understanding diabetes research
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Understanding Diabetes Research
Children With Diabetes
Friends for Life Conference
July 23-27, 2008
Orlando, Florida
H. Peter Chase, MD
Professor of Pediatrics
University of Colorado Denver
Barbara Davis Center for Childhood Diabetes
2
“HAWTHORNE Effect”
A study of productivity in a Western Electric factory in Chicago in 1924 – adjusted lighting up or down – both resulted in increased productivity.
People alter their behavior when they know it is being studied in ways that may influence study outcomes. Need to consider when doing studies.
3
Being in a Research Study:
(Gale, et al Diabetes Care 30:298,2007)
1) Improves HbA1c – even if no intervention
2) Analysis of 3 trials (429 subjects) of T1D and 3 trials (611 subjects) of T2D
3) Recruitment A1c vs Randomization visit: Second HbA1c values consistently lower (though research has not yet begun)
4) Why? a) Patient’s interest b) Attention
c) Encouragement d) BG’s ? ?
4
“Non-Inferiority” Research
Many research trials are designed to get a new medicine (e.g., a new insulin) approved by the FDA. All the company has to do is to prove that it is not “INFERIOR” to the most commonly used current similar medicine.
Examples: - Lantus vs NPH
- Humalog vs Regular
- Apidra vs Humalog
• Drug companies usually pay quite well to get participants.• Families must trust the doctor and his/her judgment
(e.g. Inhaled insulin; Islet transplant).
5
IRBs and Patient Safety
• Institutional Review Boards (IRBs) must approve all research on human subjects to ensure the safety of the participants.
• Studies are continually monitored for patient safety.
• Signing consents ensures the patients are participating voluntarily and are not coerced.
6
Human Research Approval
• Institutional Review Board (IRB)– Purpose: protect the rights and welfare of
human subjects– Consists of:
• Research faculty• At least one non-scientific member• At least one non-university affiliated member• Health care practitioners (physicians, nurses,
pharmacists, etc.)
7
The Clinical Research Process
• Identify clinical research question
• Write research protocol and obtain approval
• Recruit subjects
• Consent and screen subjects
• Conduct research study
• Analyze and publish results
8C.S. Mott Children’s Hospital National Poll on Children’s Health, January 2008
Child Participation in Research
9
Parent’s Willingness to Allow Children in Research Versus Desire For FDA-Approved Medicines for Children
10
Parents’ Willingness To Allow Children To Participate In Research
11
Child Participation in Research
Appreciation is expressed to Dr. Jay Skyler for help in development of these slides.
TrialNet GoalsTrialNet Goals
• Delay or prevent Type 1 DiabetesDelay or prevent Type 1 Diabetes– Explore new therapies in:Explore new therapies in:
• Relatives “at risk” of T1DRelatives “at risk” of T1D• High genetic risk individualsHigh genetic risk individuals• New-onset T1DNew-onset T1D
• Further define epidemiology, natural history, Further define epidemiology, natural history, and risk factors of T1Dand risk factors of T1D
• Parents must decide if they will support Parents must decide if they will support prevention researchprevention research
8 years8 years2,983 days2,983 days71,592 hours71,592 hours4,295,520 minutes4,295,520 minutes>20,000 finger sticks>20,000 finger sticks>8,000 injections>8,000 injections> 450 pump site > 450 pump site
changeschanges
age 14 monthsage 14 months age 9 yearsage 9 years
RationaleRationale
• Although there is a treatment for T1D – insulin Although there is a treatment for T1D – insulin is not a cureis not a cure
• Type 1 Diabetes is immunologically mediatedType 1 Diabetes is immunologically mediated• Our goal is to interdict the disease processOur goal is to interdict the disease process• Immunomodulatory therapies may be effectiveImmunomodulatory therapies may be effective• Yet, there must be a careful balance between Yet, there must be a careful balance between
