Natural History of Type 1 DiabetesNatural History of Type 1 Diabetes

CELLULAR (T CELL) AUTOIMMUNITYCELLULAR (T CELL) AUTOIMMUNITY

LOSS OF FIRST PHASE LOSS OF FIRST PHASE INSULIN RESPONSEINSULIN RESPONSE

(IVGTT)(IVGTT)

GLUCOSE INTOLERANCEGLUCOSE INTOLERANCE(OGTT)(OGTT)

HUMORAL AUTOANTIBODIESHUMORAL AUTOANTIBODIES(ICA, IAA, Anti-GAD(ICA, IAA, Anti-GAD6565, IA, IA22Ab, etc.) Ab, etc.)

PUTATIVEPUTATIVEENVIRONMENTALENVIRONMENTAL

TRIGGERTRIGGER

CLINICALCLINICALONSETONSET

TIMETIME

BE

TA

CE

LL

MA

SS

BE

TA

CE

LL

MA

SS

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

TrialNet Sites – North AmericaTrialNet Sites – North America

TrialNet Sites

TrialNet International SitesTrialNet International Sites

• AustraliaAustralia

• United KingdomUnited Kingdom

• FinlandFinland

• Italy & GermanyItaly & Germany

Immune Tolerance Network

Collaborate on Trials & Mechanistic Assays

Concomitant Review of Protocols

TrialNet GoalsTrialNet 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

TIMETIME

Type 1 Diabetes TrialNet StudiesType 1 Diabetes TrialNet StudiesB

ET

A C

EL

L M

AS

SB

ET

A C

EL

L M

AS

S

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

LOSS OF FIRST PHASE LOSS OF FIRST PHASE INSULIN RESPONSE INSULIN RESPONSE

MULTIPLE ANTIBODY POSITIVEMULTIPLE ANTIBODY POSITIVE

NEWLY DIAGNOSED DIABETES

GENETICALLY AT-RISKGENETICALLY AT-RISK

TrialNet Prevention TrialsTrialNet Prevention Trials

• Relatives at Risk• Current End Point – Development of

Diabetes

• Genetically at Risk Relatives• End Point – Development of

Autoantibodies

DPT-1 ObjectiveDPT-1 Objective

To determine whetherantigen based therapies

(specifically, insulin)of non-diabetic relativescan delay development

of Type 1 diabetes.

DPT·1 Intervention ProtocolsDPT·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 ResultsDPT·1 Screening Results

• 103,391 Relatives Screened

• 97,635 Eligible Samples

• 97,273 Samples Analyzed

• 3480 Samples ICA+ (3.58%)

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

241512415117181718405405378378147147

2229722297140114012972972552559595

1704917049104510452292291921926161

11807118077437431631631301304040

9052905255755711811878783030

74397439457457919149492222

61986198371371666631311616

Number at RiskNumber at Risk

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

nS

urv

ival

Dis

trib

uti

on

Fu

nct

ion

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

352435241991993535141488

00 11 22 33 44 55 66 77

Years FollowedYears Followed

STRATA:STRATA: 00 11 22

88

0011223344

33 44

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

n = 26799

1.01.0

0.90.9

0.80.8

0.70.7

0.60.6

0.50.5

0.40.4

0.30.3

0.20.2

0.10.1

0.00.0

4193341933879879372372339339

3935239352659659344344293293

3241032410527527283283223223

2443424434395395212212156156

19278192782852851561569797

146671466719319377774949

1063110631989835351212

Number at RiskNumber at Risk

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

nS

urv

ival

Dis

trib

uti

on

Fu

nct

ion

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

554455441212

44

00 11 22 33 44 55 66 77

Years FollowedYears Followed

STRATA:STRATA: ICA – SubjectsICA – Subjects Not Elig Rand (Staged)Not Elig Rand (Staged)

Rand – OralRand – Oral

88 99

11

ICA – SubjectsICA – SubjectsNot Elig Rand (Staged)Not Elig Rand (Staged)Rand – OralRand – OralRand - ParenteralRand - Parenteral

Rand - ParenteralRand - Parenteral

DPT-1 – Time to Diabetes DPT-1 – Time to Diabetes ICA- vs Staging Outcome ICA- vs Staging Outcome (Parenteral, Oral, Not Eligible)(Parenteral, Oral, Not Eligible)

n = 43523

Oral Insulin Trial

Parenteral Insulin Trial

ICA+ Not Eligible

TIMETIME

Type 1 Diabetes TrialNet StudiesType 1 Diabetes TrialNet StudiesB

ET

A C

EL

L M

AS

SB

ET

A C

EL

L M

AS

S

DIABETES

“PRE”-DIABETES

GENETICPREDISPOSITION

INSULITISBETA CELL INJURY

LOSS OF FIRST PHASE LOSS OF FIRST PHASE INSULIN RESPONSE INSULIN RESPONSE

MULTIPLE ANTIBODY POSITIVEMULTIPLE ANTIBODY POSITIVE

NEWLY DIAGNOSED DIABETES

GENETICALLY AT-RISKGENETICALLY AT-RISK

InsulinInsulin

C-peptide

A chain

B chain

S S

SNH2COOH

TrialNet Intervention TrialsTrialNet 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 TestExample of Mixed Meal Tolerance Test

Active Rx

Placebo

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

0

20

40

60

80

100

120

140

Baseline 6 months 12 months

C-P

ep

tid

e -

To

tal

AU

C

pm

ol/

ml/

24

0 m

in

Active RxComparison

Herold et al, NEJM 2002; 346:1692

Glucagon Stimulated C-Peptide Over Time Glucagon Stimulated C-Peptide Over Time

Active Rx

Placebo

TrialNet InterventionsTrialNet 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 StudiesOther 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 Key Elements of Successful Clinical TrialsClinical Trials

• Prospective

• Randomized

• Controlled

• Statistical power

• Objective endpoints

• Risk/benefit to individual

• Cost benefit to society

What We NeedWhat 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