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Immune Modulation for Prevention of Immune Modulation for Prevention of
Type 1 DiabetesType 1 Diabetes
Peter A. Gottlieb, MDBarbara Davis Center
University of Colorado Health Sciences Center Denver, CO
Main PointsMain Points
• Type 1 diabetes is an autoimmune disease• It is a predictable disease with different
phases• Approaches to prevention and cure are
possible.• New insulins, medications and devices will
improve therapy in the coming decade.
NKNK
BB
Th1Th1
MOMO
Tc1Tc1
TargetTarget
Effector CellsEffector CellsCD4CD25CD4CD25
Th2Th2
NKTNKT
Th3Th3
Tr1Tr1
Regulatory CellsRegulatory Cells
Cellular Mechanics of Autoimmune Type 1 DiabetesCellular Mechanics of Autoimmune Type 1 Diabetes
0
20
40
60
80
100
0 2.5 5 7.5 10 12.5 15
3 Abs
2 Abs
1 Ab
Progression to Diabetes vs Number of AutoantibodiesProgression to Diabetes vs Number of Autoantibodies(GAD, ICA512, Insulin)(GAD, ICA512, Insulin)Percent not Diabetic
Years of Follow-up
3 Ab n = 41 17 8 1 2 Abs n = 44 27 15 4 2 11 Abs n = 93 23 14 10 6 4
Verge et al, Diabetes 45:926-933, 1996 BDC
The Major Histocompatibility Complex
Human
Mouse
DP DQ DR B C A
K I-A I-E D L
Chromosome 6
Chromosome 17
Class II Class III Class I
Class II Class III Class IClass I
Complement Proteins
Cytokines Class I-like genesand pseduogenes
Antigen Processing Genes
Type 1a Diabetes: An Autoimmune Type 1a Diabetes: An Autoimmune DisorderDisorder
• Autoantibodies to islet proteins: insulin, Autoantibodies to islet proteins: insulin, GAD 65, IA-2 (ICA512)GAD 65, IA-2 (ICA512)
• T cell responses to islet proteinsT cell responses to islet proteins• HLA associationHLA association• Immunosuppressive drugs can ameliorate Immunosuppressive drugs can ameliorate
the disorder – ex. Cyclosporinethe disorder – ex. Cyclosporine• Recurrence of autoimmunity in pancreas Recurrence of autoimmunity in pancreas
transplants between monozygotic twinstransplants between monozygotic twins
Prevention of Type 1 diabetesPrevention of Type 1 diabetes
Primary:Primary: 1a1autoimmunityutoimmunity 1b1b-cell loss-cell loss
1c1clinical diabeteslinical diabetes
Geneticsusceptibility
Autoimmunity
No autoimmunity
Clinicaldiabetes
Complications
Clinicalremission
1c
Secondary1a
1b -cell loss
Tertiary
?
Secondary PreventionSecondary Prevention
Goal - induction of diabetes remission and preservation of C-peptide
non-antigen-specific interventions
antigen specific interventions
EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment
-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.
EDIC: Long Term Benefit of EDIC: Long Term Benefit of Intensive TreatmentIntensive Treatment
-The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000;342:381-9.
