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

Primary Purpose

Diabetes Mellitus, Type 1

Status
Active
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
Oral Insulin
Placebo
Sponsored by
Technical University of Munich
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Diabetes Mellitus, Type 1 focused on measuring 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

Eligibility Criteria

4 Months - 7 Months (Child)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • University Hospitals Leuven, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
  • Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
  • AUF DER BULT, Kinder- und Jugendkrankenhaus, Hanover, Germany
  • Klinik und Poliklinik f. Kinder und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, CRTD/DFG-Forschungszentrum für Regenerative Therapien, Dresden, Germany
  • Medical University of Warsaw, Department of Paediatrics, Warsaw, Poland
  • Lund University Dep. of Clinical Sciences Malmo, Skane University Hospital SUS, University Hospital MAS, Malmo, Sweden
  • Department of Paediatrics Clinical Vaccine Research and Immunisation Education, Children's Hospital, Headington, Oxford, UK

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

oral insulin capsule (dose escalation using 3 dose strengths)

Placebo capsule

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Any persistent confirmed beta-cell autoantibody or diabetes
At least one confirmed autoantibody, in two consecutive samples, including GADA, IA-2A, IAA, ZnT8A, or TS7A, or diabetes as defined by the American Diabetes Association (ADA).
Persistent confirmed IAA.
Confirmed IAA in two consecutive samples.
Persistent confirmed GADA.
Confirmed GADA in two consecutive samples.
Abnormal glucose tolerance (AGT) defined by dysglycemia or diabetes.
Dysglycemia is defined as impaired fasting plasma glucose of ≥110 mg/dL (6.1 mmol/L), or impaired 2-hour glucose of ≥140 mg/dL (7.8 mmol/L), or high glucose levels at intermediate time points on OGTT (30, 60, 90 min) levels of ≥200mg/dL (11.1 mmol/L)). Diabetes is defined according to the criteria of the American Diabetes Association (ADA).

Full Information

First Posted
November 13, 2017
Last Updated
September 22, 2023
Sponsor
Technical University of Munich
Collaborators
Helmholtz Zentrum München, University Hospital Carl Gustav Carus, Kinderkrankenhaus auf der Bult, Skane University Hospital, Universitaire Ziekenhuizen KU Leuven, Medical University of Warsaw, University of Oxford, Clinical Vaccine Research and Immunisation Education
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1. Study Identification

Unique Protocol Identification Number
NCT03364868
Brief Title
GPPAD-POInT (Global Platform of Autoimmune Diabetes - Primary Oral Insulin Trial)
Official Title
Oral Insulin Therapy for Prevention of Autoimmune Diabetes
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
February 7, 2018 (Actual)
Primary Completion Date
June 2024 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Technical University of Munich
Collaborators
Helmholtz Zentrum München, University Hospital Carl Gustav Carus, Kinderkrankenhaus auf der Bult, Skane University Hospital, Universitaire Ziekenhuizen KU Leuven, Medical University of Warsaw, University of Oxford, Clinical Vaccine Research and Immunisation Education

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
1050 (Actual)

8. Arms, Groups, and Interventions

Arm Title
oral insulin capsule (dose escalation using 3 dose strengths)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo capsule
Arm Type
Placebo Comparator
Arm Description
Daily treatment with placebo capsules containing filling substance (microcrystalline cellulose).
Intervention Type
Drug
Intervention Name(s)
Oral Insulin
Intervention Description
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.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
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).
Primary Outcome Measure Information:
Title
The development of persistent confirmed multiple beta-cell autoantibodies
Description
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.
Time Frame
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
Title
The development of diabetes
Description
OGTT criteria or clinical criteria for diabetes as defined by the American Diabetes Association (ADA).
Time Frame
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 Outcome Measure Information:
Title
Any persistent confirmed beta-cell autoantibody or diabetes
Description
At least one confirmed autoantibody, in two consecutive samples, including GADA, IA-2A, IAA, ZnT8A, or TS7A, or diabetes as defined by the American Diabetes Association (ADA).
Time Frame
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
Title
Persistent confirmed IAA.
Description
Confirmed IAA in two consecutive samples.
Time Frame
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.
Title
Persistent confirmed GADA.
Description
Confirmed GADA in two consecutive samples.
Time Frame
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
Title
Abnormal glucose tolerance (AGT) defined by dysglycemia or diabetes.
Description
Dysglycemia is defined as impaired fasting plasma glucose of ≥110 mg/dL (6.1 mmol/L), or impaired 2-hour glucose of ≥140 mg/dL (7.8 mmol/L), or high glucose levels at intermediate time points on OGTT (30, 60, 90 min) levels of ≥200mg/dL (11.1 mmol/L)). Diabetes is defined according to the criteria of the American Diabetes Association (ADA).
Time Frame
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Months
Maximum Age & Unit of Time
7 Months
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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: 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). Exclusion Criteria: 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.
Facility Information:
Facility Name
University Hospitals Leuven, Faculty of Medicine, Catholic University of Leuven, Leuven, Belgium
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
City
Munich
State/Province
Bavaria
ZIP/Postal Code
80804
Country
Germany
Facility Name
AUF DER BULT, Kinder- und Jugendkrankenhaus, Hanover, Germany
City
Hanover
State/Province
Lower Saxony
ZIP/Postal Code
30173
Country
Germany
Facility Name
Klinik und Poliklinik f. Kinder und Jugendmedizin, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, CRTD/DFG-Forschungszentrum für Regenerative Therapien, Dresden, Germany
City
Dresden
State/Province
Saxony
ZIP/Postal Code
01307
Country
Germany
Facility Name
Medical University of Warsaw, Department of Paediatrics, Warsaw, Poland
City
Warsaw
ZIP/Postal Code
00-001
Country
Poland
Facility Name
Lund University Dep. of Clinical Sciences Malmo, Skane University Hospital SUS, University Hospital MAS, Malmo, Sweden
City
Malmö
ZIP/Postal Code
202 13
Country
Sweden
Facility Name
Department of Paediatrics Clinical Vaccine Research and Immunisation Education, Children's Hospital, Headington, Oxford, UK
City
Oxford
ZIP/Postal Code
OX3 9DU
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
34091488
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.
Results Reference
derived
PubMed Identifier
31256036
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.
Results Reference
derived

Learn more about this trial

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

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