efficacy and safetyefficacy and safety• Successful modulation of immune Successful modulation of immune
mechanisms is also required for cellular mechanisms is also required for cellular replacement therapiesreplacement therapies
Type 1 Diabetes Prevention in Type 1 Diabetes Prevention in NODNOD MiceMice
March, 2006
AAV murine IL-10AAV rat preproinsulin gene (vLP-1)Adenovirus expressing mIL-4Aerosol insulinAllogenic thymic macrophagesAlpha GalactosylceramideAlpha-interferon (rIFN-alpha)Alpha/beta T cell receptor thymocytes AminoguanidineAndrogensAnesthesiaAntioxidant MDL 29,311Antisense GAD mRNAAzathioprineAnti-B7-1Bacille Calmette Gue’rin (BCG)BaclofenBee venomBiolistic-mediated IL-4Blocking peptide of MHC class IIBone marrow transplantationCastrationAnti-CD3Anti-CD4CD4+CD25+regulatory T cellsAnti-CD8Anti-CD28 MAbCholera toxin B subunit-insulin proteinClass I derived self-I-A beta(g7) (54-76) peptideCold exposureAnti-complement receptorComplete Freund’s adjuvantAnti-CTLA-4Cyclic nucleotide phosphodiesterases (PDEs)CyclosporinCyclosporin ADC deficient in NF-kappaBDC from pancreatic lymph nodeDC with IL-4DeflazacortDeoxysperogualinDexamethasone/progesterone/growth hormone/estradiolDiazoxide1,25 dihydroxy Vitamin D3, KH10601,25 dihydroxycholecalciferol1,25 dihydroxyl Vitamin D3Elevated temperatureEmotionalityEncephalomyocarditis virus (ECMV)Essential fatty acid deficient dietsFK506FTY720 (myriocin)GAD 65 peptides in uteroAnti-GAD monoclonal antibodyGalactosylceramideGlucose (neonatal)Glutamic acid decarboxylase(intraperitoneal, intrathymic, intravenous, oral)Glutamic acid decarboxylase 65 Th2 cell cloneGlutamic acid decarboxylase peptides(intraperitoneal, intrathymic, intravenous, oral)
GonadectomyGuanidinoethyldisulphideHeat shock protein 65Heat shock protein peptide (p277)Hematopoietic stem cells encoding proinsulinHousing aloneHuman IGF-1I-A beta g7(54-76) peptideAnti-I-A monoclonal antibodiesAnti-ICAM-1IgG2a antibodiesImmobilizationInomideAnti-integrin alpha 4Insulin (intraperitoneal, oral, subcutaneous, nasal)Insulin B chain (plasmid)Insulin B chain/B chain amino acids 9-23 (intraperitoneal, oral, subcutaneous, nasal)Insulin-like growth factor I (IGF-I)Anti-intercellular adhesion molecule-1 (ICAM-1)Interferon-alpha (oral)Interferon-gammaAnti-interferon-gammaInterferon-gamma receptor/IgG1 fusion proteinInterleukin-1Interleukin-4Interleukin-4-Ig fusion proteinInterleukin-4-plasmidInterleukin-10Interleukin-10-plasmid DNAInterleukin-10-viralInterleukin 11-human Interleukin-12Intrathymic administration of mycobacterial heat shock protein 65 Intrathymic administration of mycobacterial heat shock peptide p277Islet cells-intrathymicL-Selectin (MEL-14)Lactate dehydogenase virus (LDH)Large multilamellar liposomeLazaroidAnti-leukocyte function associated antigen (LFA-1)Anti-LFA-1Linomide (quinoline-3-carboxamide)Lipopolysaccharide-activated B cellsLisofyllineLymphocyte choriomeningitis virus (LCMV)Anti-lymphocyte serumLymphoctyte vaccinationLymphocytic choriomeningitis virusAnti-L-selectinLymphotoxinLZ8MC1288 (20-epi-1,25-dihydroxyvitamin D3)MDL 29311Metabolically inactive insulin analogAnti-MHC class IAnti-MHC class IIMHC class II derived cyclic peptideMixed allogeneic chimerismMixed bone marrow chimerasMonosodium glutamateMurine hepatitis virus (MHV)
