GPPAD Study Group

GPPAD-POInT Study Group Authors

GPPAD-Coordinating Center (CC)

Peter Achenbach ^1,2,3, Stefanie Arnolds ¹, Karina Blasius¹, Ezio Bonifacio^3,4,5,6, Michaela Dilong¹, Veronika Fendt¹, Melanie Gündert ¹, Florian Haupt¹, Martin Heigermoser¹, Maja Hergl¹, Elisabeth Huber¹, Sandra Hummel¹, Nadine Klein¹, Ramona Lickert¹, Claudia Matzke¹, Lorena Müller¹, Rebecca Niewöhner¹, Marlon Scholz¹, Katharina Schütte-Borkovec¹, Merve Vurucu ¹, José Maria Zapardiel Gonzalo¹, Anette-Gabriele Ziegler ^1,2,3

Statistical analysis team

Thomas Lang⁷, Markus Pfirrmann⁷ (independent statistician, DSMB), Andreas Weiß¹ (trial statistician)

Screening for genetic T1D risk (GPPAD-02)

Belgium, Flanders: Kristina Casteels^8,9, An Jacobs⁸, Charlien Jannsen¹⁰, Hilde Morobé¹⁰, Jasmin Paulus¹⁰, Anne Rochtus^8,9, Natalie Van den Driessche¹⁰, Renka Van Heyste¹⁰, Veerle Vanhuyse¹¹, Brontë Vrancken¹⁰

Germany, Saxony: Uta Ceglarec¹², Petrina Delivani⁴, Franziska Ehrlich⁴, Angela Hommel⁴, Anja Loff⁴, Peter Mirtschink¹⁴, Pauline Wimberger¹⁵, Nicole Zubizarreta⁴

Germany, Lower Saxony: Frank Roloff¹⁶

Germany, Bavaria: Annika Fehn¹, Stefanie Jacobson^1,2,  Elisabeth Huber¹, Christiane Winkler^1,3

Poland, Voivodship Mazowieckie: Marta Krysicka¹⁷, Mariusz Ołtarzewski¹⁷, Agnieszka Szypowska^{17,18, 19}

Sweden, Skåne Region: Helena Elding Larsson^20,21, Ida Jönsson²⁰, Dorota Lacki^20,21, Markus Lundgren^20,22, Hannah Nenonen^20,21

UK, Oxford Region: Parvinder Aley²³, Ian Smith²⁴, Matthew Snape²⁵, Nazia Taj²⁴, John A Todd²⁶, Manu Vatish²⁷, Tabitha Wishlade²⁷

POInT study (GPPAD-03)

Belgium, Leuven: Kristina Casteels^8,9, Janne Houben⁸, An Jacobs⁸, Charlien Jannsen¹⁰, Jasmin Paulus¹⁰, Anne Rochtus^8,9, Natalie Van den Driessche¹⁰, Veerle Vanhuyse¹¹, Brontë Vrancken¹⁰

Germany, Dresden: Sari Arabi^4,13, Reinhard Berner¹³, Ruth Blechschmidt⁴, Ezio Bonifacio^2,4,5,6, Sevina Dietz⁴, Franziska Ehrlich⁴, Gita Gemulla^4,13, Sophie Heinke^4,13, Raphael Hoffmann^4,13, Angela Hommel⁴, Susan Kowal⁴, Franziska Lange^4,13, Anja Loff⁴, Marie-Luise Michael^4,13, Bianca Schlee⁴, Marc Weigelt⁴, Nicole Zubizarreta⁴

Germany, Hanover: Laura Galuschka¹⁶, Olga Kordonouri¹⁶, Carolin Kruse¹⁶, Sarah Landsberg¹⁶, Erika Marquardt¹⁶, Mareike Niemeyer¹⁶, Felix Reschke¹⁶, Frank Roloff¹⁶, Bianca Schmidt¹⁶, Kerstin Semler¹⁶, Thekla von dem Berge¹⁶, Jantje Weiskorn¹⁶

Germany, Munich: Peter Achenbach ^1,2,3, Melanie Bunk ¹, Willi Grätz^1,2, Anna Hofelich ², Annette Knopff ¹, Annette Munzinger ¹, Claudia Ramminger¹, Franziska Reinmüller ², Cigdem Sanverdi¹, Katharina Sarcletti ¹ , Sarah Schill², Anette-Gabriele Ziegler^1,2,3

