1

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

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t yr

s)Hypoglycemia Hypoglycemia (seizure/coma)(seizure/coma)

00

11

22

33

44

55

(R

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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

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nS

urv

ival

Dis

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uti

on

Fu

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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

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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

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istr

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n F

un

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Dis

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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

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n F

un

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urv

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Dis

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Fu

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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

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7

Ap

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7

Ma

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7

Jun

-07

Jul-

07

Au

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7

Se

p-0

7

Oct

-07

No

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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?