Mycobacterium aviumMycobacterium lepraeNatural antibodiesNatural polyreactive autoantibodiesNeuropeptide calcitonin gene-related peptideNicotinamideNicotineNinjin-to (Ren-Shen-Tang), a Kampo (Japanese traditional) formulationNKT cellsNY4.2 cellsOK432OvercrowdingPancreatectomyPentoxifyllinePertussigenPoly [I:C]Pregestimil dietPrenatal stressPreproinsulin DNAProbucolProlactinRampamycinRecombinant vaccinia virus expressing GADReg proteinReg proteinRolipramSaline (repeated injection)Schistosoma mansoniSemi-purified diet (e.g., AIN-76)Short term chronic stressSilicaSirolimus/tacrolimusSodium fusidateSoluble interferon-gamma receptorSomatostatinNon-specific pathogen free conditionsStreptococcal enterotoxinsStreptozotocinSulfatide (3’sulfogalactosylceramide)SuperantigensSuperoxide dismutase-desferrioxamineAnti-T cell receptorTGF-beta 1 somatic gene therapyTh1 clone specific for hsp60 peptideAnti-thy-1Thymectomy (neonatal)TolbutamideTolerogenic dendritic cells induced by vitamin D receptor ligandsTop of the rackTreatment combined with a 10% w/v sucrose-supplemented drinking water Tumor necrosis factor-alphaTX527 (19-nor-14,20-bisepi-23-yne-1,25(OH)(2)D(3))Vitamin EAnti-VLA-4
TIMETIME
Potential Timing of Intervention StudiesPotential Timing of Intervention 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 NEWLY DIAGNOSED DIABETESDIABETES
GENETICALLY AT-RISKGENETICALLY AT-RISK
C-Peptide C-Peptide -cell mass-cell mass
DYSGLYCEMIADYSGLYCEMIA
DCCT: Impact of Preserved C-Peptide DCCT: Impact of Preserved C-Peptide on Hypoglycemia & Retinopathyon Hypoglycemia & Retinopathy
00
55
1010
1515
2020
(R
ate/
100
pt
yrs)
(Rat
e/10
0 p
t yr
s)Hypoglycemia Hypoglycemia (seizure/coma)(seizure/coma)
00
11
22
33
44
55
(R
ate/
100
pt
yrs)
(Rat
e/10
0 p
t yr
s)
RetinopathyRetinopathy
positivepositive
negativenegative
C-peptide C-peptide statusstatus
at entryat entry
DCCT Research Group. Ann Intern Med 1998;128:517DCCT Research Group. Ann Intern Med 1998;128:517
DPT·1 Screening ResultsDPT·1 Screening Results
• 103,391 Relatives Screened103,391 Relatives Screened
• 97,635 Eligible Samples97,635 Eligible Samples
• 97,273 Samples Analyzed97,273 Samples Analyzed
• 3483 Samples ICA+ (3.58%)3483 Samples ICA+ (3.58%)
• 2523 Subjects Staged (72%)2523 Subjects Staged (72%)
• 339 Randomized Parenteral339 Randomized Parenteral
• 372 Randomized Oral372 Randomized Oral
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 = 26799n = 26799
DPT-1 Parenteral Insulin Trial – Time to DiabetesDPT-1 Parenteral Insulin Trial – 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 RiskSu
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 FollowedSTRATA:STRATA: InterventionIntervention ObservationObservation
ControlControl
TreatedTreated
New Engl J Med 2002; 346:1685-91
DPT-1 Oral Study – Time to DiabetesDPT-1 Oral 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
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
nS
urv
ival
Dis
trib
uti
on
Fu
nct
ion
00 11 22 33 44 55 66 77
Years FollowedYears Followed
186186186186
174174170170
146146137137
110110102102
85857171
40403737
23231212
Number at RiskNumber at Risk
P- Value= 0.176P- Value= 0.176(Log Rank Test)(Log Rank Test)
Oral InsulinOral InsulinOral PlaceboOral Placebo
STRATA:STRATA: Oral InsulinOral Insulin Oral PlaceboOral Placebo
ControlControl
TreatedTreated
Diabetes Care 2005; 28:1068-76
DPT-1 Oral Study - Time to Diabetes - By TreatmentDPT-1 Oral Study - Time to Diabetes - By TreatmentSubset: IAA Confirmed Subset: IAA Confirmed >> 80 nU/ml 80 nU/ml
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
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
nS
urv
ival
Dis
trib
uti
on
Fu
nct
ion
00 11 22 33 44 55 66 77
Years FollowedYears Followed
130130133133
122122121121
1041049696
86866969
66664646
40403232
23231212
Number at RiskNumber at Risk
P- Value= 0.015P- Value= 0.015(Log Rank Test)(Log Rank Test)
Oral InsulinOral InsulinOral PlaceboOral Placebo
STRATA:STRATA: Oral InsulinOral Insulin Oral PlaceboOral Placebo
ControlControl
TreatedTreated
Diabetes Care 2005; 28:1068-76
Projected 4.5 – 5 year delayProjected 4.5 – 5 year delay
Insulin Effect Most Evident in Subjects Insulin Effect Most Evident in Subjects with Baseline IAA ≥ 300with Baseline IAA ≥ 300
N=63 (Ins.) and 69 (Plac.)
