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

• Sponsor: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00419562
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), National Institute of Allergy and Infectious Diseases (NIAID) (NIH), National Center for Research Resources (NCRR) (NIH), American Diabetes Association (Other), Juvenile Diabetes Research Foundation (Other)
• Enrollment: 560
• Locations: 18
• Arms: 2
• Duration (Months): 124
• Patients Per Site: 31.1
• Patients Per Site Per Month: 0.3

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 1	Drug: Oral Insulin; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 560 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• Official Title: Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Oral Insulin 7.5 mg oral insulin capsules given before breakfast on a daily basis.	Drug: Oral Insulin; 7.5 mg oral insulin or placebo given before breakfast on a daily basis.
Placebo Comparator: Placebo Placebo capsule designed to match appearance of treatment capsule	Drug: Placebo; Placebo capsule designed to match active drug

Outcome Measures

Primary Outcome Measures

1. Rate of Type 1 Diabetes Per Year Among Individuals in the Primary Stratum When Treated With Oral Inulin Versus Placebo [Metabolic and immunological tests were conducted every 6 months; participants were followed for a median of 2.7 years]

   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

1. 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]

   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.

2. 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]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

1. mIAA confirmed positive within the previous six months.

2. 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)

1. Subject has HLA DQA10102, DQB10602 haplotype.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California-San Francisco	San Francisco	California	United States	94143
2	Stanford University	Stanford	California	United States	94305
3	Barbara Davis Center for Childhood Diabetes	Aurora	Colorado	United States	80010
4	Yale University	New Haven	Connecticut	United States	06520
5	University of Florida	Gainesville	Florida	United States	32610-0296
6	University of Miami	Miami	Florida	United States	33136
7	Indiana University-Riley Hospital for Children	Indianapolis	Indiana	United States	46202
8	University of Minnesota	Minneapolis	Minnesota	United States	55455
9	Columbia University	New York	New York	United States	10032
10	Childrens Hospital of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213
11	Vanderbilt Eskind Diabetes Clinic	Nashville	Tennessee	United States	37232-8160
12	University of Texas	Dallas	Texas	United States	75235-8858
13	Benaroya Research Institute	Seattle	Washington	United States	98101
14	Walter and Eliza Hall Institute	Parkville	Victoria	Australia	3050
15	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G1X8
16	University of Turku	Turku		Finland	FIN-20520
17	San Raffaele Hospital	Milan		Italy	20132
18	University of Bristol	Bristol		United Kingdom	BS10 5NB

Sponsors and Collaborators

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

Investigators

• Study Chair: Carla J Greenbaum, M.D., Benaroya Research Institute
• Principal Investigator: Jeff Krischer, Ph.D., University of South Florida

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

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

• Responsible Party: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• ClinicalTrials.gov Identifier: NCT00419562
• Other Study ID Numbers: TN07 Oral Insulin; UC4DK106993; UC4DK117009
• First Posted: Jan 8, 2007
• Last Update Posted: May 7, 2020
• Last Verified: Apr 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): 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
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Insulin

Study Results

Participant Flow

Arm/Group Title	7.5 mg Oral Insulin Capsules	Placebo Capsule
Arm/Group Description	given before breakfast on a daily basis.	designed to mimic appearance of treatment capsule
Period Title: Overall Study
STARTED	283	277
COMPLETED	250	246
NOT COMPLETED	33	31