-Cell Function and Complications in the-Cell Function and Complications in theDiabetes Control and Complications TrialDiabetes Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26:832–836, 2003
-Cell Function and Hypoglycemia in the-Cell Function and Hypoglycemia in theDiabetes Control and Complications TrialDiabetes Control and Complications Trial
- Steffes MW, et al. Diabetes Care 26:832–836, 2003
Past Trials in New Onset Type 1 DMPast Trials in New Onset Type 1 DM
• Cyclosporine A - no lasting effect• Imuran - no lasting effect• Corticosteroids - no lasting effect• Plasmapheresis- no lasting effect• BCG (Denver) - no effect• Nicotinamide (DENIS) - no effect (At risk)
• Gluten-free diet (Italy) - no effect• Q fever vaccine s.c. - no effect• Nicotinamide and Vitamin E - no effect
Metabolic Effects of AZA and Prednisone Metabolic Effects of AZA and Prednisone at 1 year in New Onset T1DMat 1 year in New Onset T1DM
Treated Control Significance
HbA1c 7.2 (20) 8.6 (20) NS
Total Ins. 0.42+0.27 0.66+0.24 P<0.001
Ins. Indep. 15% 0% NS
C-peptide 0.52nmol/L
0.26nmol/L
P<0.03
Responder (HbA1c<6.8)
50% 15% NS
- Silverstein, et al. NEJM 1988, 319:599-604- Silverstein, et al. NEJM 1988, 319:599-604
Accelerated Loss of C-Peptide Accelerated Loss of C-Peptide with BCG Vaccination at Onsetwith BCG Vaccination at Onset
0
0.2
0.4
0.6
0.8
0 5 10 15 20 25 30
00.20.40.60.8
11.21.4
0 5 10 15 20 25 30
00.20.40.60.8
11.21.4
0 5 10 15 20 25 300
0.5
1
1.5
2
2.5
3
0 5 10 15 20 25 30
< 12
>=12
AgeFasting C-Peptide Stimulated C-Peptide
Adapted from Allen, et al, Diabetes Care 1999, 22:1703-07
Ongoing and Proposed Non-antigen Specific Ongoing and Proposed Non-antigen Specific Immunotherapy Trials in New Onset Type 1 DMImmunotherapy Trials in New Onset Type 1 DM
• MMF and DZB - Peter Gottlieb, TrialNet
• Multidose anti-CD3 hOKT3 - Kevan Herold, NY; Lucienne Chatenoud, France
• HSP 65 p277 s.c. - (Peptor) – Jerry Palmer, Seattle
• Multi-dose DZB - Henry Rodriguez, Indiana
• Exanitide and Rapamycin – David Harlan, NIH
• Oral hIFN-alpha - Staley Brod, Texas
• Anti-CD20 – Mark Peskovitz, Indiana, TrialNet
• ATG (Sandostat) – Steve Gitelman, UCSF, ITN, TrialNet
• Rapamycin and IL-2, Alex Rabinovitch, Canada
• Fish oil - A-G Ziegler, Germany
• Diazoxide - E Bjork+A Karlsson,
Sweden
• Lisofylline i.v. - S Kirk, Virginia
• Vitamin E+nicotinamide - P Pozzilli,
Italy
Preservation of Pancreatic Production Preservation of Pancreatic Production of Insulin (POPPI) Participating of Insulin (POPPI) Participating
CentersCenters
• The Barbara Davis Center
• Indiana University• Stanford University• University of Florida• University of
Minnesota• Virginia Mason
(Washington)
• Joslin Diabetes Center• Columbia University• UCSF• Children’s Hospital of
Los Angeles• Toronto, Canada• Milan, Italy and
Munich, Germany
New CentersExisting Centers
Preservation of Pancreatic Production of Preservation of Pancreatic Production of Insulin (POPPI) studyInsulin (POPPI) study
(Mycophenolate Mofetil and Zenapax)(Mycophenolate Mofetil and Zenapax)• MMF protects BB rats from developing DM and is effective in islet
allograft transplantation in mice• MMF effective in a number of autoimmune conditions and in
transplantation• DZB effective as part of Edmonton protocol and in other
transplantation regimens• Anti-IL2R Ab protects BB rat, but not NOD islet grafts• IL2-Receptor + Cells increased at diagnosis of DM• IL-2R+, CD4hi population harbors autoreactive T cells (mouse and
man)• Relative known toxicities of drugs are low
Mycophenolate Mofetil (MMF)Mycophenolate Mofetil (MMF)
• Inhibits inosine monophosphate dehydrogenase (IMPDH)
• Inhibits de novo pathway of guanosine nucleotide synthesis
– T and B cells need de novo pathway (other cell types use salvage pathway)
APCAPC
T cellT cell
MHC
TCR
IL-2
• Blocking of activated T and B cell proliferation and antibody formation
• Does not block IL-1, IL-2 production
MMF: Mode of action
Greenbaum, CBenaroya Research InstituteSeattle, WA
MMF (CellCept)MMF (CellCept)
• An immunosuppressive medication that is most commonly used to prevent transplant rejection.
