2. Natural History of Type 1 Diabetes CELLULAR (T CELL) AUTOIMMUNITY LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT) (IVGTT) GLUCOSE INTOLERANCE (OGTT) HUMORAL AUTOANTIBODIES (ICA, IAA, Anti-GAD 65, IA 2 Ab, etc.) PUTATIVEENVIRONMENTALTRIGGER CLINICALONSET TIME BETA CELL MASS DIABETES “PRE”- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY

3. TrialNet Sites – North America

4. TrialNet Sites

5. TrialNet International Sites AustraliaAustralia United KingdomUnited Kingdom FinlandFinland Italy & GermanyItaly & Germany

6. Immune Tolerance Network Collaborate on Trials & Mechanistic Assays Concomitant Review of Protocols

7. TrialNet Goals Explore new therapies in: –New-onset Type 1 Diabetes –Relatives “at risk” of Type 1 Diabetes –High genetic risk individuals Further define epidemiology, natural history, and risk factors of Type 1 Diabetes

8. TIME Type 1 Diabetes TrialNet Studies BETA CELL MASS DIABETES “PRE”- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY LOSS OF FIRST PHASE INSULIN RESPONSE MULTIPLE ANTIBODY POSITIVE NEWLY DIAGNOSED DIABETES GENETICALLY AT-RISK

9. TrialNet Prevention Trials Relatives at Risk Current End Point – Development of Diabetes Genetically at Risk Relatives End Point – Development of Autoantibodies

11. DPT-1 Objective To determine whether antigen based therapies (specifically, insulin) of non-diabetic relatives can delay development of Type 1 diabetes.

12. DPT·1 Intervention Protocols Parenteral Insulin In Subjects with 5 year Risk of Type 1 Diabetes > 50% Oral Insulin In Subjects with 5 year Risk of Type 1 Diabetes = 26-50%

13. DPT·1 Screening Results 103,391 Relatives Screened 97,635 Eligible Samples 97,273 Samples Analyzed 3480 Samples ICA+ (3.58%)

14. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 24151171840537814722297140129725595170491045229192611180774316313040905255711878307439457914922 6198371663116 Number at Risk Survival Distribution Function P- Value< 0.001 (Log Rank Test) 352419935148 0 1234567 Years Followed STRATA: 0 1 2 8 01234 3 4 DPT-1 – Time to Diabetes By Number of Antibodies n = 26799

15. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 41933879372339393526593442933241052728322324434395212156192782851569714667193774910631983512 Number at Risk Survival Distribution Function P- Value< 0.001 (Log Rank Test) 5544124 0 1234567 Years Followed STRATA: ICA – Subjects Not Elig Rand (Staged) Rand – Oral 89 1 ICA – Subjects Not Elig Rand (Staged) Rand – Oral Rand - Parenteral DPT-1 – Time to Diabetes ICA- vs Staging Outcome (Parenteral, Oral, Not Eligible) n = 43523 Oral Insulin Trial Parenteral Insulin Trial ICA+ Not Eligible

16. TIME Type 1 Diabetes TrialNet Studies BETA CELL MASS DIABETES “PRE”- DIABETES GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY LOSS OF FIRST PHASE INSULIN RESPONSE MULTIPLE ANTIBODY POSITIVE NEWLY DIAGNOSED DIABETES GENETICALLY AT-RISK

17. Insulin C-peptide A chain B chain S S S NH2 COOH

18. TrialNet Intervention Trials Recent Onset Type 1 Diabetes Current End Point – Preservation of C- Peptide Later Stage Type 1 Diabetes with Preserved C-Peptide Potential End Point – Preservation of C- Peptide

19. Example of Mixed Meal Tolerance Test Active Rx Placebo

20. Changes in C-Peptide Responses During MMTT Over Time Herold et al, NEJM 2002; 346:1692

21. Glucagon Stimulated C-Peptide Over Time Active Rx Placebo

22. TrialNet Interventions New-Onset Diabetes –Anti-CD3 (via ITN collaboration) –Mycophenolate Mofetil +/- Anti-CD25 –Anti-CD20 –Anti-CD3 + Exenatide –IL-2 plus Sirolimus – Phase 1 Safety Study Relatives At Risk –Natural History –Oral Insulin –Beta Cell Preservation (exenatide) – pilot study –Anti-CD3 Newborns –Nutritional : Omega-3-Fatty Acids

23. Other TrialNet Studies Comparison of Mixed Meal Tolerance Test and Glucagon Stimulation Test for Stimulation of C-Peptide Reproducibility and Validation of T-Cell Assays for Monitoring of Diabetes Intervention Trials Collaboration with Type 1 Diabetes Genetics Consortium (T1DGC)

24. Key Elements of Successful Clinical Trials Prospective Randomized Controlled Statistical power Objective endpoints Risk/benefit to individual Cost benefit to society

25. What We Need Proven biomarkers for disease progression or improvement Better mechanistic assays Study designs that involve fewer subjects Better rationale for moving potential interventions to RCTs The courage to study interventions with potential adverse side effects