Modern Insulin Therapy

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 30298,2007)

• Improves HbA1c even if no intervention
• Analysis of 3 trials (429 subjects) of T1D and 3
  trials (611 subjects) of T2D
• Recruitment A1c vs Randomization visit Second
  HbA1c values consistently lower (though research
  has not yet begun)
• Why? a) Patients interest b) Attention
• c) Encouragement d) BGs ? ?

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

8
Child Participation in Research
C.S. Mott Childrens Hospital National Poll on
Childrens Health, January 2008
9
Parents 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
12
Appreciation is expressed to Dr. Jay Skyler for
help in development of these slides.
13
TrialNet Goals

• Delay or prevent Type 1 Diabetes
• Explore new therapies in
• Relatives at risk of T1D
• High genetic risk individuals
• New-onset T1D
• Further define epidemiology, natural history, and
  risk factors of T1D
• Parents must decide if they will support
  prevention research

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8 years 2,983 days 71,592 hours 4,295,520
minutes gt20,000 finger sticks gt8,000 injections gt
450 pump site changes
age 14 months
age 9 years
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Rationale

• Although there is a treatment for T1D insulin
  is not a cure
• Type 1 Diabetes is immunologically mediated
• Our goal is to interdict the disease process
• Immunomodulatory therapies may be effective
• Yet, there must be a careful balance between
  efficacy and safety
• Successful modulation of immune mechanisms is
  also required for cellular replacement therapies

