Back to resultsTrial of Otelixizumab for Adolescents and Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-2 (DEFEND-2)
Primary Purpose
Diabetes Mellitus, Type 1
Status
Completed
Phase
Phase 3
Locations
Italy
Study Type
Interventional
Intervention
Otelixizumab
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring new onset type 1 diabetes, juvenile diabetes, T1DM, Type 1 diabetes
Eligibility Criteria
Inclusion Criteria:
- Ages 12-17
- Diagnosis of diabetes mellitus, consistent with ADA criteria
- No more than 90 days between diagnosis and administration of study compounds
- Requires insulin for type 1 diabetes mellitus, or has required insulin at some time between diagnosis and administration of study compounds. In Canada, has to be using insulin at the time of dosing.
- Stimulated C-peptide level greater than 0.20 nmol/L and less than or equal to 3.50 nmol/L
- Positive for one or more of the autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti-GAD); antibody to protein tyrosine phosphatase-like protein (anti-IA-2); zinc transporter autoantibodies (ZNT8); insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will only be eligible if the subject has used insulin for less than 7 days total.
Exclusion Criteria:
•Other, significant medical conditions based on the study doctor's evaluation
Sites / Locations
- GSK Investigational Site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
otelixizumab
placebo
Arm Description
otelixizumab
placebo
Outcomes
Primary Outcome Measures
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12
C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg per deciliter (mg/dL) and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the value at Month 12 from the Baseline value.
Secondary Outcome Measures
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months
C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18
C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Number of Participants With Responder Status
A participant was considered a responder when, at the given time point, the participant had: glycosylated hemoglobin (HbA1c) less than or equal to 6.5 percent and mean daily insulin use less than 0.5 international unit per kilogram per day (IU/kg/day) over 7 consecutive days during the 2 weeks preceding the visit.
Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment
Mean daily insulin use over 7 consecutive days during the 2 weeks preceding each key visit was calculated as the mean of the values of amount of insulin used per day on each of the 7 consecutive days. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment
HbA1c level was recorded at Baseline, Month 3, 6 and 12. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12
Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The numbers of participant-reported hypoglycemic events per participant of severe hypoglycemia and documented symptomatic hypoglycemia have been reported.
Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12
Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The percentage of participant with incidence of severe hypoglycemia and documented symptomatic hypoglycemia have been reported.
Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months
O'Brien mean rank analyses was performed on a two-part composite of the Baseline-adjusted HbA1c level and the Baseline-adjusted mean total daily insulin use per kg body weight in the otelixizumab group compared with the placebo group at Months 6 and 12. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. For the O'Brien mean rank analysis at a particular time point, adjusted HbA1c values (for both treatment groups together) and adjusted mean daily insulin use values was ranked from smallest to largest. For each participant, the HbA1c and insulin use ranks were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks. If otelixizumab treatment was effective on this composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group.
Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months
O'Brien analyses was performed on a three-part composite of HbA1c level, C-peptide AUC, and mean daily insulin use in the otelixizumab group compared with the placebo group at Months 6 and 12. The three variables was adjusted for Baseline values. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. HbA1c and insulin use was ranked from smallest to largest, and C-peptide AUC was ranked from largest to smallest. If otelixizumab treatment was effective on the composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group.
Full Information
NCT ID
NCT01123083
First Posted
May 11, 2010
Last Updated
August 17, 2017
Sponsor
GlaxoSmithKline
Collaborators
Juvenile Diabetes Research Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01123083
Brief Title
Trial of Otelixizumab for Adolescents and Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-2
Acronym
DEFEND-2
Official Title
Durable-Response Therapy Evaluation For Early- or New-Onset Type 1 Diabetes
Study Type
Interventional
2. Study Status
Record Verification Date
August 2017
Overall Recruitment Status
Completed
Study Start Date
May 17, 2010 (Actual)
Primary Completion Date
March 9, 2012 (Actual)
Study Completion Date
March 9, 2012 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
GlaxoSmithKline
Collaborators
Juvenile Diabetes Research Foundation
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
DEFEND-2 is a Phase 3 confirmatory study for the Phase 3 DEFEND-1 study. The study objective is to find out if an 8-day series of otelixizumab infusions leads to greater improvement in insulin secretion as compared with placebo. Insulin secretion will be assessed using mixed meal-stimulated C-peptide.
Subjects will be assigned to receive either otelixizumab or placebo at a ratio of 2:1 (2/3 otelixizumab, 1/3 placebo). These study agents will be administered as an addition to insulin, diet, and other standard of care treatments.
Detailed Description
The following visits are required:
Screening Visits: 2 to 3 appointments will be conducted to determine eligibility. At 2 of these visits participants will drink a liquid meal and have blood tests done over the post-meal period. Participants will also be required to wear a continuous glucose monitor for a short period of time.
Dosing Visits: 8 outpatient visits on consecutive days, each lasting about 2-4 hours.