Baseline Characteristics

Arm/Group Title	Oral Insulin	Placebo	Total
Arm/Group Description	7.5 mg oral insulin capsules given before breakfast on a daily basis.	Placebo capsule designed to mimic appearance of treatment capsule	Total of all reporting groups
Overall Participants	283	277	560
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	8.2	8.2	8.2
Sex: Female, Male (Count of Participants)
Female	113 39.9%	107 38.6%	220 39.3%
Male	170 60.1%	170 61.4%	340 60.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	27 9.5%	25 9%	52 9.3%
Not Hispanic or Latino	256 90.5%	252 91%	508 90.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	252 89%	249 89.9%	501 89.5%
African American	8 2.8%	9 3.2%	17 3%
Asian/Pacific Islander	4 1.4%	6 2.2%	10 1.8%
Not Reported	19 6.7%	13 4.7%	32 5.7%
Region of Enrollment (Count of Participants)
Canada	17 6%	15 5.4%	32 5.7%
United States	226 79.9%	227 81.9%	453 80.9%
Finland	4 1.4%	5 1.8%	9 1.6%
Italy	7 2.5%	7 2.5%	14 2.5%
United Kingdom	6 2.1%	6 2.2%	12 2.1%
Australia	7 2.5%	4 1.4%	11 2%
Sweden	5 1.8%	3 1.1%	8 1.4%
Germany	9 3.2%	6 2.2%	15 2.7%
New Zealand	3 1.1%	5 1.8%	8 1.4%
Stratum (Count of Participants)
1	203 71.7%	186 67.1%	389 69.5%
2	28 9.9%	27 9.7%	55 9.8%
3	51 18%	63 22.7%	114 20.4%
4	1 0.4%	1 0.4%	2 0.4%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Oral Insulin	Placebo
Arm/Group Description	7.5 mg oral insulin capsules given before breakfast on a daily basis.	Placebo capsule designed to mimic appearance of treatment capsule
Measure Participants	203	186
Number (95% Confidence Interval) [Proportion with diabetes/year]	0.088	0.102

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Stratum 2: mIAA Confirmed, (ICA Confirmed) OR (ICA Not Confirmed AND ICA512+ AND GAD65ab+), low functioning beta cells

Arm/Group Title	Oral Insulin	Placebo
Arm/Group Description	7.5 mg oral insulin capsules given before breakfast on a daily basis.	Placebo capsule designed to mimic appearance of treatment capsule
Measure Participants	28	27
Number (95% Confidence Interval) [Proportion with diabetes/year]	0.181	0.341

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Combine stratum 3 (mIAA Confirmed, ICA Not Confirmed, ICA512+ OR GAD65ab+, high functioning beta cells) and stratum 4 (mIAA Confirmed, ICA Not Confirmed, ICA512+ OR GAD65ab+, low functioning beta cells)

Arm/Group Title	Oral Insulin	Placebo
Arm/Group Description	7.5 mg oral insulin capsules given before breakfast on a daily basis.	Placebo capsule designed to mimic appearance of treatment capsule
Measure Participants	52	64
Number (95% Confidence Interval) [Proportion with diabetes/year]	0.051	0.047

Adverse Events

Arm/Group Title	Oral Insulin		Placebo
Arm/Group Description	7.5 mg oral insulin capsules given before breakfast on a daily basis.		Placebo capsule designed to mimic appearance of treatment capsule
All Cause Mortality
	Oral Insulin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/283 (0%)		0/277 (0%)
Serious Adverse Events
	Oral Insulin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/283 (0%)		0/277 (0%)
Other (Not Including Serious) Adverse Events
	Oral Insulin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	150/283 (53%)		133/277 (48%)
Endocrine disorders
Endocrine	18/283 (6.4%)	18	12/277 (4.3%)	12
Gastrointestinal disorders
Gastrointestinal	28/283 (9.9%)	30	25/277 (9%)	34
Immune system disorders
Allergy/Immunology	17/283 (6%)	18	11/277 (4%)	11
Infections and infestations
Infection	67/283 (23.7%)	134	62/277 (22.4%)	120
Musculoskeletal and connective tissue disorders
Musculoskeletal/Soft Tissue	38/283 (13.4%)	45	18/277 (6.5%)	20
Respiratory, thoracic and mediastinal disorders
Pulmonary/Upper Respiratory	30/283 (10.6%)	51	30/277 (10.8%)	37
Skin and subcutaneous tissue disorders
Dermatology/Skin	25/283 (8.8%)	29	18/277 (6.5%)	20

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.