Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus

NCT00419562 | Completed Phase 3 Results DMC FDA Drug

• 3 other identifiers: TN07 Oral InsulinUC4DK106993UC4DK117009
• Study Type: interventional
• Target: 560
• Locations: 6 countries
• Sites: 18

Brief Summary

Type 1 diabetes (T1D) is an autoimmune disease. This means that the immune system (the part of the body which helps fight infections) mistakenly attacks and destroys the cells that produce insulin (islet cells found in the pancreas). As these cells are destroyed, the body's ability to produce insulin decreases. There is evidence suggesting that repeated oral administration of an autoantigen (the same protein that the immune system is reacting to) may introduce a protective immunity and cause the immune system to stop its attack. An earlier, large scale study was done to see if oral insulin could delay or prevent the development of Type 1 diabetes in relatives at risk for developing Type 1 diabetes. The overall results showed that for the entire study population, oral insulin did not delay or prevent Type 1 diabetes. However, an analysis that was done after the conclusion of the trial suggested a potential beneficial effect in a subgroup of participants. The participants who seemed to benefit from oral insulin had higher levels of insulin autoantibodies which are directed against insulin itself ( called mIAA). The Type 1 Diabetes TrialNet study group will further explore the potential role of oral insulin to delay or prevent Type 1 diabetes in a similar group of people. The study will also include a secondary group of individuals at different levels of risk than those in the primary cohort to gather information for future studies.

Conditions

Diabetes Mellitus, Type 1

Keywords

oral insulin; autoantigen; self tolerance; oral tolerance; Diabetes Prevention Trial - 1 (DPT-1); prevention; "at risk" for developing type 1 diabetes; juvenile diabetes; Type 1 diabetes (T1D); diabetes mellitus; Type 1 diabetes TrialNet; TrialNet

Outcome Measures

Primary Outcomes (1)

• Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo

  Primary outcome is reported as the rate of type 1 diabetes per year among the primary stratum; type 1 diabetes was diagnosed based on metabolic testing and assessment of symptoms. This is calculated by dividing the number of participants who develop diabetes by the total number of years of follow-up.

  Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years

Secondary Outcomes (2)

• Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo

  Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years

• Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo

  Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years

Study Arms (2)

Oral Insulin

EXPERIMENTAL

7.5 mg oral insulin capsules given before breakfast on a daily basis.

Drug: Oral Insulin

Placebo

PLACEBO COMPARATOR

Placebo capsule designed to match appearance of treatment capsule

Drug: Placebo

Interventions

Oral Insulin DRUG

7.5 mg oral insulin or placebo given before breakfast on a daily basis.

Oral Insulin

Placebo DRUG

Placebo capsule designed to match active drug

Placebo

Eligibility Criteria

• Age: 3 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Have a proband with Type 1 diabetes mellitus (T1DM). A proband is an individual diagnosed with diabetes before age 40 and started on insulin therapy within 1-year of diagnosis. Probands considered to have type 1 diabetes by their physician who do not meet this definition will be referred to the TrialNet Eligibility Committee.
• If the proband is a parent, sibling or a child, the study participant must be 3 -45 years of age. If the proband is a second or third degree relative (i.e. niece, nephew, aunt, uncle, grandparent, cousin, or half-sibling), the study participant must be 3-20 years of age.
• Willing to sign Informed Consent Form.
• Oral glucose tolerance test (OGTT) performed within 7 weeks prior to randomization in which:
• fasting plasma glucose \< 110 mg/dL (6.1 mmol/l), and
• hour plasma glucose \< 140 mg/dL (7.8 mmol/l)
• mIAA confirmed positive within the previous six months.
• Two samples with at least one autoantibody other than mIAA positive within the previous six months.

You may not qualify if:

• Has severe active disease, e.g. chronic active hepatitis, severe cardiac, pulmonary, renal, hepatic, immune deficiency and/or disease that is likely to limit life expectancy or lead to therapies such as immunosuppression during the time of the study.
• Prior participation in a trial for prevention of T1DM, e.g. nicotinamide, insulin, immunosuppressive drugs.
• History of treatment with insulin or oral hypoglycemic agent.
• History of therapy with immunosuppressive drugs or glucocorticoids within the past two years for a period of more than three months.
• Ongoing use of medications known to influence glucose, i.e. sulfonylureas, growth hormone, metformin, anticonvulsants, thiazide or potassium depleting diuretics, beta adrenergic blockers, niacin. Subjects on such medications should be changed to a suitable alternative, if available, and will become eligible one month after medication is discontinued.
• Pregnant or intends to become pregnant while on study or lactating.
• Deemed unlikely or unable to comply with the protocol.
• OGTT that reveals Diabetes, Impaired Glucose Tolerance (IGT), or Impaired Fasting Glucose (IFG).
• Diabetes is defined by:
• fasting plasma glucose ³ 126 mg/dL (7 mmol/l), OR
• hour plasma glucose ³ 200 mg/dL (11.1 mmol/l)
• IGT is defined by:
• fasting plasma glucose \< 126 mg/dL (7 mmol/l), and
• hour plasma glucose 140-199 mg/dL (7.8 - 11mmol/l),
• IFG is defined by:

