women’s & Reproductive Health, University of Oxford, Oxford, UK; 3Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; 4Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, German Research Center for Environmental Health, Munich, Germany; 5Forschergruppe Diabetes, Technical University Munich, at Klinikum rechts der Isar, Munich, Germany; 6Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany; 7Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK; 8NIHR Oxford Biomedical Research Centre, Oxford, UK; 9Helmholtz Zentrum München, Munich, UK

Introduction: The successful prevention of type 1 diabetes (T1D) is a major clinical goal. The pathogenesis is multifactorial, with genetic and environmental influences that lead to a break in immune tolerance toward pancreatic beta cells. Through a number of prospective cohort studies, it is now understood that the presence of two or more diabetes-associated autoantibodies is highly predictive of future T1D diagnosis. In addition to the genetic rationale (insulin gene sequence variations increasing T1D risk four fold), insulin autoantibodies, often appearing first within 9 months after birth, indicate that the loss of tolerance to insulin is an important step in the progression of T1D and therefore if prevented, T1D could be delayed or avoided.

Aim: As part of the Global Platform for the Prevention of Autoimmune Diabetes (GPPAD), the aim of POInT (Primary Oral Insulin Trial) is to conduct a T1D primary prevention, double-blind randomised controlled trial, aiming to induce tolerance towards insulin by administering oral insulin.

Design: Through the INGR1D study (Investigating Genetic Risk for T1D) babies are genetically screened for a 1:10 chance of developing multiple autoantibodies (against a background risk of 1:250). Between 4 and 7 months of age, participants with an increased risk of T1D can enrol to POInT and are subsequently randomised 1:1 to receive either daily placebo or oral insulin until their 3rd birthday. Follow-ups are mostly at 6-monthly intervals thereafter, with a maximum 7-year follow-up. There are currently seven study centres across five European countries recruiting to INGR1D and POInT, with the aim to screen 300 000 newborns over 3.5 years, leading to randomisation of 1,040 children into the trial.

Analysis: At every visit, participants are tested for the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8. The primary outcome is the development of multiple autoantibodies or diabetes. Secondary outcomes include single autoantibodies or an abnormal glucose tolerance test. The POInT accrual objective of 1040 children provides 80% power to detect a 50% reduction in the incidence of beta-cell autoantibodies by age 6 years.

Accruals to date: Between October 2017 and June 2019, over 95 000 and 290 participants have enrolled to INGR1D and POInT respectively.

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