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

Diabetes Mellitus, Type 1 Clinical Trial

— TN07  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00419562
• Other study ID #: TN07 Oral Insulin
• Secondary ID: UC4DK106993UC4DK
• Status: Completed
• Phase: Phase 3
• Start date: February 2007
• Est. completion date: June 2017

Study information

• Verified date: April 2020
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 560
• Est. completion date: June 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 45 Years

Eligibility

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.

Exclusion Criteria:

1. Does not satisfy the above inclusion criteria. Subjects with mIAA positive but no other autoantibodies positive are not eligible for randomization.

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.

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1

Intervention

Drug:
• Oral Insulin
7.5 mg oral insulin or placebo given before breakfast on a daily basis.
• Placebo
Placebo capsule designed to match active drug

Locations

Country	Name	City	State
Australia	Walter and Eliza Hall Institute	Parkville	Victoria
Canada	The Hospital for Sick Children	Toronto	Ontario
Finland	University of Turku	Turku
Italy	San Raffaele Hospital	Milan
United Kingdom	University of Bristol	Bristol
United States	Barbara Davis Center for Childhood Diabetes	Aurora	Colorado
United States	University of Texas	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Indiana University-Riley Hospital for Children	Indianapolis	Indiana
United States	University of Miami	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt Eskind Diabetes Clinic	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of California-San Francisco	San Francisco	California
United States	Benaroya Research Institute	Seattle	Washington
United States	Stanford University	Stanford	California

Sponsors (6)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	American Diabetes Association, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Juvenile Diabetes Research Foundation, National Center for Research Resources (NCRR), National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Finland,  Italy,  United Kingdom, 

References & 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. — View Citation

Lachin JM. Maximum information designs. Clin Trials. 2005;2(5):453-64. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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 Tr — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo	Secondary outcome is reported as the rate of type 1 diabetes per year among secondary stratum 2; 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	Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo	Secondary outcome is reported as the rate of type 1 diabetes per year among secondary stratum 3+4; 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

External Links

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