Poland, Warsaw: Adrianna Cieloch¹⁸, Wiktoria Czerwińska¹⁸, Sylwia Dybkowska¹⁸, Natalia Dziedzic¹⁸, Elżbieta Górska^18,19, Lidia Groele^18,19, Agnieszka Mroczek¹⁸, Dorota Owczarek¹⁸, Katarzyna Popko^18,19, Agnieszka Szypowska^{17, 18,19}, Beata Zduńczyk¹⁸, Anna Zych¹⁸

Sweden, Malmö: Sofie Alström Mortin²⁰, Susanne Dahlberg²² Helena Elding Larsson^20,21, Lina Fransson^20,21, Malin Goldman-Tsubarah^20,21, Markus Lundgren^20,22, Jessica Melin^20,21, Hannah Nenonen^20,21, Kobra Rhamati^20,21, Falastin Salami^20,21, Carina Törn²⁸

UK, Oxford: Parvinder Aley²³, Owen Bendor-Samuel²³, Rachel E J Besser^25,29,30, Rachel Craik²³, Sophia Hawkins^.23,32, Alice Lelliott^23,32, Helen Ratcliffe^23,32, Matthew Snape²⁹, John A Todd²⁴, Sophie Vernon^23,32, Connor Whelan^23,32, Louise Willis²³

Affiliations

1 Institute of Diabetes Research, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany

2 Technical University of Munich, School of Medicine and Health, Forschergruppe Diabetes, TUM University Hospital, Munich, Germany

3 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany  

4 Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany

5 Paul Langerhans Institute Dresden of Helmholtz Munich at University Hospital Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

6 Institute of Diabetes and Obesity (IDO), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany

7 Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany

8 Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium

9  Department of Development and Regeneration, KU Leuven, Leuven, Belgium

10 Research & Development Endocrinology, University Hospital Gasthuisberg, Leuven, Belgium

11 Clinical & Experimental Endocrinology, KU Leuven, Leuven, Belgium

12 Department of Medicine, University of Leipzig, Leipzig, Germany

13 Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

14 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

15 Department of Obstetrics and Gynecology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

16 Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany 

17 Department of Screening and Metabolic Diagnostics, Institute of Mother and Child, Warsaw, Poland

18 Department of Paediatric Diabetology and Paediatrics, The Children’s Clinical Hospital Józef Polikarp Brudziński, University Clinical Centre of the Medical University of Warsaw, Warsaw, Poland

19 Department of Paediatric Diabetology and Paediatrics, Medical University of Warsaw, Warsaw, Poland

20 Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden

21 Department of Paediatrics, Skåne University Hospital, Malmö/Lund, Sweden

22 Department of Paediatrics, Skåne University Hospital, Kristianstad, Sweden

23 Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK

24 Oxford Screening Laboratory, Department of Clinical Biochemistry, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

25 Department of Paediatrics, University of Oxford, Oxford, UK

26 Diabetes and Inflammation Laboratory, Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centres, University of Oxford, Oxford, UK

27 Nuffield Department of Women’s & Reproductive Health, University of Oxford, John Radcliffe Hospital, Oxford, UK

28 Unit for Celiac and Diabetes, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden

29 Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford UK

30 Department of Paediatric Diabetes and Endocrinology, Oxford Children’s Hospital, The John Radcliffe, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

32 NIHR Oxford Biomedical Research Centre, Oxford, UK

Declarations

Acknowledgements

We sincerely thank the participating families for their contribution to type 1 diabetes research and their support in advancing therapies for prevention. We also greatly acknowledge the following support:

GPPAD coordination center: Robin Assfalg, Gertrud Goppel, Bianca Höfelschweiger, Stephanie Löbner, Claudia Peplow, Eva-Maria Sedlmeier, Sandra Steinebrunner

Clinical site, Germany, Dresden: Irena Drozd, Robert Morgenstern, Maike Sigg, Andre Weise

Clinical site, Germany, Munich: Melanie Heinrich, Kerstin Kick, Benjamin Marcus (Klinikum rechts der Isar, Technical University of Munich), Theresa Faure, Melina Kaiser (Helmholtz Munich).

Clinical site, UK, Oxford: Patrick Bose (Royal Berkshire Hospital, Reading), Edel Claire, Eleni Fotaki, Jude Mossop, Dorota Pietrzak, Fenella Roseman (Nuffield Department of Women’s & Reproductive Health, University of Oxford), Yama F Mujadidi, Sophie Vernon, Rachel White (Oxford Vaccine Group, Department of Paediatrics, University of Oxford), Aparna Reddy (Stoke Mandeville Hospital, Aylesbury).

