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

NCT ID: NCT00419562

Last Updated: 2020-05-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 560 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-02-28
• Study Completion Date: 2017-06-30

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.

Detailed Description

Eligible participants will be randomized to receive either oral insulin (7.5 mg of recombinant human insulin crystals) or placebo daily.

All participants randomized into this study will be seen at a study site for a follow-up evaluation, three and six months after randomization, and every six months thereafter. Participants will be contacted by phone between 6-monthly clinic visits to assess changes in diabetes status, medication compliance and adverse events. These phone contacts will occur approximately 3 months from the date of the participants previous clinic visit.

At the study visits, participants will undergo assessments of their insulin production, immunologic status, and overall health. As the primary outcome measure, subjects will be followed until development of type 1 diabetes or the conclusion of the study. The trial is expected to last approximately 7-8 years or until the required amount of information is gathered.

Conditions

Diabetes Mellitus, Type 1

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: TRIPLE

Study Groups

Oral Insulin

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

Group Type: EXPERIMENTAL

Oral Insulin

Intervention Type: DRUG

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

Placebo

Placebo capsule designed to match appearance of treatment capsule

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo capsule designed to match active drug

Interventions

Oral Insulin

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

Intervention Type: DRUG

Placebo

Placebo capsule designed to match active drug

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. 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.

2. 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.

3. Willing to sign Informed Consent Form.

4. 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
• 2 hour plasma glucose < 140 mg/dL (7.8 mmol/l)

5. mIAA confirmed positive within the previous six months.

6. Two samples with at least one autoantibody other than mIAA positive within the previous six months.

2. 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.

3. Prior participation in a trial for prevention of T1DM, e.g. nicotinamide, insulin, immunosuppressive drugs.

4. History of treatment with insulin or oral hypoglycemic agent.

5. History of therapy with immunosuppressive drugs or glucocorticoids within the past two years for a period of more than three months.

6. 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.

7. Pregnant or intends to become pregnant while on study or lactating.

8. Deemed unlikely or unable to comply with the protocol.

9. 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
• 2 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
• 2 hour plasma glucose 140-199 mg/dL (7.8 - 11mmol/l),

IFG is defined by:

• fasting plasma glucose 110-125 mg/dL (6.1-6.9 mmol/l) AND
• 2 hour plasma glucose < 140 mg/dL (7.8 mmol/l)

10. Subject has HLA DQA1*0102, DQB1*0602 haplotype.

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

National Center for Research Resources (NCRR)

NIH

Sponsor Role: collaborator

American Diabetes Association

OTHER

Sponsor Role: collaborator

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carla J Greenbaum, M.D.

Role: STUDY_CHAIR

Benaroya Research Institute

Jeff Krischer, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

University of South Florida

Locations

University of California-San Francisco

San Francisco, California, United States

Stanford University

Stanford, California, United States

Barbara Davis Center for Childhood Diabetes

Aurora, Colorado, United States

Yale University

New Haven, Connecticut, United States

University of Florida

Gainesville, Florida, United States

University of Miami

Miami, Florida, United States

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, United States

University of Minnesota

Minneapolis, Minnesota, United States

Columbia University

New York, New York, United States

Childrens Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States

Vanderbilt Eskind Diabetes Clinic

Nashville, Tennessee, United States

University of Texas

Dallas, Texas, United States

Benaroya Research Institute

Seattle, Washington, United States

Walter and Eliza Hall Institute

Parkville, Victoria, Australia

The Hospital for Sick Children

Toronto, Ontario, Canada

University of Turku

Turku, , Finland

San Raffaele Hospital

Milan, , Italy

University of Bristol

Bristol, , United Kingdom

Countries

United States; Australia; Canada; Finland; Italy; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 7860747 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 1946445 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15855569 (View on PubMed)

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

Reference Type: BACKGROUND

PMID: 16315649 (View on PubMed)

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.

Reference Type: RESULT

PMID: 29164254 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 7840857 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 7924825 (View on PubMed)

Related Links

http://www.diabetestrialnet.org

Type 1 Diabetes TrialNet

http://www.diabetes.org

American Diabetes Association

http://www.jdrf.org

Juvenile Diabetes Foundation International

Other Identifiers

UC4DK106993

Identifier Type: NIH

Identifier Source: secondary_id

View Link

UC4DK117009

Identifier Type: NIH

Identifier Source: secondary_id

View Link

TN07 Oral Insulin

Identifier Type: -

Identifier Source: org_study_id