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PUTATIVE ENVIRONMENTAL TRIGGER. HUMORAL AUTOANTIBODIES. (ICA, IAA, Anti-GAD 65 , IA 2 Ab, etc.). CLINICAL ONSET. Natural History of Type 1 Diabetes. CELLULAR (T CELL) AUTOIMMUNITY. LOSS OF FIRST PHASE INSULIN RESPONSE (IVGTT). BETA CELL MASS. GLUCOSE INTOLERANCE (OGTT). GENETIC - PowerPoint PPT Presentation
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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