Medical Monitor: Katharina Warncke (Technical University of Munich, Department of Pediatrics, Kinderklinik München Schwabing)

Data Safety and Monitoring Board: Polly Bingley (University of Bristol, Bristol, UK), Ulrich Heininger (University of Basel Children’s Hospital, Basel, Switzerland), Markus Pfirrmann (Ludwig-Maximilians-Universität, Munich, Germany), Wolfgang Rascher (Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany), Paul Turner (University of Oxford, Oxford, UK).

Islet Autoantibody and Confirmatory Laboratory: Institute of Diabetes Research, Helmholtz Munich, Neuherberg, Germany; Bristol Medical School, University of Bristol, Bristol, UK, (Kathleen Gillespie, Kyla Chandler).

Genotyping Laboratory: LGC Genomics Limited, Hoddesdon, Hertfordshire, UK.

Data Management: PHARMALOG, GmbH, Ismaning, Germany.

Pharmacovigilance: Dr. Nibler & Partner, Munich, Germany.

Randomization and Study Product Logistics: GxP Brain GmbH, Berlin, Germany.

Insulin Crystal Supply: Eli Lilly Product Research and Development (PR&D), Eli Lilly Indianapolis, USA.

IMP Supply: Allphamed Pharbil Arzneimittel GmbH, Göttingen, Germany.

Biorepository: Integrated BioBank of Luxembourg (IBBL), Dudelange, Luxembourg.

Funding

The GPPAD studies were supported by The Leona M. and Harry B. Helmsley Charitable Trust grants (#2018PG-T1D022: The Global Platform for Prevention of Autoimmune Diabetes (GPPAD)-02 study and GPPAD coordinating center; #2018PG-T1D023: GPPAD-03 study – POInT; #2018PG-T1D062: Biobanking for POInT). The GPPAD Coordination Center at Helmholtz Munich, Germany, was also supported by internal funding from Helmholtz Munich; the Bavarian Ministry of Economic Affairs, Energy, and Technology (Prevention of Autoimmune Diabetes – Digital Lab), German Federal Ministry of Education and Research (BMBF, FKZ: 01KX1818), German Center for Diabetes Research (DZD e.V.); and an EASD-Novo Nordisk Foundation Diabetes Prize for Excellence (NNF22SA0081044). The Malmö clinical site was also supported by the Swedish Diabetes Foundation, and the Oxford clinical site was also supported by Wellcome (107212/Z/15/Z), JDRF (5-SRA-2015-130-A-N) and the 2021 EASD-Novo Nordisk Foundation Diabetes Prize for Excellence.

GPPAD-SINT1A Study Group Authors

GPPAD-Coordinating Center (CC)

Peter Achenbach ^1,2,3, Stefanie Arnolds ¹, Karina Blasius¹, Ezio Bonifacio^3,4,5,6, Michaela Dilong¹, Annika Fehn¹, Gertrud Göppel¹, Melanie Gündert ¹, Florian Haupt¹, Martin Heigermoser¹, Maja Hergl¹, Elisabeth Huber¹, Sandra Hummel¹, Nadine Klein¹, Kristina Korhonova¹, Ramona Lickert¹, Claudia Matzke¹, Lorena Müller¹, Rebecca Niewöhner¹, Marlon Scholz¹, Merve Vurucu ¹, José Maria Zapardiel Gonzalo¹, Anette-Gabriele Ziegler ^1,2,3

Statistical analysis team

Markus Pfirrmann⁷ (independent statistician, DSMB), Andreas Weiß¹ (trial statistician)

Screening for genetic T1D risk (GPPAD-02)

Belgium, Flanders: Kristina Casteels^8,9, An Jacobs⁸, Charlien Janssen¹⁰, Hilde Morobé¹⁰, Jasmin Paulus¹⁰, Anne Rochtus^8,9, Natalie Van den Driessche¹⁰, Renka Van Heyste¹⁰

Germany, Bavaria: Stefanie Jacobson^1,2, Manja Jolink¹, Alexandra Käßl¹, Christiane Winkler^1,3

Germany, Lower Saxony: Frank Roloff¹¹

Germany, Saxony: Lisa Barbknecht⁴, Uta Ceglarec¹², Franziska Ehrlich⁴, Angela Hommel⁴, Anja Loff⁴, Peter Mirtschink¹³, Pauline Wimberger¹⁴, Nicole Zubizarreta⁴

Poland, Voivodship Mazowieckie: Marta Krysicka¹⁵, Mariusz Ołtarzewski¹⁵, Agnieszka Szypowska^{15,16, 17}

Sweden, Skåne Region: Helena Elding Larsson^18,19, Ida Jönsson¹⁸, Dorota Lacki^18,19, Markus Lundgren^18,20, Hannah Nenonen^18,19

