Clinical trial NCT03364868: GPPAD-POInT (Global Platform of Autoimmune Diabetes - Primary Oral Insulin Trial)
Official title: Oral Insulin Therapy for Prevention of Autoimmune Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Technical University of Munich
Sponsor class: OTHER
Collaborators: name: Helmholtz Zentrum München
name: University Hospital Carl Gustav Carus
name: Kinderkrankenhaus auf der Bult
name: Skane University Hospital
name: Universitaire Ziekenhuizen KU Leuven
name: Medical University of Warsaw
name: University of Oxford, Clinical Vaccine Research and Immunisation Education
First posted: 2017-12-07
Enrollment: 1050
Sex: ALL
Minimum age (years): 4
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Detailed description: The GPPAD-POInT-Study aims to determine whether daily administration of oral insulin to children from age 4 months - 7 months with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies and diabetes in childhood. The purpose of the GPPAD-POInT-Study is to induce immune tolerance to beta-cell autoantigens through regular exposure to oral insulin for a period of 29 to 32 months. Together with the results of the Pre-POINT-Early Study, this phase IIb study aims to investigate and consolidate the findings from the pilot Pre-POINT Study, namely safety and immune efficacy at a daily dose of 67.5 mg oral insulin. Since babies and young children will be tested in the GPPAD-POInT-Study, the 67.5 mg dose will be reached by dose escalation starting at 7.5 mg for 2 months, followed by exposure to 22.5 mg for 2 months, and reaching the desired 67.5 mg dose. The GPPAD-POInT-Study aims to recruit 1040 children into the trial.

The active substance for oral application is human insulin. Oral Insulin will be applied as a capsule containing 7.5, 22.5 and 67.5 mg of the active substance together with filling substance microcrystalline cellulose.

Eligibility criteria: Inclusion Criteria:

1. Infant between the ages of 4 months and 7 months at the time of randomization.

2. A high genetic risk (\>10%) to develop beta-cell autoantibodies by age 6 years:

1. 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.
2. 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.
3. Solid foods introduced into diet of infant
4. Written informed consent signed by the custodial parent(s).

Exclusion Criteria:

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

Primary outcomes:
measure: The development of persistent confirmed multiple beta-cell autoantibodies
timeFrame: 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
measure: The development of diabetes
timeFrame: 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:
measure: Any persistent confirmed beta-cell autoantibody or diabetes
timeFrame: 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
measure: Persistent confirmed IAA.
timeFrame: 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.
measure: Persistent confirmed GADA.
timeFrame: 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
measure: Abnormal glucose tolerance (AGT) defined by dysglycemia or diabetes.
timeFrame: 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
Other outcomes:
Locations:
city: Leuven
country: Belgium
facility: University Hospitals Leuven, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
city: Munich
country: Germany
facility: Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
state: Bavaria
city: Hanover
country: Germany
facility: AUF DER BULT, Kinder- und Jugendkrankenhaus, Hanover, Germany
state: Lower Saxony
city: Dresden
country: Germany
facility: Klinik und Poliklinik f. Kinder und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, CRTD/DFG-Forschungszentrum für Regenerative Therapien, Dresden, Germany
state: Saxony
city: Warsaw
country: Poland
facility: Medical University of Warsaw, Department of Paediatrics, Warsaw, Poland
city: Malmö
country: Sweden
facility: Lund University Dep. of Clinical Sciences Malmo, Skane University Hospital SUS, University Hospital MAS, Malmo, Sweden
city: Oxford
country: United Kingdom
facility: Department of Paediatrics Clinical Vaccine Research and Immunisation Education, Children's Hospital, Headington, Oxford, UK
Study officials:
References:
citation: 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.
citation: 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.