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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
1
“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.
2
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 ? ?
3
“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).
4
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.
5
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.)
6
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
7
Child Participation in Research
C.S. Mott Children’s Hospital National Poll on Children’s Health, January 2008
8
Parent’s Willingness to Allow Children in Research Versus
Desire For FDA-Approved Medicines for Children
9
Parents’ Willingness To Allow Children To
Participate In Research
10
Child Participation in Research
11
Appreciation is expressed to Dr. Jay Skyler for help in
development of these slides.
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
8 years
2,983 days
71,592 hours
4,295,520 minutes
>20,000 finger sticks
>8,000 injections
> 450 pump site
changes
age 14 months
age 9 years
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
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
Antioxidant MDL 29,311
Antisense GAD mRNA
Azathioprine
Anti-B7-1
Bacille Calmette Gue’rin (BCG)
Baclofen
Bee venom
Biolistic-mediated IL-4
Blocking peptide of MHC class II
Bone marrow transplantation
Castration
Anti-CD3
Anti-CD4
CD4+CD25+regulatory 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 Freund’s 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
Deoxysperogualin
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
Galactosylceramide
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
Immobilization
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
Interferon-gamma receptor/IgG1 fusion protein
Interleukin-1
Interleukin-4
Interleukin-4-Ig fusion protein
Interleukin-4-plasmid
Interleukin-10
Interleukin-10-plasmid DNA
Interleukin-10-viral
Interleukin 11-human
Interleukin-12
Intrathymic 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-activated 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
Pentoxifylline
Pertussigen
Poly [I:C]
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
Streptozotocin
Sulfatide (3’sulfogalactosylceramide)
Superantigens
Superoxide dismutase-desferrioxamine
Anti-T cell receptor
TGF-beta 1 somatic gene therapy
Th1 clone specific for hsp60 peptide
Anti-thy-1
Thymectomy (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-23-yne-1,25(OH)(2)D(3))
Vitamin E
Anti-VLA-4
March, 2006
Potential Timing of Intervention Studies
GENETICALLY AT-RISK
BETA CELL MASS
MULTIPLE ANTIBODY POSITIVE
LOSS OF FIRST PHASE
INSULIN RESPONSE
DYSGLYCEMIA
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
C-Peptide
“PRE”DIABETES
b-cell mass
DIABETES
TIME
NEWLY DIAGNOSED DIABETES
DCCT: Impact of Preserved C-Peptide
on Hypoglycemia & Retinopathy
C-peptide
status
at entry
Hypoglycemia
(seizure/coma)
5
(Rate/100 pt yrs)
15
10
5
0
(Rate/100 pt yrs)
20
positive
negative
Retinopathy
4
3
2
1
0
DCCT Research Group. Ann Intern Med 1998;128:517
DPT·1 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
Survival Distribution Function
DPT-1 – Time to Diabetes
By Number of Antibodies
1.0
0.9
0.8
0.7
0.6
0.5
P- Value< 0.001
(Log Rank Test)
Number at Risk
0.4
0.3
24151
1718
405
378
147
0.2
0.1
0.0
0
22297
1401
297
255
95
17049
1045
229
192
61
1
2
3
9052
557
118
78
30
7439
457
91
49
22
6198
371
66
31
16
4
5
6
3524
199
35
14
8
0
1
2
3
4
7
8
Years Followed
n = 26799
STRATA:
11807
743
163
130
40
0
1
2
3
4
DPT-1 Parenteral Insulin Trial – Time to Diabetes
By Treatment
Survival Distribution Function
1.0
0.9
0.8
0.7
0.6
Treated
0.5
0.4
Control
0.3
0.2
0.1
P- Value= 0.796
(Log Rank Test)
Number at Risk
169
170
0.0
0
144
131
96
101
69
69
39
40
13
14
1
2
3
4
5
1
6
Years Followed
STRATA:
New Engl J Med 2002; 346:1685-91
Intervention
Observation
Intervention
Observation
7
Survival Distribution Function
DPT-1 Oral Study – Time to Diabetes
By Treatment
1.0
0.9
0.8
Treated
0.7
0.6
Control
0.5
0.4
P- Value= 0.176
(Log Rank Test)
0.3
0.2
Number at Risk
0.1
186
186
174
170
146
137
110
102
1
2
3
85
71
40
37
23
12
Oral Insulin
Oral Placebo
0.0
0
4
5
6
Years Followed
STRATA:
Diabetes Care 2005; 28:1068-76
Oral Insulin
Oral Placebo
7
DPT-1 Oral Study - Time to Diabetes - By Treatment
Subset: IAA Confirmed > 80 nU/ml
Survival Distribution Function
1.0
Projected 4.5 – 5 year delay
0.9
0.8
Treated
0.7
0.6
0.5
Control
0.4
P- Value= 0.015
(Log Rank Test)
0.3
0.2
Number at Risk
0.1
130
133
122
121
104
96
86
69
66
46
40
32
23
12
1
2
3
4
5
6
Oral Insulin
Oral Placebo
0.0
0
Years Followed
STRATA:
Diabetes Care 2005; 28:1068-76
Oral Insulin
Oral Placebo
7
1.0
Insulin Effect Most Evident in Subjects
with Baseline
IAA ≥ 300
IAA >= 300
0.6
Projected 10 year delay
Log- r ank P=0.01
0.4
Peto Pr . P=0.01
0.2
H az ar d R atio: 0.41 ( 0.21, 0.80)
N=63 (Ins.) and 69 (Plac.)
