Clinical trial NCT00419562: Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
Official title: Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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
Lead sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Sponsor class: NIH
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: National Institute of Allergy and Infectious Diseases (NIAID)
name: National Center for Research Resources (NCRR)
name: American Diabetes Association
name: Juvenile Diabetes Research Foundation
First posted: 2007-01-08
Enrollment: 560
Sex: ALL
Minimum age (years): 3
Maximum age (years): 45
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

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.

Primary outcomes:
measure: Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo
timeFrame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
Secondary outcomes:
measure: Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo
timeFrame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
measure: Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo
timeFrame: Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California-San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Aurora
country: United States
facility: Barbara Davis Center for Childhood Diabetes
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Gainesville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Indianapolis
country: United States
facility: Indiana University-Riley Hospital for Children
state: Indiana
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: New York
country: United States
facility: Columbia University
state: New York
city: Pittsburgh
country: United States
facility: Childrens Hospital of Pittsburgh
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt Eskind Diabetes Clinic
state: Tennessee
city: Dallas
country: United States
facility: University of Texas
state: Texas
city: Seattle
country: United States
facility: Benaroya Research Institute
state: Washington
city: Parkville
country: Australia
facility: Walter and Eliza Hall Institute
state: Victoria
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Turku
country: Finland
facility: University of Turku
city: Milan
country: Italy
facility: San Raffaele Hospital
city: Bristol
country: United Kingdom
facility: University of Bristol
Study officials:
affiliation: Benaroya Research Institute
name: Carla J Greenbaum, M.D.
role: STUDY_CHAIR
affiliation: University of South Florida
name: Jeff Krischer, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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. doi: 10.1002/dmr.5610090408. No abstract available.
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. doi: 10.1172/JCI117707.
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. doi: 10.1073/pnas.88.22.10252.
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. doi: 10.2337/diacare.28.5.1068.
citation: Lachin JM. Maximum information designs. Clin Trials. 2005;2(5):453-64. doi: 10.1191/1740774505cn115oa.
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 Trial. JAMA. 2017 Nov 21;318(19):1891-1902. doi: 10.1001/jama.2017.17070.