search
Back to results

Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus (TN07)

Primary Purpose

Diabetes Mellitus, Type 1

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Oral Insulin
Placebo
Sponsored by
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Diabetes Mellitus, Type 1 focused on measuring 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

Eligibility Criteria

3 Years - 45 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of California-San Francisco
  • Stanford University
  • Barbara Davis Center for Childhood Diabetes
  • Yale University
  • University of Florida
  • University of Miami
  • Indiana University-Riley Hospital for Children
  • University of Minnesota
  • Columbia University
  • Childrens Hospital of Pittsburgh
  • Vanderbilt Eskind Diabetes Clinic
  • University of Texas
  • Benaroya Research Institute
  • Walter and Eliza Hall Institute
  • The Hospital for Sick Children
  • University of Turku
  • San Raffaele Hospital
  • University of Bristol

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Oral Insulin

Placebo

Arm Description

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

Placebo capsule designed to match appearance of treatment capsule

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.

Full Information

First Posted
January 4, 2007
Last Updated
April 27, 2020
Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID), National Center for Research Resources (NCRR), American Diabetes Association, Juvenile Diabetes Research Foundation
search

1. Study Identification

Unique Protocol Identification Number
NCT00419562
Brief Title
Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
Acronym
TN07
Official Title
Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
Study Type
Interventional

2. Study Status

Record Verification Date
April 2020
Overall Recruitment Status
Completed
Study Start Date
February 2007 (undefined)
Primary Completion Date
December 2016 (Actual)
Study Completion Date
June 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Allergy and Infectious Diseases (NIAID), National Center for Research Resources (NCRR), American Diabetes Association, Juvenile Diabetes Research Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
560 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Oral Insulin
Arm Type
Experimental
Arm Description
7.5 mg oral insulin capsules given before breakfast on a daily basis.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo capsule designed to match appearance of treatment capsule
Intervention Type
Drug
Intervention Name(s)
Oral Insulin
Intervention Description
7.5 mg oral insulin or placebo given before breakfast on a daily basis.
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo capsule designed to match active drug
Primary Outcome Measure Information:
Title
Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo
Description
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.
Time Frame
Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
Secondary Outcome Measure Information:
Title
Rate of Type 1 Diabetes Per Year in Secondary Stratum (Stratum 2) When Treated With Oral Insulin Versus Placebo
Description
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.
Time Frame
Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years
Title
Rate of Type 1 Diabetes in Secondary Stratum (Stratum 3+4) When Treated With Oral Insulin Versus Placebo
Description
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.
Time Frame
Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
3 Years
Maximum Age & Unit of Time
45 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 2 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. Exclusion Criteria: Does not satisfy the above inclusion criteria. Subjects with mIAA positive but no other autoantibodies positive are not eligible for randomization. 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 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) Subject has HLA DQA1*0102, DQB1*0602 haplotype.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carla J Greenbaum, M.D.
Organizational Affiliation
Benaroya Research Institute
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Jeff Krischer, Ph.D.
Organizational Affiliation
University of South Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California-San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
Facility Name
Barbara Davis Center for Childhood Diabetes
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80010
Country
United States
Facility Name
Yale University
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
Facility Name
University of Florida
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610-0296
Country
United States
Facility Name
University of Miami
City
Miami
State/Province
Florida
ZIP/Postal Code
33136
Country
United States
Facility Name
Indiana University-Riley Hospital for Children
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46202
Country
United States
Facility Name
University of Minnesota
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Columbia University
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Childrens Hospital of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
Vanderbilt Eskind Diabetes Clinic
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232-8160
Country
United States
Facility Name
University of Texas
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235-8858
Country
United States
Facility Name
Benaroya Research Institute
City
Seattle
State/Province
Washington
ZIP/Postal Code
98101
Country
United States
Facility Name
Walter and Eliza Hall Institute
City
Parkville
State/Province
Victoria
ZIP/Postal Code
3050
Country
Australia
Facility Name
The Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G1X8
Country
Canada
Facility Name
University of Turku
City
Turku
ZIP/Postal Code
FIN-20520
Country
Finland
Facility Name
San Raffaele Hospital
City
Milan
ZIP/Postal Code
20132
Country
Italy
Facility Name
University of Bristol
City
Bristol
ZIP/Postal Code
BS10 5NB
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Data are available at the NIDDK Central Repository: https://repository.niddk.nih.gov/studies/tn07-oral-insulin/?query=tn07
IPD Sharing URL
https://repository.niddk.nih.gov/studies/tn07-oral-insulin/?query=tn07
Citations:
PubMed Identifier
7840857
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.
Results Reference
background
PubMed Identifier
7924825
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.
Results Reference
background
PubMed Identifier
7860747
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.
Results Reference
background
PubMed Identifier
1946445
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.
Results Reference
background
PubMed Identifier
15855569
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.
Results Reference
background
PubMed Identifier
16315649
Citation
Lachin JM. Maximum information designs. Clin Trials. 2005;2(5):453-64. doi: 10.1191/1740774505cn115oa.
Results Reference
background
PubMed Identifier
29164254
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.
Results Reference
result
Links:
URL
http://www.diabetestrialnet.org
Description
Type 1 Diabetes TrialNet
URL
http://www.diabetes.org
Description
American Diabetes Association
URL
http://www.jdrf.org
Description
Juvenile Diabetes Foundation International

Learn more about this trial

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

We'll reach out to this number within 24 hrs