• Capsules, taken by mouth, twice a day for two years.
• Most common side effects: Diarrhea, vomiting, nausea, decreased white blood cells.
MMF ToxicitiesMMF Toxicities
• LeukopeniaLeukopenia
• Gastrointestinal Gastrointestinal
• Increased rate of viral infectionsIncreased rate of viral infections
• Lymphoproliferative disorder? No Lymphoproliferative disorder? No increase in multidrug regimens. No increase in multidrug regimens. No increase in single drug use increase in single drug use (Psoriasis). (Psoriasis).
• Cancer? (Psoriasis data – No).Cancer? (Psoriasis data – No).
Daclizumab (Zenapax)Daclizumab (Zenapax)
Humanized IgG monoclonal antibody that binds to the alpha subunit (CD25, p55alpha, Tac) of IL-2 receptor on the surface of activated lymphocytes
Greenbaum, CBenaroya Research InstituteSeattle, WA
Activated T cell
α γ
IL-2
ß
Activated T cell
α γ
IL-2
ß
DZB
DZB: Mode of action
Inhibit IL-2 mediated activation of lymphocytes
Greenbaum, C;Benaroya Research Institute; Seattle, WA
DACLIZUMAB (DZB)DACLIZUMAB (DZB)
• An immunosuppressive medication, commonly used in patients receiving kidney transplants.
• IV infusion, twice during the study (Baseline and Week 2).
• Most common side effects: Diarrhea, vomiting, nausea, decreased white blood cells.
No increase in most frequently reported AEs in No increase in most frequently reported AEs in Zenapax-treated patients*Zenapax-treated patients*
% of Patients with Adverse Event% of Patients with Adverse Event
Safety ResultsSafety Results
00 2020 4040 6060 8080 100100
TremorTremor
HeadacheHeadache
Pain PosttraumaticPain Posttraumatic
Wound HealingWound Healing
InsomniaInsomnia
Musculoskeletal PainMusculoskeletal Pain
* Pooled data.* Pooled data.
PlaceboPlacebo (n=293) (n=293)
ZenapaxZenapax (n=336) (n=336)
POPPI StudyPOPPI Study• 3 arm study: MMF alone, MMF and 2 doses of DZB 3 arm study: MMF alone, MMF and 2 doses of DZB
and placeboand placebo• 60 subjects per arm, 180 total, through TrialNet 60 subjects per arm, 180 total, through TrialNet
centers (6 initially)centers (6 initially)• Type 1 diabetes (autoantibodies) within 12 weeks Type 1 diabetes (autoantibodies) within 12 weeks
of diagnosisof diagnosis• Ages 12-35, without significant other diseaseAges 12-35, without significant other disease• Outcomes: HbA1c, C-peptide, hypoglycemia, T Outcomes: HbA1c, C-peptide, hypoglycemia, T
cell assayscell assays• Start Date: July 27, 2005. 23 patients enrolled.Start Date: July 27, 2005. 23 patients enrolled.
Potential Benefits of the StudyPotential Benefits of the Study
• Patient will be the most important part of a research team that is attempting to learn more about type 1 diabetes.
• Diabetes may be easier to manage.
• Less chance for long-term complications of diabetes.
Anti-CD3 Monoclonal Antibody in Anti-CD3 Monoclonal Antibody in New-Onset Type 1 Diabetes MellitusNew-Onset Type 1 Diabetes Mellitus
Kevan C. Herold, MD; William Hagopian, MD, PhD;
Julie A. Auger, BA; Ena Poumian-Ruiz, BS;
Lesley Taylor, BA, David Donaldson, MD;
Stephen E. Gitelman, MD, David M. Harlan, MD;
Danlin Xu, PhD; Robert A. Zivin, PhD;
& Jeffrey A. Bluestone, PhD
Herold K. et al., N Engl J Med 2002; 346:1692-8.