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• National Center for Research Resources (NCRR): collaborator
• American Diabetes Association: collaborator
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (18)

University of California-San Francisco

San Francisco, California, 94143, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

Barbara Davis Center for Childhood Diabetes

Aurora, Colorado, 80010, United States

Location

Yale University

New Haven, Connecticut, 06520, United States

Location

University of Florida

Gainesville, Florida, 32610-0296, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Vanderbilt Eskind Diabetes Clinic

Nashville, Tennessee, 37232-8160, United States

Location

University of Texas

Dallas, Texas, 75235-8858, United States

Location

Benaroya Research Institute

Seattle, Washington, 98101, United States

Location

Walter and Eliza Hall Institute

Parkville, Victoria, 3050, Australia

Location

The Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

University of Turku

Turku, FIN-20520, Finland

Location

San Raffaele Hospital

Milan, 20132, Italy

Location

University of Bristol

Bristol, BS10 5NB, United Kingdom

Location

Related Publications (7)

• Bergerot I, Fabien N, Maguer V, Thivolet C. Oral administration of human insulin to NOD mice generates CD4+ T cells that suppress adoptive transfer of diabetes. J Autoimmun. 1994 Oct;7(5):655-63. doi: 10.1006/jaut.1994.1050.

  PMID: 7840857 BACKGROUND

• Muir A, Schatz D, Maclaren N. Antigen-specific immunotherapy: oral tolerance and subcutaneous immunization in the treatment of insulin-dependent diabetes. Diabetes Metab Rev. 1993 Dec;9(4):279-87. doi: 10.1002/dmr.5610090408. No abstract available.

  PMID: 7924825 BACKGROUND

• Muir A, Peck A, Clare-Salzler M, Song YH, Cornelius J, Luchetta R, Krischer J, Maclaren N. Insulin immunization of nonobese diabetic mice induces a protective insulitis characterized by diminished intraislet interferon-gamma transcription. J Clin Invest. 1995 Feb;95(2):628-34. doi: 10.1172/JCI117707.

  PMID: 7860747 BACKGROUND

• Zhang ZJ, Davidson L, Eisenbarth G, Weiner HL. Suppression of diabetes in nonobese diabetic mice by oral administration of porcine insulin. Proc Natl Acad Sci U S A. 1991 Nov 15;88(22):10252-6. doi: 10.1073/pnas.88.22.10252.

  PMID: 1946445 BACKGROUND

• Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-Mervis LE, Chase HP, Leschek E. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial--Type 1. Diabetes Care. 2005 May;28(5):1068-76. doi: 10.2337/diacare.28.5.1068.

  PMID: 15855569 BACKGROUND

• Lachin JM. Maximum information designs. Clin Trials. 2005;2(5):453-64. doi: 10.1191/1740774505cn115oa.

  PMID: 16315649 BACKGROUND

• Writing Committee for the Type 1 Diabetes TrialNet Oral Insulin Study Group; Krischer JP, Schatz DA, Bundy B, Skyler JS, Greenbaum CJ. Effect of Oral Insulin on Prevention of Diabetes in Relatives of Patients With Type 1 Diabetes: A Randomized Clinical Trial. JAMA. 2017 Nov 21;318(19):1891-1902. doi: 10.1001/jama.2017.17070.

  PMID: 29164254 RESULT

Related Links

• Type 1 Diabetes TrialNet
• American Diabetes Association
• Juvenile Diabetes Foundation International

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

Results Point of Contact

• Title: Carla Greenbaum
• Organization: Benaroya Research Institute

cjgreen@benaroyaresearch.org

Study Officials

• Carla J Greenbaum, M.D.

  Benaroya Research Institute

  STUDY CHAIR

• Jeff Krischer, Ph.D.

  University of South Florida

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 4, 2007
• First Posted: January 8, 2007
• Study Start: February 1, 2007
• Primary Completion: December 1, 2016
• Study Completion: June 1, 2017
• Last Updated: May 7, 2020
• Results First Posted: February 18, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share

Locations

FI (1); CA (1); AU (1); IT (1); US (13); GB (1)