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Type 1 Diabetes Prevention in NOD Mice
AAV murine IL-10 AAV rat preproinsulin gene
(vLP-1) Adenovirus expressing mIL-4 Aerosol
insulin Allogenic thymic macrophages Alpha
Galactosylceramide Alpha-interferon
(rIFN-alpha) Alpha/beta T cell receptor
thymocytes Aminoguanidine Androgens Anesthesia An
tioxidant MDL 29,311 Antisense GAD
mRNA Azathioprine Anti-B7-1 Bacille Calmette
Guerin (BCG) Baclofen Bee venom Biolistic-mediate
d IL-4 Blocking peptide of MHC class II Bone
marrow transplantation Castration Anti-CD3 Anti-CD
4 CD4CD25regulatory T cells Anti-CD8 Anti-CD28
MAb Cholera toxin B subunit-insulin protein Class
I derived self-I-A beta(g7) (54-76) peptide Cold
exposure Anti-complement receptor Complete
Freunds adjuvant Anti-CTLA-4 Cyclic nucleotide
phosphodiesterases (PDEs) Cyclosporin Cyclosporin
A DC deficient in NF-kappaB DC from pancreatic
lymph node DC with IL-4 Deflazacort Deoxysperogual
in Dexamethasone/progesterone/growth
hormone/estradiol Diazoxide 1,25 dihydroxy
Vitamin D3, KH1060 1,25 dihydroxycholecalciferol 1
,25 dihydroxyl Vitamin D3 Elevated
temperature Emotionality Encephalomyocarditis
virus (ECMV) Essential fatty acid deficient
diets FK506 FTY720 (myriocin) GAD 65 peptides in
utero Anti-GAD monoclonal antibody Galactosylceram
ide Glucose (neonatal) Glutamic acid
decarboxylase (intraperitoneal, intrathymic,
intravenous, oral) Glutamic acid decarboxylase 65
Th2 cell clone Glutamic acid decarboxylase
peptides (intraperitoneal, intrathymic,
intravenous, oral)
Gonadectomy Guanidinoethyldisulphide Heat shock
protein 65 Heat shock protein peptide
(p277) Hematopoietic stem cells encoding
proinsulin Housing alone Human IGF-1 I-A beta
g7(54-76) peptide Anti-I-A monoclonal
antibodies Anti-ICAM-1 IgG2a antibodies Immobiliza
tion Inomide Anti-integrin alpha 4 Insulin
(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-gamma Anti-interferon-gamma Inte
rferon-gamma receptor/IgG1 fusion
protein Interleukin-1 Interleukin-4 Interleukin-4-
Ig fusion protein Interleukin-4-plasmid Interleuki
n-10 Interleukin-10-plasmid DNA Interleukin-10-vir
al Interleukin 11-human Interleukin-12 Intrathymi
c administration of mycobacterial heat shock
protein 65 Intrathymic administration of
mycobacterial heat shock peptide p277 Islet
cells-intrathymic L-Selectin (MEL-14) Lactate
dehydogenase virus (LDH) Large multilamellar
liposome Lazaroid Anti-leukocyte function
associated antigen (LFA-1) Anti-LFA-1 Linomide
(quinoline-3-carboxamide) Lipopolysaccharide-activ
ated B cells Lisofylline Lymphocyte
choriomeningitis virus (LCMV) Anti-lymphocyte
serum Lymphoctyte vaccination Lymphocytic
choriomeningitis virus Anti-L-selectin Lymphotoxin
LZ8 MC1288 (20-epi-1,25-dihydroxyvitamin D3) MDL
29311 Metabolically inactive insulin
analog Anti-MHC class I Anti-MHC class II MHC
class II derived cyclic peptide Mixed allogeneic
chimerism Mixed bone marrow chimeras Monosodium
glutamate Murine hepatitis virus (MHV)
Mycobacterium avium Mycobacterium leprae Natural
antibodies Natural polyreactive
autoantibodies Neuropeptide calcitonin
gene-related peptide Nicotinamide Nicotine Ninjin-
to (Ren-Shen-Tang), a Kampo (Japanese
traditional) formulation NKT cells NY4.2
cells OK432 Overcrowding Pancreatectomy Pentoxifyl
line Pertussigen Poly IC Pregestimil
diet Prenatal stress Preproinsulin
DNA Probucol Prolactin Rampamycin Recombinant
vaccinia virus expressing GAD Reg protein Reg
protein Rolipram Saline (repeated
injection) Schistosoma mansoni Semi-purified diet
(e.g., AIN-76) Short term chronic
stress Silica Sirolimus/tacrolimus Sodium
fusidate Soluble interferon-gamma
receptor Somatostatin Non-specific pathogen free
conditions Streptococcal enterotoxins Streptozotoc
in Sulfatide (3sulfogalactosylceramide) Superanti
gens Superoxide dismutase-desferrioxamine Anti-T
cell receptor TGF-beta 1 somatic gene therapy Th1
clone specific for hsp60 peptide Anti-thy-1 Thymec
tomy (neonatal) Tolbutamide Tolerogenic dendritic
cells induced by vitamin D receptor ligands Top
of the rack Treatment combined with a 10 w/v
sucrose-supplemented drinking water Tumor
necrosis factor-alpha TX527 (19-nor-14,20-bisepi-2
3-yne-1,25(OH)(2)D(3)) Vitamin E Anti-VLA-4
234
March, 2006
18
Potential Timing of Intervention Studies
BETA CELL MASS
GENETIC PREDISPOSITION
INSULITIS BETA CELL INJURY
PRE-DIABETES
DIABETES
TIME
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DCCT Impact of Preserved C-Peptide on
Hypoglycemia Retinopathy
C-peptide statusat entry
Hypoglycemia (seizure/coma)
Retinopathy
positive
5
20
negative
4
15
(Rate/100 pt yrs)
(Rate/100 pt yrs)
3
10
2
5
1
0
0
DCCT Research Group. Ann Intern Med 1998128517
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DPT1 Screening Results

• 103,391 Relatives Screened
• 97,635 Eligible Samples
• 97,273 Samples Analyzed
• 3483 Samples ICA (3.58)
• 2523 Subjects Staged (72)
• 339 Randomized Parenteral
• 372 Randomized Oral