hOKT3hOKT31(Ala-Ala)1(Ala-Ala)
Ala-A
la
Binds to CD3hOKT3hOKT31(Ala-Ala) is a monoclonal1(Ala-Ala) is a monoclonalantibody that binds to the CD3antibody that binds to the CD3(T cell receptor) on human T cells. (T cell receptor) on human T cells. The drug is a “humanized” antibodyThe drug is a “humanized” antibodywith a mutation in the Fc chain towith a mutation in the Fc chain toprevent binding to the Fc receptor.prevent binding to the Fc receptor.Binding to the Fc receptor and Binding to the Fc receptor and crosslinking of the CD3 moleculecrosslinking of the CD3 moleculeis thought to activate T cells, is thought to activate T cells, cause release of cytokines, and cause release of cytokines, and account for the toxicity of OKT3.account for the toxicity of OKT3.
Changes from Study Entry to 12 Months in the Total C-Peptide Response to Mixed-Meal Tolerance Testing
Herold K. et al., N Engl J Med 2002; 346:1692-8.
To
tal
Are
a u
nd
er t
he
C-P
epti
de
Res
po
nse
Cu
rve
(nm
ol/
l/4
hr)
Monoclonal-Antibody Group
To
tal
Are
a u
nd
er t
he
C-P
epti
de
Res
po
nse
Cu
rve
(nm
ol/
l/4
hr)
Control Group
A single course of h(Ala-Ala) at dx of diabetes improves insulin secretion for over 2
years
Month
0 6 12 18 24
AU
C (
pm
ol/m
l/2
40
min
)
0
20
40
60
80
100
120
140
160
DrugControl ** ** **
(p<0.0001(p<0.0001**p<0.02)**p<0.02)
Hemoglobin A1c levels in Drug treated and Control Subjects
P<0.0001 by RPANOVAP<0.0001 by RPANOVA
4.5
5.5
6.5
7.5
8.5
9.5
0 6 12 18 24
Month
He
mo
glo
bin
A1
c (
%)
Drug treated
Control
****
** p<0.01, * p<0.1** p<0.01, * p<0.1
**
Before treatment 1 wk after treatment
Induction of IL-10+CD4+ cells in vivo following Treatment with hOKT3g1(Ala-Ala)
IL-10+, IFN-g-CD45RO+CTLA-4-Some TGF-b+CCR4+
CFSE
hOKT3g1(Ala-Ala) induces proliferation of CD8+T cells in vitro
CD4CD8
PHA
hOKT3(Ala-Ala)5 ug/ml
CD25
CD25
CD3 engagementand signaling
Postulated Induction of CD8+ regulatory T cells by hOKT3γ1(Ala-Ala)
CD8
CD8 CD8
CD8
CD8
CD8
CD4
CD8+ T cell proliferation
Inhibition of antigen-reactiveCD4+ cells
Antigen Specific TherapyAntigen Specific Therapy
• Magic bullet Approach
• Targets autoreactive cells
• Generates protective cells
• Spares rest of immune system
• Minimal Toxicity
• Timing may be critical to efficacy
InsulinInsulin• Beta Cell Specific
• Predominant T-cell reactivity islets NOD
• Insulin expressed lymphoid tissue by dendritic and macrophage-like cells
• Thymic messenger RNA for insulin related to “protective” insulin allele
• Proinsulin expression in thymus prevents NOD diabetes
Effect of Insulin Injections on Effect of Insulin Injections on Diabetes & InsulitisDiabetes & Insulitis
0
10
2030
40
50
60
7080
90
100
Placebo Insulin
% D
iab
etes
Female NOD MiceFemale NOD Mice
Atkinson, Diabetes 1991Atkinson, Diabetes 1991
0
0.5
1
1.5
2
2.5
3
Placebo Insulin
Insu
liti
s S
core
Prevention of Diabetes with B:9-23 Prevention of Diabetes with B:9-23 Peptide “Immunization” Peptide “Immunization”
0 10 20 30 40 50 60
0
20
40
60
80
100
Age in Weeks
Pe
rce
nt
No
t D
iab
eti
c
Tetanus control
B:9-23 peptide
D.Daniel ,D.Wegmann . PNAS,1996D.Daniel ,D.Wegmann . PNAS,1996
Altered Peptide LigandAPCAPC
T cellT cell
MH
CT
CR
IFNγ
APCAPC
T cellT cell
MH
CT
CR
IL-4
Greenbaum, C;Benaroya Research Institute; Seattle, WA
NBI 6024-003 New Onset TrialNBI 6024-003 New Onset TrialAltered Peptide Ligand B:9-23Altered Peptide Ligand B:9-23
• Double-blind Phase I/II trial to test safety and Double-blind Phase I/II trial to test safety and efficacy of an altered insulin peptide ligand efficacy of an altered insulin peptide ligand
• Forty Patients (12-40) were randomized to receive 5 Forty Patients (12-40) were randomized to receive 5 doses of NBI-6024 (0.1mg, 1.0 mg, or 5.0mg) or doses of NBI-6024 (0.1mg, 1.0 mg, or 5.0mg) or placebo biweekly and monthly. placebo biweekly and monthly.