UK, Newcastle Region: Hazel Alexander²¹, Marie Appleton²², Vicki Atkinson²³, Angela Ayuk²⁴, Christine Beardmore²², Kelly Chambers²², Marc Davies²², Sharon Gowans²⁵, Rebecca Haycox²², Fiona Jenkinson²², Anna McSkeane²⁶, Christine Moller-Christenson²⁷, Stephen Robson^22,28, Sandra Temple²², Eileen Walton²⁹, Fiona Yelnoorkar²²

SINT1A study (GPPAD-04)

Belgium, Leuven: Kristina Casteels^8,9, Janne Houben⁸, An Jacobs⁸, Charlien Janssen¹⁰, Jasmin Paulus¹⁰, Anne Rochtus^8,9, Natalie Van den Driessche¹⁰

Germany, Dresden: Reinhard Berner³⁰, Ruth Blechschmidt⁴, Sophie Bierkämper⁴, Ezio Bonifacio^3,4,5,6, Sevina Dietz⁴, Irena Drozd³⁰, Franziska Ehrlich⁴, Gita Gemulla^4,30, Raphael Hoffmann^4,30, Angela Hommel⁴, Franziska Lange⁴, Anja Loff⁴, Christin Rade⁴, Maike Sigg³⁰, Katja Steinberg-Bains³⁰, Christian Vogelberg³⁰, Marc Weigelt⁴, Ivonne Zeißig³⁰, Nicole Zubizarreta⁴

Germany, Hanover: Ann-Kristin Frerking¹¹, Olga Kordonouri¹¹, Carolin Kruse¹¹, Sarah Landsberg¹¹, Erika Marquardt¹¹, Mareike Niemeyer¹¹, Felix Reschke¹¹, Frank Roloff¹¹, Bianca Schmidt¹¹, Thekla von dem Berge¹¹, Jantje Weiskorn¹¹

Germany, Munich: Peter Achenbach ^1,2,3, Willi Grätz^1,2, Anna Hofelich ², Annette Munzinger¹, Annette Knopf¹, Franziska Reinmüller ², Laura Sander¹, Cigdem Sanverdi¹, Katharina Sarcletti¹, Sarah Schill², Anette-Gabriele Ziegler^1,2,3

Poland, Warsaw: Adrianna Cieloch¹⁶, Wiktoria Czerwińska¹⁶, Natalia Dziedzic¹⁶, Lidia Groele^16,17, Dorota Owczarek¹⁶, Katarzyna Popko^16,17, Agnieszka Szypowska^{15,16, 17}, Anna Zych¹⁶

Sweden, Malmö: Sofie Alström Mortin¹⁸, Helena Elding Larsson^18,19, Lina Fransson^18,19, Malin Goldman-Tsubarah¹⁸, Maria Hyllengren¹⁸, Markus Lundgren^18,20, Jessica Melin^18,19, Hannah Nenonen^18,19, Kobra Rhamati^18,19, Falastin Salami^18,19, Carina Törn³¹

UK, Newcastle: Stephen Crulley²², Sharon King²², Catherine Owen²², Maria Robinson²², Claire Wood^22,28

Affiliations

1 Institute of Diabetes Research, Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany

2 Technical University of Munich, School of Medicine and Health, Forschergruppe Diabetes, TUM University Hospital, Munich, Germany

3 German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany

4 Center for Regenerative Therapies Dresden, Technische Universität Dresden, Dresden, Germany

5 Paul Langerhans Institute Dresden of Helmholtz Munich at University Hospital Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

6 Institute of Diabetes and Obesity (IDO), Helmholtz Munich, German Research Center for Environmental Health, Neuherberg, Germany

7 Institute for Medical Information Processing, Biometry, and Epidemiology (IBE), Faculty of Medicine, Ludwig-Maximilians-Universität, Munich, Germany

8 Department of Pediatrics, University Hospital Gasthuisberg, Leuven, Belgium

9 Department of Development and Regeneration, KU Leuven, Leuven, Belgium

10 Research & Development Endocrinology, University Hospital Gasthuisberg, Leuven, Belgium

11 Kinder- und Jugendkrankenhaus AUF DER BULT, Hannover, Germany

12 Department of Medicine, University of Leipzig, Leipzig, Germany

13 Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany

14 Department of Obstetrics and Gynecology, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

15 Department of Screening and Metabolic Diagnostics, Institute of Mother and Child, Warsaw, Poland

16 Department of Paediatric Diabetology and Paediatrics, The Children’s Clinical Hospital Józef Polikarp Brudziński, University Clinical Centre of the Medical University of Warsaw, Warsaw, Poland