Projected 10 year delayProjected 10 year delay
TrialNet Sites in North AmericaTrialNet Sites in North America+ 117 North American Affiliates+ 117 North American Affiliates
Melbourne, AustraliaMelbourne, AustraliaMilan, Italy Milan, Italy
Turku, FinlandTurku, Finland
Bristol, UK Bristol, UK
TrialNet International SitesTrialNet International Sites
Malmo, SwedenMalmo, Sweden
Munich, GermanyMunich, Germany
+ 25 International Affiliates+ 25 International Affiliates
I) Prevention Studies
versus
II) New-Onset Studies
(To preserve some insulin production)
TrialNet Natural History StudyTrialNet Natural History Studyand and
Oral Insulin TrialOral Insulin Trial
Enrollment in Natural History StudyEnrollment in Natural History StudyMarch 31, 2008March 31, 2008
Expected Enrolled
NHS Phase I New Screenings 2004 - 2007NHS Phase I New Screenings 2004 - 2007
Enrollment in Oral Insulin StudyEnrollment in Oral Insulin StudyMarch 31, 2008March 31, 2008
0
10
20
30
40
50
60
70
80
90F
eb
-07
Ma
r-0
7
Ap
r-0
7
Ma
y-0
7
Jun
-07
Jul-
07
Au
g-0
7
Se
p-0
7
Oct
-07
No
v-0
7
De
c-0
7
Jan
-08
Fe
b-0
8
Ma
r-0
8
Su
bje
cts
En
roll
ed
Study Month
Cumulative Enrollment by Study Month for the Oral Insulin Trial
n = 79
Expected Enrolled
Omega 3 fatty acid Omega 3 fatty acid (Docosahexanoic acid or DHA)(Docosahexanoic acid or DHA)
Primary Prevention PilotPrimary Prevention Pilot
Nutritional Intervention to Nutritional Intervention to Prevent Type 1 Diabetes (NIP) Prevent Type 1 Diabetes (NIP)
Enrollment in NIP Pilot StudyEnrollment in NIP Pilot StudyMarch 31, 2008March 31, 2008
Anti-CD3 for Prevention Anti-CD3 for Prevention of Diabetesof Diabetes
In Relatives At-Risk forIn Relatives At-Risk forType 1 Diabetes Mellitus Type 1 Diabetes Mellitus
Normal Glucose ToleranceNormal Glucose Tolerance
IGT onlyIGT only
IFG onlyIFG only
Indeterminate onlyIndeterminate onlyCombinedCombined
• Identified in Natural History StudyIdentified in Natural History Study– Oral InsulinOral Insulin– GAD-AlumGAD-Alum– Anti-CD3Anti-CD3
• Primary Prevention in NewbornsPrimary Prevention in Newborns– NIP (Omega-3-Fatty Acids)NIP (Omega-3-Fatty Acids)
SUMMARYSUMMARYTrialNet Prevention StudiesTrialNet Prevention Studies
Studies in Newly-DiagnosedStudies in Newly-Diagnosed(Mostly Potent Immunosuppressants)(Mostly Potent Immunosuppressants)
Risks of Interventions:Risks of Interventions:• Much stress already presentMuch stress already present• Infectious disease exposureInfectious disease exposure• Viral studiesViral studies• Little past data on immunizations, etc.Little past data on immunizations, etc.• Immune compromiseImmune compromise
– Purpose: To try to preserve somePurpose: To try to preserve some
insulin productioninsulin production
Pathways Being EvaluatedPathways Being Evaluated
• Immunosuppression (MMF)Immunosuppression (MMF)• T-cell modulation (Anti-CD3, Thymoglobulin)T-cell modulation (Anti-CD3, Thymoglobulin)• B-cell modulation (Rituximab)B-cell modulation (Rituximab)• Co-stimulation blockade (Abatacept)Co-stimulation blockade (Abatacept)• Antigen specific therapy (Oral insulin, GAD-Alum)Antigen specific therapy (Oral insulin, GAD-Alum)• Metabolic control (CSII with CGM)Metabolic control (CSII with CGM)• Nutritional therapy (Omega-3-fatty acid)Nutritional therapy (Omega-3-fatty acid)
TrialNet AchievementsTrialNet Achievements• Effective, multidisciplinary, international, Effective, multidisciplinary, international,
network….network….• 4 Prevention Studies – only possible through 4 Prevention Studies – only possible through
TrialNetTrialNet• 8 New-Onset Studies8 New-Onset Studies• Immune agents from bench to bedside and back Immune agents from bench to bedside and back
again (mechanistic studies)again (mechanistic studies)• Methodologic refinementMethodologic refinement• Open resource for investigators worldwide to Open resource for investigators worldwide to
conduct T1D clinical protocols & ancillary conduct T1D clinical protocols & ancillary studiesstudies
• TrialNet will enable the prevention of TrialNet will enable the prevention of type 1 diabetestype 1 diabetes
oror
• ““We’ve had a tremendous amount of We’ve had a tremendous amount of progress in diabetes in recent years. progress in diabetes in recent years. We’re at a stage now where we can We’re at a stage now where we can sense that we can lick this thing. We’re sense that we can lick this thing. We’re going to get there.”going to get there.”
- - USA Today November 14 2007USA Today November 14 2007
SUMMARY
Family Presentations
1) How to decide to be in a research trial?
2) The “Good” and the “Bad”
3) What to tell other families?
4) Other?
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