• No side effects. No obvious benefit to subjects, but No side effects. No obvious benefit to subjects, but study was primarily a safety study. study was primarily a safety study.
• Evidence of immunologic effect on T cells was Evidence of immunologic effect on T cells was observed in a dose dependent fashion in adolescent observed in a dose dependent fashion in adolescent groups particularly.groups particularly.
ELISPOT analysis of Th1 and Th2 Responses to ELISPOT analysis of Th1 and Th2 Responses to Insulin B(9-23)Insulin B(9-23) ((▲);); NBI-6024 (NBI-6024 () or Medium only () or Medium only ( ); ); 0.1 mg Adolescent0.1 mg Adolescent Tx’ed Patients from NBI- Tx’ed Patients from NBI-
6024-00036024-0003
0
10
20
30
40
50
60
70
0 5 10 15 20 25 30
Weeks After Initiation
0
100
200
300
400
500
600
700
800
0 5 10 15 20 25 30
Weeks After Initiation
IFN-
IL-5
Patient #O
0
10
20
30
40
50
60
70
80
90
100
0 5 10 15 20 25 30
Weeks After Initiation
0
50
100
150
200
250
300
350
400
450
500
0 5 10 15 20 25 30
Weeks After Initiation
Patient #PIFN-
IL-5
IFNIFN IFNIFN
IL-5IL-5IL-5IL-5
Recent and Ongoing Antigen-specific Recent and Ongoing Antigen-specific Immunotherapy Trials in T1DMImmunotherapy Trials in T1DM
• Joslin Parenteral Insulin: “Delay”• Schwabing Parenteral Insulin: “Delay”• DPT-1 Parenteral: No Effect• DIPP (intranasal): ?• Melbourne (intranasal): ?• DPT-1 Oral Insulin: Possible for subgroup• Italy/France Oral Insulin: No Effect• Maclaren Oral Insulin: ?• NBI 6024-0003 - Neurocrine, BDC No effect• B chain – Orban, Joslin ?• hGAD s.c. in alum (Diamyd) 20ug dose only• Peptor Heat Shock Protein ?
Pre
diab
ete
Pre
diab
ete
ssN
ew O
nset
New
Ons
et
PREVENTIONPREVENTION
Primary PreventionPrimary Prevention
autoantibodies or diabetes as the endpoint
avoidance of environmental agents ?
induction of autoantigen tolerance ?