0.0
Proportion Free of Diabetes
0.8
Or al Ins ulin
Plac ebo
0
1
2
3
Year s
4
5
6
TrialNet Sites in North America
+ 117 North American Affiliates
TrialNet International Sites
+ 25 International Affiliates
Turku, Finland
Malmo, Sweden
Bristol, UK
Melbourne, Australia
Milan, Italy
Munich, Germany
I) Prevention Studies
versus
II) New-Onset Studies
(To preserve some insulin
production)
TrialNet Natural History Study
and
Oral Insulin Trial
Study Period
Mar-08
Jan-08
Nov-07
Sep-07
Jul-07
15,000
May-07
20,000
Mar-07
Jan-07
Nov-06
Sep-06
Jul-06
May-06
Mar-06
Jan-06
Nov-05
Sep-05
Jul-05
May-05
Mar-05
Jan-05
Nov-04
Sep-04
Jul-04
May-04
Mar-04
Number of Participants Enrolled
Enrollment in Natural History Study
March 31, 2008
n=60,007
60,000
55,000
50,000
45,000
n=54,076
40,000
35,000
30,000
25,000
 Expected
 Enrolled
10,000
5,000
0
NHS Phase I New Screenings 2004 - 2007
Cumulative Enrollment by Study Month for the Oral Insulin Trial
Enrollment in Oral Insulin Study
March 31, 2008
90
80
n = 79
70
50
40
30
 Expected
 Enrolled
20
10
Study Month
Mar-08
Feb-08
Jan-08
Dec-07
Nov-07
Oct-07
Sep-07
Aug-07
Jul-07
Jun-07
May-07
Apr-07
Mar-07
0
Feb-07
Subjects Enrolled
60
Primary Prevention Pilot
Nutritional Intervention to
Prevent Type 1 Diabetes (NIP)
Omega 3 fatty acid
(Docosahexanoic acid or DHA)
Enrollment in NIP Pilot Study
March 31, 2008
100
n = 90
90
n = 90
80
Subjects Enrolled
70
60
50
40
30
 Expected
 Enrolled
20
10
0
Dec-06 Jan-07 Feb-07 Mar-07 Apr-07 May-07 Jun-07 Jul-07 Aug-07 Sep-07 Oct-07 Nov-07 Dec-07 Jan-08 Feb-08 Mar-08
Study Month
Anti-CD3 for Prevention
of Diabetes
In Relatives At-Risk for
Type 1 Diabetes Mellitus
SUMMARY
TrialNet Prevention Studies
• Identified in Natural History Study
– Oral Insulin
– GAD-Alum
– Anti-CD3
• Primary Prevention in Newborns
– NIP (Omega-3-Fatty Acids)
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
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)
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
SUMMARY
• TrialNet will enable the prevention of
type 1 diabetes
or
• “We’ve had a tremendous amount of
progress in diabetes in recent years.
We’re at a stage now where we can
sense that we can lick this thing. We’re
going to get there.”
- USA Today November 14 2007
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?