Introduction The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.
Methods and analysis Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.
Ethics and dissemination The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.
Trial registration number NCT03364868.
- general diabetes
- paediatric endocrinology
- clinical trials
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Contributors AGZ and EB conceived the trial. AGZ, EB, JH and HEL led protocol development, and design of clinical trial governance. AGZ, PA, EB and JH led regulatory authority submission. MG, AGZ and EB wrote the manuscript. All authors (AGZ, PA, RB, KC, TD, MG, JH, VH, OK, KL, HEL, ML, MS, AS, JAT, EB) contributed to protocol development. AGZ, MS, KC, HEL and AS coordinated site specific ethical board application and review. EB, JH and VH developed the statistical design for the trial and wrote the statistical section of the protocol. EB and PA developed the outcome definition of the trial and wrote the autoantibody and outcome section of the protocol. KL developed the psychological section of the study. All authors reviewed the protocol as well as this manuscript.
Funding The POInT study is supported by The Leona M. and Harry B. Helmsley Charitable Trust (Helmsley) Grants#2018PG-T1D023 (The Global Platform for Prevention of Autoimmune Diabetes (GPPAD)-03 study: POInT –Primary Oral Insulin Trial) and #2018PG-T1D062 (Biobanking for the Primary Oral Insulin Trial).”, by the Helmholtz Zentrum München, Germany and the BMBF Grant#01KX1818, Germany. UK Clinical Centre is also supported by Wellcome [107212/Z/15/Z] and JDRF [5-SRA-2015-130- A-N]. The German Clinical Centers Munich and Dresden are also supported by the Deutsches Zentrum für Diabetesforschung DZD. Funding organizations had no role in the design of the trial. The authors AGZ, EB, and PA are inventors of a patent entitled “Method for determining the risk to develop type1 diabetes” (WO 2019/002364).
Competing interests Matthew Snape has received research grants paid to his institution for work as an investigator on clinical trials from the GSK group of companies, Pfizer, Janssen, Novavax, MedImmune, Alios BioPharma and Ablynx. He has also received support for travel and accommodation to attend international conferences from GSK group of companies, and, prior to 2017, received support paid to his institution as a member of the advisory board for Sanofi-Pasteur MSD and as a consultant for MedImmune.
Ethics approval The study was approved by the local ethical committees and regulatory authorities of the Technische Universität München, Medical Faculty (326/17 Af), the Medical University of Warsaw (Instytucie Matki I Dziecka w Warszawie) (199/2017), the UK Health Research Authority (18/SC/0019), Onderzoek UZ/KU Leuven (S60711) and the Regionala etikprövningsnämnden i Lund (2017/918).
Provenance and peer review Not commissioned; externally peer reviewed.
Collaborators GPPADSTUDYGROUP. GPPAD-Coordinating Centre (CC). MGü1, Stefanie Arnolds1, Robin Assfalg1, Corinna Barz1, Karina Blasius1, Cigdem Gezginci1, Cordula Falk1, JH2, Florian Haupt1, Martin Heigermoser1, Bianca Höfelschweiger1, Verena Sophia Hoffmann1, Manja Jolink1, Nana Kwarteng1, Ramona Lickert1, Claudia Matzke1, Rebecca Niewöhner1, Michaela Ott1, Peter Ruile1, Marlon Scholz1, Katharina Schütte-Borkovec1, Mira Taulien1, Lorena Wendel1, Katharina Wystub-Lis1, José Maria Zapardiel Gonzalo1. 1. Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany. 2. Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München, Munich, Germany. Medical Monitor: Katharina Warncke. Eligibility Committee: EB, JH, Åke Lernmark, JAT. Outcome Committee: PA, EB. Type 1 diabetes endpoint committee: HEL, Anette G. Ziegler. Pharmacovigilance Committee: PA, Katharina Schütte-Borkovec, Anette G. Ziegler. Belgium Clinical Centre. KC, Hilde Laeremans, Hilde Morobé, Jasmin Paulus. Germany, Dresden Clinical Centre. EB, RB, Uta Ceglarek (Leipzig), Petrina Delivani, Sevina Dietz, Yannick Fuchs, Gita Gemulla, Manja Gottschalk, Sophie Heinke, Angela Hommel, Anne Karasinsky, Susann Kowal, Fabian Lander, Robert Morgenstern, Katharina Nitzsche, Bianca Schlee, Marina Stopsack, Marc Weigelt, Pauline Wimberger, Marie-Luise Zielmann, Nicole Zubizarreta. Germany, Hannover Clinical Centre. OK, Torben Biester, TD, Nils Janzen, Ute Holtkamp, KL, Erika Marquardt, Frank Roloff, Kerstin Semler, Thekla von dem Berge. Germany, Munich Clinical Centre. Anette G. Ziegler1,2, PA1, Melanie Bunk1, Anita Gavrisan1, Katharina Gestrich1, Willi Grätz1, Pascale Heim-Ohmayer1, Melanie Herbst1, Julia Hirte1, Theresa Hoefs1, Anna Hofelich1, Evdokia Kalideri1, Cornelia Kraus1, Yvonne Kriesen1, KL1, Jasmin Ohli1, Claudia Ramminger1, Jennifer Schairer1, Christiane Winkler1, Susanne Wittich1, Stephanie Zillmer1. 1 Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany. 2 Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Medical faculty, Munich, Germany. Poland Clinical Centre. AS, Mariusz Ołtarzewski, Sylwia Dybkowska, Katarzyna Dżygało, Lidia Groele, Dorota Owczarek, Katarzyna Popko, Agnieszka Skrobot, Anna Taczanowska, Beata Zduńczyk. Sweden Clinical Centre. HEL, Markus Lundgren, Åke Lernmark, Daniel Agardh, Jeanette Åkerström Kördel, Carin Andrén Aronsson, Rasmus Bennet, Charlotte Brundin, Annika Fors, Lina Fransson, Berglind Jónsdóttir, Ida Jönsson, Zeliha Mestan, Anita Ramelius, Evelyn Tekum Amboh, Carina Törn. UK Clinical Centre. MS, JAT, Owen Bendor-Samuel, James Bland, Edward Choi, Rachel Craik, Kimberly Davis, Arancha de la Horra, Yama Farooq, Clare Scudder, Ian Smith, Manu Vatish, Louise Willis, Tabitha Wishlade.
Patient consent for publication Not required.
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