Rewers-BDC
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
Primary Prevention TrialsPrimary Prevention Trials• DPT-1 - Parenteral - Ineffective
- Oral Insulin – May be effective in subgroup
• DIPP - Nasal Insulin• INIT - IntraNasal Insulin Trial
• ENDIT - Nicotinamide - Ineffective
• TRIGR - Casein Hydrolysate (Cow’s Milk Elimination)
• NIP - Nutritional Intervention to Prevent T1DM
DPT-1 Parenteral Study – Time to DiabetesDPT-1 Parenteral Study – Time to DiabetesBy TreatmentBy Treatment
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
169169170170
144144131131
9696101101
69696969
39394040
13131414 11
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= 0.796P- Value= 0.796(Log Rank Test)(Log Rank Test)
InterventionInterventionObservationObservation
00 11 22 33 44 55 66 77
Years FollowedYears Followed
STRATA:STRATA: InterventionIntervention ObservationObservation
ControlControl
TreatedTreated
New Engl J Med 2002; 346:1679
ENDIT: Kaplan-Meier failure curveENDIT: Kaplan-Meier failure curve
- European Nicotinamide Diabetes Intervention Trial (ENDIT) Group Lancet 2004; 363: 925–31
Rationale for Oral InsulinRationale for Oral Insulin
TH1Cell
s
IFN-, IL-2
DestructiveCytokines
TH2Cells
IL-4, IL-5, IL-10 TGF-
TH3Cells
ProtectiveCytokines
Oral Antigen ProtocolOral Antigen Protocol
• Initial results appeared to suggest no effect of oral insulinInitial results appeared to suggest no effect of oral insulin• Secondary analysis suggests that for original cohort Secondary analysis suggests that for original cohort
there is delay in onset compared to placebo treated there is delay in onset compared to placebo treated patiens.patiens.
• A new trial to confirm these observations is being A new trial to confirm these observations is being planned by TrialNetplanned by TrialNet
• Additional arms including intranasal insulin are being Additional arms including intranasal insulin are being consideredconsidered
Nutritional Intervention to Prevent Type 1 Diabetes (NIP – Diabetes)
Plan: Use of an omega 3 fatty acid (Docosahexanoic acid or DHA) to prevent the initial autoimmune process.
DHA supplementation will begin in:
• the last trimester of pregnancy
• the first 6 months after birth
It will be continued in medium or high risk infants for 3 years.
Dietary Intake – Western DietsDietary Intake – Western Diets
The Ratio of n-6 to n-3 Fatty Acids in our diet:
1800’s = 1 or 2 (n-6) to 1 (n-3)
Present = 20 or 30 (n-6) to 1 (n-3)
High n-3: anti-inflammatory anti-thrombotic hypolipidemic vasodilatory
(High n-6 has the opposite effect)(Am J. Clin Nutr. 70, 560-569, 1999)
III) Mechanisms of Action of Omega 3 Fatty Acids
Decrease AA in cell membranes alters PGE 1 and 2 production (inflammatory prostaglandins)
Decrease pro-inflammatory cytokines TNF, IL-1 and IL6 ( efficacy of IL4 and IL10)
Decrease ICAM-1 on monocyte surfaces in humans fed 3g fish oil/dx 21 days ( chronic inflammation)
DHA and /or vit D may have important immune modulating effects in babies at risk for developing
T1DM
Mechanistic Studies
Biomarker: Omega-3 FA will be measured
Reduction of inflammation
• CRP (with DHA) (Am J Cardiol 88:1139,2001)
• inflammatory PGs: PGE-1 and 2
• Inflammatory cytokines: IL-1 and IL-6
Islet cell antibodies
TrialNet Sites
TrialNet International SitesTrialNet International Sites
• AustraliaAustralia
• United KingdomUnited Kingdom
• FinlandFinland
• Italy & GermanyItaly & Germany
Type 1 Diabetes TrialNet Protocol Development Procedure
Stage 1: Concept Proposal
Stage 2: Draft Protocol
Stage 3: Full Protocol
Prioritization & Implementation
Types of Trials
• Phase 1 – Safety and/or Proof of Concept
• Phase 2 – New-Onset Diabetes
• Phase 2 – Prevention of Diabetes
• Natural History & Epidemiology
TrialNet Interventions• New-Onset Diabetes
– Anti-CD3 (via ITN collaboration)– Mycophenolate Mofetil +/- Anti-CD25– Anti-CD20– IL-2 plus Sirolimus – Phase 1 Safety Study
• Relatives At Risk– Natural History– Oral Insulin– Beta Cell Preservation (exenatide) – pilot study
• 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
• Better rationale for moving potential interventions to RCTs
• The courage to study interventions with potential adverse side effects
1-800-HALT-DM1 (1-800 – 425-8361)www.diabetestrialnet.org