17 Department of Paediatric Diabetology and Paediatrics, Medical University of Warsaw, Warsaw, Poland

18 Unit for Pediatric Endocrinology, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden

19 Department of Paediatrics, Skåne University Hospital, Malmö/Lund, Sweden

20 Department of Paediatrics, Skåne University Hospital, Kristianstad, Sweden

21 South Tees Hospitals NHS Foundation Trust, United Kingdom

22 The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

23 County Durham & Darlington NHS Foundation Trust, United Kingdom

24 Northumbria Healthcare NHS Foundation Trust, United Kingdom

25 North Tees & Hartlepool NHS Foundation Trust, United Kingdom

26 North Cumbria Integrated Care NHS Foundation Trust, United Kingdom

27 Gateshead Health NHS Foundation Trust, United Kingdom

28 Newcastle University, Newcastle upon Tyne, United Kingdom

29 South Tyneside & Sunderland NHS Foundation Trust, United Kingdom

30 Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

31 Unit for Celiac and Diabetes, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden

Declarations

Acknowledgements

We sincerely thank the participating families for their contribution to type 1 diabetes research and their support in advancing therapies for prevention. We also greatly acknowledge the following support:

GPPAD coordination center: Bianca Höfelschweiger, Katharina Schütte-Borkovec, Sandra Steinebrunner

Clinical site, Germany, Munich: Helmholtz Munich: Simone Färber-Meisterjahn, Ines Greif, Melina Kaiser, Heidi Kapfelsberger, Esra Karapinar, Tiziana Welzhofer; TUM Klinikum Rechts der Isar, Technical University of Munich: Benjamin Marcus

Clinical site, UK, Newcastle: The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom: Ashley Bell, Rachel Boal, Martin Edney, Andrea Fenn, Trevor Liddle, Caroline Miller, Rachel Percival, Chris Rouse, Sulemana Saibu

Medical Monitor: Katharina Warncke (Technical University of Munich, Department of Pediatrics, Kinderklinik München Schwabing)

Data Safety and Monitoring Board: Polly Bingley (University of Bristol, Bristol, UK), Ulrich Heininger (University of Basel Children’s Hospital, Basel, Switzerland), Markus Pfirrmann (Ludwig-Maximilians-Universität, Munich, Germany), Wolfgang Rascher (Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany), Paul Turner (University of Oxford, Oxford, UK).

Beta-cell Autoantibody and Confirmatory Laboratory: Institute of Diabetes Research, Helmholtz Munich, Neuherberg, Germany; Bristol Medical School, University of Bristol, Bristol, UK

Genotyping Laboratory: Grace London, LGC Genomics Limited, Hoddesdon, Hertfordshire, UK.

Study management/ monitoring: Helmholtz Munich, Neuherberg, Germany.

Database/ Electronic Questionnaires: PHARMALOG, GmbH, Ismaning, Germany.

Pharmacovigilance: Pharmacy of the University Hospital of Heidelberg, Germany

Randomization and Study Product Logistics: GxP Brain GmbH, Berlin, Germany.

Study Product Supply: Infinant Health Davis, California, USA.

Biorepository: Integrated BioBank of Luxembourg (IBBL), Dudelange, Luxembourg.

Funding

The GPPAD studies were supported by The Leona M. and Harry B. Helmsley Charitable Trust grants (#2110-04841 (GPPAD-02 study continuation), #2302-06623 (GPPAD-02 study continuation 2), #2003-04286 (GPPAD coordinating center continuation), #2007-04031 (GPPAD-04 study: Supplementation with B. Infantis for Mitigation of Type 1 Diabetes Autoimmunity (SINT1A)). The GPPAD Coordination Center at Helmholtz Munich, Germany, was also supported by internal funding from Helmholtz Munich; the Bavarian Ministry of Economic Affairs, Energy, and Technology (Prevention of Autoimmune Diabetes – Digital Lab), German Federal Ministry of Education and Research (BMBF, FKZ: 01KX1818), German Center for Diabetes Research (DZD e.V.); and an EASD-Novo Nordisk Foundation Diabetes Prize for Excellence (NNF22SA0081044). The Malmö clinical site was also supported by the Swedish Diabetes Foundation, and the Oxford clinical site was also supported by Wellcome (107212/Z/15/Z), JDRF (5-SRA-2015-130-A-N) and the 2021 EASD-Novo Nordisk Foundation Diabetes Prize for Excellence.