# Presentation: 351033

## Slide 1

## Natural History of Type 1 Diabetes

**CELLULAR (T CELL) AUTOIMMUNITY**

**LOSS OF FIRST PHASE **
**INSULIN RESPONSE**
**    ****(IVGTT)**

**GLUCOSE INTOLERANCE**
**(OGTT)**

**TIME**

**BETA CELL MASS**

**DIABETES**

**“****PRE”-DIABETES**

**GENETIC**
**PREDISPOSITION**

**INSULITIS**
**BETA CELL INJURY**

## TrialNet Sites – North America

## TrialNet Sites

**TrialNet Sites**

## TrialNet International Sites

**TrialNet International Sites**

**Australia**
**United Kingdom**
**Finland**
**Italy & Germany**

## Collaborate on Trials & Mechanistic Assays

***Collaborate on Trials & Mechanistic Assays***
***Concomitant Review of Protocols***

## 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**

## Type 1 Diabetes TrialNet Studies

**Type 1 Diabetes TrialNet Studies**

**BETA CELL MASS**

**DIABETES**

**“****PRE”-DIABETES**

**GENETIC**
**PREDISPOSITION**

**INSULITIS**
**BETA CELL INJURY**

***GENETICALLY AT-RISK***

## TrialNet Prevention Trials

**Relatives at Risk**
**Current End Point – Development of Diabetes**
**Genetically at Risk Relatives**
**End Point – Development of Autoantibodies**

## Slide 10

## DPT-1 Objective

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

## 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%**

## DPT·1 Screening Results

**DPT·1 Screening Results**

**103,391 Relatives Screened**
**  ****97,635 Eligible Samples**
**  ****97,273 Samples Analyzed**
**    ****3480 Samples ICA+ (3.58%)**

## DPT-1 – Time to Diabetes 

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**0.0**

**24151**
**1718**
**405**
**378**
**147**

**22297**
**1401**
**297**
**255**
**95**

**17049**
**1045**
**229**
**192**
**61**

**11807**
**743**
**163**
**130**
**40**

**9052**
**557**
**118**
**78**
**30**

**7439**
**457**
**91**
**49**
**22**

**6198**
**371**
**66**
**31**
**16**

**Number at Risk**

**Survival Distribution Function**

**P- Value< 0.001**
**(Log Rank Test)**

**3524**
**199**
**35**
**14**
**8**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Years Followed**

**STRATA:**

**0**

**1**

**2**

**8**

**0**
**1**
**2**
**3**
**4**

**3**

**4**

**DPT-1 – Time to Diabetes **
**By Number of Antibodies**

**n = 26799**

## DPT-1 – Time to Diabetes 

**1.0**

**0.9**

**0.8**

**0.7**

**0.6**

**0.5**

**0.4**

**0.3**

**0.2**

**0.1**

**0.0**

**41933**
**879**
**372**
**339**

**39352**
**659**
**344**
**293**

**32410**
**527**
**283**
**223**

**24434**
**395**
**212**
**156**

**19278**
**285**
**156**
**97**

**14667**
**193**
**77**
**49**

**10631**
**98**
**35**
**12**

**Number at Risk**

**Survival Distribution Function**

**P- Value< 0.001**
**(Log Rank Test)**

**5544**
**12**
**4**

**0**

**1**

**2**

**3**

**4**

**5**

**6**

**7**

**Years Followed**

**STRATA:**

**ICA – Subjects**

**Not Elig Rand (Staged)**

**Rand – Oral**

**8**

**9**

**1**

**ICA – Subjects**
**Not Elig Rand (Staged)**
**Rand – Oral**
**Rand - Parenteral**

**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**

## Type 1 Diabetes TrialNet Studies

**Type 1 Diabetes TrialNet Studies**

**BETA CELL MASS**

**DIABETES**

**“****PRE”-DIABETES**

**GENETIC**
**PREDISPOSITION**

**INSULITIS**
**BETA CELL INJURY**

***GENETICALLY AT-RISK***

## Insulin

## 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**

## Example of Mixed Meal Tolerance Test

**Active Rx**

**Placebo**

## Changes in C-Peptide Responses During MMTT Over Time

**Herold et al, NEJM 2002; 346:1692**

## Glucagon Stimulated C-Peptide Over Time 

**Active Rx**

**Placebo**

## 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**

## 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)**

## Key Elements of Successful Clinical Trials

**Prospective**
**Randomized**
**Controlled**
**Statistical power**
**Objective endpoints**
**Risk/benefit to individual**
**Cost benefit to society**

## 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**

## Slide 26

## Slide 27