Rationale and study design of the adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D): A non-randomised, open label, adaptive dose finding trial

BMJ Open

Volumn 4, Issue 6, 2014, Pages

  Waldron Lynch, Frank ^a   Kareclas, Paula ^b   Irons, Kathryn ^b   Walker, Neil M ^a   Mander, Adrian ^c   Wicker, Linda S ^a   Todd, John A ^a   Bond, Simon ^b,c  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b CAMBRIDGE UNIVERSITY HOSPITALS NHS FOUNDATION TRUST   (United Kingdom)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

INTERLEUKIN 2;

ADULT; ARTICLE; CLINICAL TRIAL (TOPIC); DOSE CALCULATION; DOSE RESPONSE; DRUG DOSE ESCALATION; HUMAN; HUMAN CELL; INSULIN DEPENDENT DIABETES MELLITUS; OPEN STUDY; PATIENT MONITORING; REGULATORY T LYMPHOCYTE; CLINICAL TRIAL; DIABETES MELLITUS, TYPE 1; DRUG EFFECTS; IMMUNOLOGY; METHODOLOGY; PHYSIOLOGY;

DIABETES MELLITUS, TYPE 1; DRUG DOSAGE CALCULATIONS; HUMANS; INTERLEUKIN-2; RESEARCH DESIGN; T-LYMPHOCYTES, REGULATORY;

EID: 84901931670     PISSN: None     EISSN: 20446055     Source Type: Journal    
DOI: 10.1136/bmjopen-2014-005559     Document Type: Article

References (32)

1. Patterson CC, Dahlquist GG, Gyurus E, et al. Incidence trends for childhood type 1 diabetes in Europe during 1989-2003 and predicted new cases 2005-20: a multicentre prospective registration study. Lancet 2009;373:2027-33.
2. Daneman D. Type 1 diabetes. Lancet 2006;367:847-58. (Pubitemid 43363372)
3. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med 1993;329:977-86.
4. Diabetes Control and Complications Trial Research Group. Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 1997;46:271-86.
5. Steffes MW, Sibley S, Jackson M, et al. Beta-cell function and the development of diabetes-related complications in the diabetes control and complications trial. Diabetes Care 2003;26:832-6. (Pubitemid 36929351)
6. Todd JA. Etiology of type 1 diabetes. Immunity 2010;32:457-67.
7. Todd JA, Walker NM, Cooper JD, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007;39:857-64. (Pubitemid 47018195)
8. Dendrou CA, Plagnol V, Fung E, et al. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet 2009;41:1011-15.
9. Yamanouchi J, Rainbow D, Serra P, et al. Interleukin-2 gene variation impairs regulatory T cell function and causes autoimmunity. Nat Genet 2007;39:329-37. (Pubitemid 46328484)
10. Delgoffe GM, Kole TP, Zheng Y, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009;30:832-44.
11. Burchill MA, Yang J, Vogtenhuber C, et al. IL-2 receptor beta-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J Immunol 2007;178:280-90. (Pubitemid 46033611)
12. Dendrou CA, Wicker LS. The IL-2/CD25 pathway determines susceptibility to T1D in humans and NOD mice. J Clin Immunol 2008;28:685-96.
13. Doyle MV, Lee MT, Fong S. Comparison of the biological activities of human recombinant interleukin-2(125) and native interleukin-2. J Biol Response Mod 1985;4:96-109.
14. Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-96.
15. Rosenberg SA, Yang JC, White DE, et al. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann Surg 1998;228:307-19. (Pubitemid 30191694)
16. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. N Engl J Med 1998;338:1272-8. (Pubitemid 28216581)
17. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127-32. (Pubitemid 46606294)
18. Abrams D, Lévy Y, Losso MH, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med 2009;361:1548-59.
19. Rabinovitch A, Suarez-Pinzon WL, Shapiro AM, et al. Combination therapy with sirolimus and interleukin-2 prevents spontaneous and recurrent autoimmune diabetes in NOD mice. Diabetes 2002;51:638-45. (Pubitemid 34760170)
20. Turnquist HR, Raimondi G, Zahorchak AF, et al. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J Immunol 2007;178:7018-31. (Pubitemid 46847428)
21. Long SA, Rieck M, Sanda S, et al. Rapamycin/IL-2 combination therapy in patients with type 1 diabetes augments Tregs yet transiently impairs β-Cell function. Diabetes 2012;61:2340-8.
22. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med 2011;365:2055-66.
23. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011;365:2067-77.
24. ADDRESS2. After Diabetes Diagnosis REsearch Support System (ADDRESS). 2014. http://wwwaddress2org
25. DGAP. Diabetes: genes, autoimmunity and prevention. 2014. http://paediatricsmedschlcamacuk/research/clinical-trials/d-gap-diabetes-genes- auto-immunity-and-prevention/
26. Dette H, Bornkamp B, Bretz F. On the efficiency of two-stage response-adaptive designs. Stat Med 2012;32:1646-60.
27. Group OMTS. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985;313:337-42.
28. Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, et al. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med 2009;361:2143-52.
29. Kremer JM, Dougados M, Emery P, et al. Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2005;52:2263-71. (Pubitemid 41117408)
30. Orban T, Bundy B, Becker DJ, et al. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet 2011;378:412-9.
31. Edwards JC, Szczepanski L, Szechinski J, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81. (Pubitemid 38758544)
32. Defend-1. Trial of otelixizumab for adults with newly diagnosed type 1 diabetes mellitus (autoimmune): DEFEND-1. 2010. http://clinicaltrialsgov/ct2/ show/NCT00678886