Follow-up Visits: weekly for the first month, then every 2 weeks for 3 months, followed by monthly visits through 1 year. There will be 3 visits in the second year.
The total duration of the study is 2 years.
Glucose test strips and glucose monitors will be provided to participants for the duration of the study. Frequent glycemic monitoring will occur through lab testing and blood glucose self-monitoring to help facilitate tight glycemic control in all subjects. Subjects will be asked to intermittently record their insulin doses using a telephone or web based system and continuous glucose monitoring will be performed every 6 months.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
Keywords
new onset type 1 diabetes, juvenile diabetes, T1DM, Type 1 diabetes
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
179 (Actual)
8. Arms, Groups, and Interventions
Arm Title
otelixizumab
Arm Type
Experimental
Arm Description
otelixizumab
Arm Title
placebo
Arm Type
Placebo Comparator
Arm Description
placebo
Intervention Type
Biological
Intervention Name(s)
Otelixizumab
Other Intervention Name(s)
ChAglyCD3, TRX4, monoclonal antibody, anti-CD3
Intervention Description
infusion
Intervention Type
Biological
Intervention Name(s)
Placebo
Intervention Description
Infusion
Primary Outcome Measure Information:
Title
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide Area Under Curve (AUC) (Normalized for 120-minute Time Interval) at Month 12
Description
C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg per deciliter (mg/dL) and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the value at Month 12 from the Baseline value.
Time Frame
Baseline (Day 1) and Month 12
Secondary Outcome Measure Information:
Title
Change From Baseline in 2 Hour Mixed Meal-stimulated C-peptide AUC (Normalized for 120-minute Time Interval) at Week 12 and 6 Months
Description
C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Time Frame
Baseline (Day 1) and Week 12, Month 6
Title
Change From Baseline in Stimulated C-Peptide Mean AUC at Week 12, Month 6, 12 and 18
Description
C-peptide is a protein that shows how much insulin the body is producing. For 3 days before the mixed meal tolerance test participants were asked to eat a balanced diet. The test was performed only when the finger-stick blood glucose level was above 70 mg/dL and no higher than 200 mg/dL. Mixed meal-stimulated C-peptide AUC was the area under the C-peptide/time curve from time 0 to 120-minutes, calculated using the trapezoidal rule. This AUC was normalized for time interval by dividing it by 120-minutes (the number of minutes over which it was determined), and was adjusted by inclusion of Baseline C-peptide AUC as a covariate in the analysis. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Time Frame
Baseline (Day 1) and Week 12, Month 6, 12, 18
Title
Number of Participants With Responder Status
Description
A participant was considered a responder when, at the given time point, the participant had: glycosylated hemoglobin (HbA1c) less than or equal to 6.5 percent and mean daily insulin use less than 0.5 international unit per kilogram per day (IU/kg/day) over 7 consecutive days during the 2 weeks preceding the visit.
Time Frame
Month 3, 6 and 12
Title
Change From Baseline in Mean Daily Insulin Use Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment
Description
Mean daily insulin use over 7 consecutive days during the 2 weeks preceding each key visit was calculated as the mean of the values of amount of insulin used per day on each of the 7 consecutive days. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Time Frame
Baseline (Day 1) and Month 3, 6, 12
Title
Change From Baseline in HbA1c Levels Over 7 Consecutive Days During the 2 Weeks Prior to the Assessment
Description
HbA1c level was recorded at Baseline, Month 3, 6 and 12. Baseline was defined at Day 1. Change from Baseline was calculated by subtracting the post Baseline value from the Baseline value.
Time Frame
Baseline (Day 1) and Month 3, 6, 12
Title
Average Number of Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events From Baseline to Month 12
Description
Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The numbers of participant-reported hypoglycemic events per participant of severe hypoglycemia and documented symptomatic hypoglycemia have been reported.
Time Frame
Baseline (Day 1) and Month 12
Title
Percentage of Participants With Change From Baseline in Severe Hypoglycemic Events and Documented Symptomatic Hypoglycemic Events at Month 12
Description
Severe hypoglycemia was considered as an event that required assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. These episodes may be associated with sufficient neuroglycopenia to induce seizure or coma. Plasma glucose measurements may not be available during such an event, but neurological recovery attributable to the restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration. Documented symptomatic hypoglycemia was considered as an event during which typical symptoms of hypoglycemia are accompanied by a measured plasma glucose concentration less than or equal to 70 mg/dL and it was collected in (1) eCRF using two forms - for single event and for mutiple events, and (2) the IVRS system. The percentage of participant with incidence of severe hypoglycemia and documented symptomatic hypoglycemia have been reported.
