GPPAD-POInT (Global Platform of Autoimmune Diabetes - Primary Oral Insulin Trial)

NCT03364868 | Completed Phase 2 DMC

• 1 other identifier: GPPAD-03-POInT
• Study Type: interventional
• Target: 1,050
• Locations: 5 countries
• Sites: 7

Brief Summary

The GPPAD-POInT Study is designed as a randomized, placebo-controlled, double blind, multicentre, multinational primary prevention phase IIb study aiming to induce immune tolerance to beta-cell autoantigens through regular exposure to oral insulin for a period of 29 to 32 months. The hypothesis is that regular exposure to oral insulin throughout the period in life where beta-cell autoimmunity usually initiates will tolerize against insulin and train the body's immune system to recognize the treatment product without reacting adversely to it in a manner seen in children who develop T1D. This immune tolerance induction therapy would reduce the likelihood of beta-cell autoimmunity. The study objective is to determine whether daily administration of oral insulin from age 4 months - 7 months until age 3.00 years to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies and diabetes in childhood.

Conditions

Diabetes Mellitus, Type 1

Keywords

Type 1 diabetes; T1D; diabetes mellitus; oral insulin; oral tolerance; autoantigen; self tolerance; prevention; at risk for developing type 1 diabetes; juvenile diabetes; autoimmune diabetes

Outcome Measures

Primary Outcomes (2)

• The development of persistent confirmed multiple beta-cell autoantibodies

  development of persistent confirmed multiple beta-cell autoantibodies (defined as confirmed IAA, confirmed GADA, confirmed IA-2A, or confirmed ZnT8A in two consecutive samples, AND a confirmed second antibody from these four antibodies in one sample.

  elapsed time from treatment assignment (baseline) to first positive sample visit (>2 beta-cell antibodies) in children who develop persistent confirmed multiple beta-cell antibodies. Primary outcome can develop any time up to last study visit at 7.5 yrs

• The development of diabetes

  OGTT criteria or clinical criteria for diabetes as defined by the American Diabetes Association (ADA).

  elapsed time from random treatment assignment (baseline) to the development diabetes (date of diagnosis). This primary outcome measure can develop any time during treatment or follow-up period up to the last study visit at 7.5 years of age

Secondary Outcomes (4)

• Any persistent confirmed beta-cell autoantibody or diabetes

  elapsed time from treatm. assignm. (baseline) to 1st pos. sample for >1 beta-cell antibody in children who developed persist. confirm. beta-cell antibodies OR diabetes onset, whichever is first. outcome can develop any time up to last visit at 7.5 yr

• Persistent confirmed IAA.

  elapsed time from treatment assignment (baseline) to first sample that is positive for IAA in children who develop persistent confirmed IAA. Outcome can develop any time during treatment or follow-up period up to the last study visit at 7.5 years of age.

• Persistent confirmed GADA.

  elapsed time from treatment assignment (baseline) to the first sample that is positive for GADA in children who develop persistent confirmed GADA. Outcome can develop any time up to the last study visit at 7.5 years of age

• Abnormal glucose tolerance (AGT) defined by dysglycemia or diabetes.

  elapsed time from treatment assignment to the date at which abnormal glucose tolerance or diabetes is diagnosed. Outcome can develop any time up to the last study visit at 7.5 years of age

Study Arms (2)

oral insulin capsule (dose escalation using 3 dose strengths)

EXPERIMENTAL

Dose 1 is 7.5 mg rH-insulin crystals; dose 2 is 22.5 mg rH-insulin crystals; dose 3 is 67.5 mg rH-insulin crystals. The insulin crystals are formulated together with filling substance (microcrystalline cellulose to a total weight of 200 mg) and contained in hard gelatine capsules. The study treatment will be given orally.

Drug: Oral Insulin

Placebo capsule

PLACEBO COMPARATOR

Daily treatment with placebo capsules containing filling substance (microcrystalline cellulose).

Other: Placebo

Interventions

Oral Insulin DRUG

treatment starting at 4 months - 7 months until age 3.0 years; dose escalation scheme: daily treatment with 7.5 mg or placebo for 2 months; increasing to daily treatment with 22.5 mg or placebo for the following 2 months; increasing to daily treatment with 67.5 mg or placebo until the end of the treatment period.

oral insulin capsule (dose escalation using 3 dose strengths)

Placebo OTHER

treatment starting at age 4 months - 7 months until age 3.0 years; daily treatment with insulin or placebo capsules containing filling substance (microcrystalline cellulose).

