Efficacy of once-daily, high-dose, oral insulin immunotherapy in children genetically at risk for type 1 diabetes (POInT): a European, randomised, placebo-controlled, primary prevention trial
Anette‐Gabriele Ziegler, Peter Achenbach, Andreas Weiß, Reinhard Berner, Kristina Casteels, Helena Elding Larsson, Florian Haupt, Florian Haupt, An Jacobs, Olga Kordonouri, Markus Lundgren, Mariusz Ołtarzewski, Markus Pfirrmann, Matthew D. Snape, Agnieszka Szypowska, John A. Todd, Manu Vatish, Thekla von dem Berge, Christiane Winkler, Ezio Bonifacio, Ezio Bonifacio, Kristina Casteels, Janne Houben, An Jacobs, Charlien Jannsen, Hilde Morobé, Jasmin Paulus, Anne Rochtus, Natalie Van den Driessche, Renka Van Heyste, Veerle Vanhuyse, Brontë Vrancken, Sari Arabi, Reinhard Berner, Ruth Blechschmidt, Ezio Bonifacio, Uta Ceglarec, Petrina Delivani, Sevina Dietz, Franziska Ehrlich, Gita Gemulla, Sophie Heinke, Raphael Hoffmann, Angela Hommel, Susan Kowal, Franziska Lange, Anja Loff, Marie-Luise Michael, Peter Mirtschink, Bianca Schlee, Marc Weigelt, Pauline Wimberger, Nicole Zubizarreta, Laura Galuschka, Nils Janzen, Olga Kordonouri, Carolin Kruse, Sarah Landsberg, Erika Marquardt, Mareike Niemeyer, Felix Reschke, Frank Roloff, Bianca Schmidt, Kerstin Semler, Thekla von dem Berge, Jantje Weiskorn, Peter Achenbach, Stefanie Arnolds, Karina Blasius, Melanie Bunk, Michaela Dilong, Annika Fehn, Veronika Fendt, Willi Grätz, Melanie Gündert, Florian Haupt, Martin Heigermoser, Maja Hergl, Anna Hofelich, Elisabeth Huber, Sandra Hummel, Stefanie Jacobson, Nadine Klein, Annette Knopff, Thomas Lang, Karin Lange, Ramona Lickert, Claudia Matzke, Lorena Müller, Annette Munzinger, Rebecca Niewöhner, Markus Pfirrmann, Claudia Ramminger, Franziska Reinmüller, Cigdem Sanverdi, Katharina Sarcletti, Sarah Schill, Marlon Scholz, Katharina Schütte-Borkovec, Merve Vurucu
Abstract
BACKGROUND: Type 1 diabetes begins with autoimmunity against pancreatic islet antigens, including insulin. The aim of the Primary Oral Insulin Trial (POInT) was to evaluate the efficacy and safety of daily high-dose oral insulin to prevent the development of islet autoantibodies and diabetes. METHODS: In this randomised, controlled, primary prevention trial, genetic screening in seven obstetric and paediatric clinics in Germany, Poland, Sweden, Belgium, and the UK identified newborns with a greater than 10% risk of developing islet autoimmunity. Eligible infants aged 4-7 months were randomly assigned in a 1:1 ratio to receive insulin manufactured from human zinc-insulin crystals administered orally at a once-daily dose of 7·5 mg for 2 months, increasing to 22·5 mg for 2 months and 67·5 mg until age 3 years, or placebo. Participants were randomly assigned via a web-based application and were stratified by site. The primary outcome was the development of two or more islet autoantibodies or diabetes assessed throughout follow-up until a maximum age of 6·5 years. A secondary outcome was the development of dysglycaemia or diabetes. Islet autoantibodies were measured in samples collected at baseline and during study visits conducted at outpatient clinics at 2, 4, and 8 months after randomisation, at age 18 months, and every 6 months thereafter. All participants and their family members, investigators of the study, and laboratory personnel remained masked to treatment allocation during the whole study. All randomly assigned participants who correctly fulfilled eligibility criteria and had not reached the primary outcome at the baseline visit (modified intention-to-treat) were included in the primary analysis. All participants who received at least one dose of study drug were included in the safety analysis. POInT is registered with ClinicalTrials.gov (NCT03364868) and is complete. FINDINGS: Of 241 977 screened newborns, 2750 (1·14%) had an elevated genetic risk of developing islet autoimmunity and 1050 (38·2%) of the eligible infants (531 males [51%], 519 females [49%]), were assigned to oral insulin or placebo between Feb 7, 2018, and March 24, 2021. Two participants in the oral insulin group and none in the placebo group were excluded from the modified intention-to-treat analysis. The primary outcome developed in 52 (10%) participants in the insulin group and 46 (9%) in the placebo group (hazard ratio 1·12 [95% CI 0·76-1·67], p=0·57). An interaction between treatment and the INS rs1004446 genotype was observed, with an increase in the primary outcome in participants in the insulin group carrying non-susceptible INS genotypes compared with the placebo group (2·10 [1·08-4·09]) and protection against diabetes or dysglycaemia in participants in the insulin group carrying susceptible INS genotypes compared with the placebo group (0·38 [0·17-0·86]). Blood glucose values less than 50 mg/dL were observed in two (0·03%) of 7210 measurements in the insulin group and six (0·08%) of 7070 measurements in the placebo group. Of 10 252 reported adverse events, 5076 (49·5%) occurred in 507 (96·0%) of 528 participants in the oral insulin group and 5176 (50·5%) occurred in 500 (95·8%) of 522 participants in the placebo group. One death occurred in the oral insulin group and was unrelated to the study drug following independent review. INTERPRETATION: There was no evidence that high-dose, daily oral insulin prevents the development of islet autoantibodies. Further studies are needed to assess the benefit of primary oral insulin therapy for preventing diabetes in INS genotype-selected infants. FUNDING: Leona M and Harry B Helmsley Charitable Trust.