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DPT-1 Time to Diabetes By Number of Antibodies
1.0
0.9
0.8
0.7
0.6
Survival Distribution Function
0.5
P- Valuelt 0.001 (Log Rank Test)
0.4
Number at Risk
0.3
24151 1718 405 378 147
22297 1401 297 255 95
17049 1045 229 192 61
11807 743 163 130 40
9052 557 118 78 30
7439 457 91 49 22
6198 371 66 31 16
3524 199 35 14 8
0 1 2 3 4
0.2
0.1
0.0
0
1
2
3
4
5
6
7
8
Years Followed
n 26799
1
2
STRATA
0
3
4
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DPT-1 Parenteral Insulin Trial Time to
Diabetes By Treatment
1.0
0.9
0.8
0.7
0.6
Treated
Survival Distribution Function
0.5
0.4
Control
0.3
P- Value 0.796 (Log Rank Test)
0.2
Number at Risk
0.1
169 170
144 131
96 101
69 69
39 40
13 14
Intervention Observation
1
0.0
0
1
2
3
4
5
6
7
Years Followed
Observation
STRATA
Intervention
New Engl J Med 2002 3461685-91
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DPT-1 Oral Study Time to Diabetes By Treatment
1.0
0.9
0.8
Treated
0.7
0.6
Survival Distribution Function
Control
0.5
0.4
P- Value 0.176 (Log Rank Test)
0.3
Number at Risk
0.2
Oral Insulin Oral Placebo
186 186
174 170
146 137
110 102
85 71
40 37
23 12
0.1
0.0
0
1
2
3
4
5
6
7
Years Followed
Oral Placebo
STRATA
Oral Insulin
Diabetes Care 2005 281068-76
27
DPT-1 Oral Study - Time to Diabetes - By
Treatment Subset IAA Confirmed gt 80 nU/ml
1.0
Projected 4.5 5 year delay
0.9
0.8
Treated
0.7
0.6
Survival Distribution Function
0.5
Control
0.4
P- Value 0.015 (Log Rank Test)
0.3
Number at Risk
0.2
130 133
122 121
104 96
86 69
66 46
40 32
23 12
Oral Insulin Oral Placebo
0.1
0.0
0
1
2
3
4
5
6
7
Years Followed
Oral Placebo
STRATA
Oral Insulin
Diabetes Care 2005 281068-76
28
Insulin Effect Most Evident in Subjects with
Baseline IAA 300
Projected 10 year delay
N63 (Ins.) and 69 (Plac.)
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TrialNet Sites in North America
117 North American Affiliates
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TrialNet International Sites
25 International Affiliates
Turku, Finland
Malmo, Sweden
Bristol, UK
Melbourne, Australia
Milan, Italy
Munich, Germany
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• I) Prevention Studies
• versus
• New-Onset Studies
• (To preserve some insulin production)

33
TrialNet Natural History Studyand Oral Insulin
Trial
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Enrollment in Natural History Study
March 31, 2008
? Expected ? Enrolled
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NHS Phase I New Screenings 2004 - 2007
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Enrollment in Oral Insulin Study
March 31, 2008
? Expected ? Enrolled
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Primary Prevention Pilot Nutritional
Intervention to Prevent Type 1 Diabetes (NIP)
Omega 3 fatty acid (Docosahexanoic acid or DHA)
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Enrollment in NIP Pilot Study
March 31, 2008
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Anti-CD3 for Prevention of Diabetes In Relatives
At-Risk for Type 1 Diabetes Mellitus
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SUMMARYTrialNet Prevention Studies

• Identified in Natural History Study
• Oral Insulin
• GAD-Alum
• Anti-CD3
• Primary Prevention in Newborns
• NIP (Omega-3-Fatty Acids)

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Studies in Newly-Diagnosed(Mostly Potent
Immunosuppressants)

• Risks of Interventions
• Much stress already present
• Infectious disease exposure
• Viral studies
• Little past data on immunizations, etc.
• Immune compromise
• Purpose To try to preserve some
• insulin production

42
Pathways Being Evaluated

• Immunosuppression (MMF)
• T-cell modulation (Anti-CD3, Thymoglobulin)
• B-cell modulation (Rituximab)
• Co-stimulation blockade (Abatacept)
• Antigen specific therapy (Oral insulin, GAD-Alum)
• Metabolic control (CSII with CGM)
• Nutritional therapy (Omega-3-fatty acid)

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TrialNet Achievements

• Effective, multidisciplinary, international,
  network.
• 4 Prevention Studies only possible through
  TrialNet
• 8 New-Onset Studies
• Immune agents from bench to bedside and back
  again (mechanistic studies)
• Methodologic refinement
• Open resource for investigators worldwide to
  conduct T1D clinical protocols ancillary
  studies

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SUMMARY

• TrialNet will enable the prevention of type 1
  diabetes
• or
• Weve had a tremendous amount of progress in
  diabetes in recent years. Were at a stage now
  where we can sense that we can lick this thing.
  Were going to get there.
• - USA Today November 14 2007

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Family Presentations

• 1) How to decide to be in a research trial?
• The Good and the Bad
• What to tell other families?
• Other?