Placebo capsule

Eligibility Criteria

• Age: 4 Months - 7 Months
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)

You may qualify if:

• \. Infant between the ages of 4 months and 7 months at the time of randomization.
• \. A high genetic risk (\>10%) to develop beta-cell autoantibodies by age 6 years:
• For infants without a first degree family history of type 1 diabetes, high genetic risk is defined as a DR3/DR4-DQ8 or DR4-DQ8/DR4-DQ8 genotype, and a genetic risk score that is \>14.4.
• For infants with a first degree family history of type 1 diabetes, high genetic risk is defined as having HLA DR4 and DQ8, and none of the following protective alleles: DRB1\*1501, DQB1\*0503.
• Solid foods introduced into diet of infant
• Written informed consent signed by the custodial parent(s).

You may not qualify if:

• Concomitant disease or treatment that may interfere with the assessments, as judged by the investigators.
• Any condition that could be associated with poor compliance.
• Any medical condition or medical condition coexisting, which, in the opinion of the investigator, may jeopardize the participant's safe participation in the study.
• Diagnosis of diabetes at the time of recruitment.
• Participation in another clinical trial.

Sponsors & Collaborators

• Technical University of Munich: lead
• Helmholtz Zentrum München: collaborator
• University Hospital Carl Gustav Carus: collaborator
• Kinderkrankenhaus auf der Bult: collaborator
• Skane University Hospital: collaborator
• Universitaire Ziekenhuizen KU Leuven: collaborator
• Medical University of Warsaw: collaborator
• University of Oxford, Clinical Vaccine Research and Immunisation Education: collaborator

Study Sites (7)

University Hospitals Leuven, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium

Leuven, 3000, Belgium

Location

Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany

Munich, Bavaria, 80804, Germany

Location

AUF DER BULT, Kinder- und Jugendkrankenhaus, Hanover, Germany

Hanover, Lower Saxony, 30173, Germany

Location

Klinik und Poliklinik f. Kinder und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, CRTD/DFG-Forschungszentrum für Regenerative Therapien, Dresden, Germany

Dresden, Saxony, 01307, Germany

Location

Medical University of Warsaw, Department of Paediatrics, Warsaw, Poland

Warsaw, 00-001, Poland

Location

Lund University Dep. of Clinical Sciences Malmo, Skane University Hospital SUS, University Hospital MAS, Malmo, Sweden

Malmo, 202 13, Sweden

Location

Department of Paediatrics Clinical Vaccine Research and Immunisation Education, Children's Hospital, Headington, Oxford, UK

Oxford, OX3 9DU, United Kingdom

Location

Related Publications (3)

• Ziegler AG, Achenbach P, Weiss A, Berner R, Casteels K, Elding Larsson H, Haupt F, Hommel A, Jacobs A, Kordonouri O, Lundgren M, Oltarzewski M, Pfirrmann M, Snape MD, Szypowska A, Todd JA, Vatish M, von dem Berge T, Winkler C, Bonifacio E; GPPAD-POInT Study Group. 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. Lancet. 2025 Nov 29;406(10519):2564-2576. doi: 10.1016/S0140-6736(25)01726-X. Epub 2025 Nov 11.

  PMID: 41237794 DERIVED

• Jacobsen LM, Schatz DA. Insulin immunotherapy for pretype 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2021 Aug 1;28(4):390-396. doi: 10.1097/MED.0000000000000648.

  PMID: 34091488 DERIVED

• Ziegler AG, Achenbach P, Berner R, Casteels K, Danne T, Gundert M, Hasford J, Hoffmann VS, Kordonouri O, Lange K, Elding Larsson H, Lundgren M, Snape MD, Szypowska A, Todd JA, Bonifacio E; GPPAD Study group. Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol. BMJ Open. 2019 Jun 28;9(6):e028578. doi: 10.1136/bmjopen-2018-028578.

  PMID: 31256036 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus

Interventions

Insulin

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Proinsulin; Insulins; Pancreatic Hormones; Peptide Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptides; Amino Acids, Peptides, and Proteins

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2017
• First Posted: December 7, 2017
• Study Start: February 7, 2018
• Primary Completion: June 28, 2024
• Study Completion: June 28, 2024
• Last Updated: October 8, 2024

Record last verified: 2024-10

Locations

BE (1); PL (1); DE (3); GB (1); SE (1)