Time Frame
Baseline (Day 1) and Month 12
Title
Composite Rank Sum: HbA1c and Exogenous Insulin Use at 6 and 12 Months
Description
O'Brien mean rank analyses was performed on a two-part composite of the Baseline-adjusted HbA1c level and the Baseline-adjusted mean total daily insulin use per kg body weight in the otelixizumab group compared with the placebo group at Months 6 and 12. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. For the O'Brien mean rank analysis at a particular time point, adjusted HbA1c values (for both treatment groups together) and adjusted mean daily insulin use values was ranked from smallest to largest. For each participant, the HbA1c and insulin use ranks were added together, producing a composite rank. A treatment comparison test was then performed on the composite ranks. If otelixizumab treatment was effective on this composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group.
Time Frame
Month 6 and 12
Title
Composite Rank Sum: C-Peptide AUC, HbA1c and Exogenous Insulin Use at 6 and 12 Months
Description
O'Brien analyses was performed on a three-part composite of HbA1c level, C-peptide AUC, and mean daily insulin use in the otelixizumab group compared with the placebo group at Months 6 and 12. The three variables was adjusted for Baseline values. Baseline adjustment was used to reduce the potential impact of imbalances in Baseline levels between treatment groups on the treatment comparisons at later time points. HbA1c and insulin use was ranked from smallest to largest, and C-peptide AUC was ranked from largest to smallest. If otelixizumab treatment was effective on the composite endpoint, then the mean of the ranks sum in the otelixizumab group was smaller than the mean of the ranks sum in the placebo group.
Time Frame
Month 6 and 12
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Ages 12-17
Diagnosis of diabetes mellitus, consistent with ADA criteria
No more than 90 days between diagnosis and administration of study compounds
Requires insulin for type 1 diabetes mellitus, or has required insulin at some time between diagnosis and administration of study compounds. In Canada, has to be using insulin at the time of dosing.
Stimulated C-peptide level greater than 0.20 nmol/L and less than or equal to 3.50 nmol/L
Positive for one or more of the autoantibodies typically associated with T1DM: antibody to glutamic acid decarboxylase (anti-GAD); antibody to protein tyrosine phosphatase-like protein (anti-IA-2); zinc transporter autoantibodies (ZNT8); insulin autoantibodies (IAA). A subject who is positive for insulin autoantibodies (IAA) and negative for the other autoantibodies will only be eligible if the subject has used insulin for less than 7 days total.
Exclusion Criteria:
•Other, significant medical conditions based on the study doctor's evaluation
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
GSK Clinical Trials
Organizational Affiliation
GlaxoSmithKline
Official's Role
Study Director
Facility Information:
Facility Name
GSK Investigational Site
City
Roma
ZIP/Postal Code
00155
Country
Italy
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.
Citations:
PubMed Identifier
15972866
Citation
Keymeulen B, Vandemeulebroucke E, Ziegler AG, Mathieu C, Kaufman L, Hale G, Gorus F, Goldman M, Walter M, Candon S, Schandene L, Crenier L, De Block C, Seigneurin JM, De Pauw P, Pierard D, Weets I, Rebello P, Bird P, Berrie E, Frewin M, Waldmann H, Bach JF, Pipeleers D, Chatenoud L. Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes. N Engl J Med. 2005 Jun 23;352(25):2598-608. doi: 10.1056/NEJMoa043980.
Results Reference
background
PubMed Identifier
20225393
Citation
Keymeulen B, Walter M, Mathieu C, Kaufman L, Gorus F, Hilbrands R, Vandemeulebroucke E, Van de Velde U, Crenier L, De Block C, Candon S, Waldmann H, Ziegler AG, Chatenoud L, Pipeleers D. Four-year metabolic outcome of a randomised controlled CD3-antibody trial in recent-onset type 1 diabetic patients depends on their age and baseline residual beta cell mass. Diabetologia. 2010 Apr;53(4):614-23. doi: 10.1007/s00125-009-1644-9. Epub 2010 Jan 14.
Results Reference
background
PubMed Identifier
19111162
Citation
You S, Candon S, Kuhn C, Bach JF, Chatenoud L. CD3 antibodies as unique tools to restore self-tolerance in established autoimmunity their mode of action and clinical application in type 1 diabetes. Adv Immunol. 2008;100:13-37. doi: 10.1016/S0065-2776(08)00802-X. No abstract available.
Results Reference
background
Links:
URL
http://www.defendagainstdiabetes.com
Description
Website containing information regarding the DEFEND-2 trial
Available IPD and Supporting Information:
Available IPD/Information Type
Clinical Study Report
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Annotated Case Report Form
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Statistical Analysis Plan
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Informed Consent Form
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Dataset Specification
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Study Protocol
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Available IPD/Information Type
Individual Participant Data Set
Available IPD/Information URL
https://www.clinicalstudydatarequest.com
Available IPD/Information Identifier
115494
Available IPD/Information Comments
For additional information about this study please refer to the GSK Clinical Study Register
Learn more about this trial
Trial of Otelixizumab for Adolescents and Adults With Newly Diagnosed Type 1 Diabetes Mellitus (Autoimmune): DEFEND-2
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