1 / 45

Understanding Diabetes Research

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. “HAWTHORNE Effect”.

isi
Télécharger la présentation

Understanding Diabetes Research

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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) • 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) 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

  8. Child Participation in Research C.S. Mott Children’s Hospital National Poll on Children’s Health, January 2008

  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

  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

  14. 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

  15. 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

  16. Type 1 Diabetes Prevention in NODMice 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-4 234 March, 2006

  17. GENETICALLY AT-RISK MULTIPLE ANTIBODY POSITIVE LOSS OF FIRST PHASE INSULIN RESPONSE DYSGLYCEMIA C-Peptide b-cell mass NEWLY DIAGNOSED DIABETES Potential Timing of Intervention Studies BETA CELL MASS GENETIC PREDISPOSITION INSULITIS BETA CELL INJURY “PRE”-DIABETES DIABETES TIME

  18. 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 1998;128:517

  19. 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

  20. 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- Value< 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 0 1 2 3 4 3524 199 35 14 8 0.2 0.1 0.0 0 1 2 3 4 5 6 7 8 Years Followed n = 26799 1 2 4 0 3 STRATA:

  21. 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 Intervention STRATA: New Engl J Med 2002; 346:1685-91

  22. 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 Oral Insulin STRATA: Diabetes Care 2005; 28:1068-76

  23. DPT-1 Oral Study - Time to Diabetes - By Treatment Subset: IAA Confirmed > 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 Oral Insulin STRATA: Diabetes Care 2005; 28:1068-76

  24. Insulin Effect Most Evident in Subjects with Baseline IAA ≥ 300 Projected 10 year delay N=63 (Ins.) and 69 (Plac.)

  25. TrialNet Sites in North America + 117 North American Affiliates

  26. TrialNet International Sites + 25 International Affiliates Turku, Finland Malmo, Sweden Bristol, UK Melbourne, Australia Milan, Italy Munich, Germany

  27. I) Prevention Studies • versus • New-Onset Studies • (To preserve some insulin production)

  28. TrialNet Natural History Studyand Oral Insulin Trial

  29. Enrollment in Natural History Study March 31, 2008  Expected  Enrolled

  30. NHS Phase I New Screenings 2004 - 2007

  31. Enrollment in Oral Insulin Study March 31, 2008  Expected  Enrolled

  32. Primary Prevention Pilot Nutritional Intervention to Prevent Type 1 Diabetes (NIP) Omega 3 fatty acid (Docosahexanoic acid or DHA)

  33. Enrollment in NIP Pilot Study March 31, 2008

  34. Anti-CD3 for Prevention of Diabetes In Relatives At-Risk for Type 1 Diabetes Mellitus

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

  36. 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

  37. 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)

  38. 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

  39. 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

  40. Family Presentations • 1) How to decide to be in a research trial? • The “Good” and the “Bad” • What to tell other families? • Other?

More Related