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

• ClinicalTrials.gov Identifier: NCT03364868
• Recruitment Status: Active, not recruiting
• First Posted: December 7, 2017
• Last Update Posted: September 25, 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
• Information provided by (Responsible Party): Technical University of Munich

Tracking Information

• First Submitted Date: November 13, 2017
• First Posted Date: December 7, 2017
• Last Update Posted Date: September 25, 2023
• Actual Study Start Date: February 7, 2018
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 6, 2017)

• The development of persistent confirmed multiple beta-cell autoantibodies [ 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 ]
  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 [ 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 ]
  OGTT criteria or clinical criteria for diabetes as defined by the American Diabetes Association (ADA).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: December 6, 2017)

• Any persistent confirmed beta-cell autoantibody or diabetes [ 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 ]
  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. [ 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. ]
  Confirmed IAA in two consecutive samples.
• Persistent confirmed GADA. [ 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 ]
  Confirmed GADA in two consecutive samples.
• Abnormal glucose tolerance (AGT) defined by dysglycemia or diabetes. [ 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 ]
  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).

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: GPPAD-POInT (Global Platform of Autoimmune Diabetes - Primary Oral Insulin Trial)
• Official Title: Oral Insulin Therapy for Prevention of Autoimmune Diabetes
• 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Prevention
• Condition: Diabetes Mellitus, Type 1

Intervention

• Drug: Oral Insulin
  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.
• Other: Placebo
  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).

Study Arms

• Experimental: oral insulin capsule (dose escalation using 3 dose strengths)
  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.
  Intervention: Drug: Oral Insulin
• Placebo Comparator: Placebo capsule
  Daily treatment with placebo capsules containing filling substance (microcrystalline cellulose).
  Intervention: Other: Placebo

Publications *

• 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.
• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 25, 2021): 1050
• Original Estimated Enrollment (submitted: December 6, 2017): 1040
• Estimated Study Completion Date: June 2024
• Estimated Primary Completion Date: June 2024 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 4 Months to 7 Months (Child)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Germany, Poland, Sweden, United Kingdom

Administrative Information

• NCT Number: NCT03364868
• Other Study ID Numbers: GPPAD-03-POInT
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Technical University of Munich
• Original Responsible Party: Same as current
• Current Study Sponsor: Technical University of Munich
• Original Study Sponsor: Same as current

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

• Investigators: Not Provided
• PRS Account: Technical University of Munich
• Verification Date: September 2023