Anti-IL-1 Treatment in Children Diabetic Keto-Acidosis (DKA) at Diagnosis of Type 1 Diabetes

Summary

This is a randomized, double-blind, placebo-controlled phase 2 study. Specific aim is to evaluate feasibility and safety of anti-IL-1 (interleukin 1) treatment in the course of standard therapy for diabetic ketoacidosis in children and its effect on intracranial pressure.

Timeline

Start

2012-03

Primary completion

2016-03

Completion

2016-04-22

Publications

• Background Rewers A, Chase HP, Mackenzie T, Walravens P, Roback M, Rewers M, Hamman RF, Klingensmith G. Predictors of acute complications in children with type 1 diabetes. JAMA. 2002 May 15;287(19):2511-8. doi: 10.1001/jama.287.19.2511.
• Background Rewers A, Klingensmith G, Davis C, Petitti DB, Pihoker C, Rodriguez B, Schwartz ID, Imperatore G, Williams D, Dolan LM, Dabelea D. Presence of diabetic ketoacidosis at diagnosis of diabetes mellitus in youth: the Search for Diabetes in Youth Study. Pediatrics. 2008 May;121(5):e1258-66. doi: 10.1542/peds.2007-1105.
• Background Maniatis AK, Goehrig SH, Gao D, Rewers A, Walravens P, Klingensmith GJ. Increased incidence and severity of diabetic ketoacidosis among uninsured children with newly diagnosed type 1 diabetes mellitus. Pediatr Diabetes. 2005 Jun;6(2):79-83. doi: 10.1111/j.1399-543X.2005.00096.x.
• Background Muir AB, Quisling RG, Yang MC, Rosenbloom AL. Cerebral edema in childhood diabetic ketoacidosis: natural history, radiographic findings, and early identification. Diabetes Care. 2004 Jul;27(7):1541-6. doi: 10.2337/diacare.27.7.1541.
• Background Glaser NS, Wootton-Gorges SL, Buonocore MH, Marcin JP, Rewers A, Strain J, DiCarlo J, Neely EK, Barnes P, Kuppermann N. Frequency of sub-clinical cerebral edema in children with diabetic ketoacidosis. Pediatr Diabetes. 2006 Apr;7(2):75-80. doi: 10.1111/j.1399-543X.2006.00156.x.
• Background Edge JA, Hawkins MM, Winter DL, Dunger DB. The risk and outcome of cerebral oedema developing during diabetic ketoacidosis. Arch Dis Child. 2001 Jul;85(1):16-22. doi: 10.1136/adc.85.1.16.
• Background Edge JA. Cerebral oedema during treatment of diabetic ketoacidosis: are we any nearer finding a cause? Diabetes Metab Res Rev. 2000 Sep-Oct;16(5):316-24. doi: 10.1002/1520-7560(2000)9999:99993.0.co;2-r.
• Background Glaser N, Barnett P, McCaslin I, Nelson D, Trainor J, Louie J, Kaufman F, Quayle K, Roback M, Malley R, Kuppermann N; Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. Risk factors for cerebral edema in children with diabetic ketoacidosis. The Pediatric Emergency Medicine Collaborative Research Committee of the American Academy of Pediatrics. N Engl J Med. 2001 Jan 25;344(4):264-9. doi: 10.1056/NEJM200101253440404.
• Background Wolfsdorf J, Glaser N, Sperling MA; American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care. 2006 May;29(5):1150-9. doi: 10.2337/diacare.2951150. No abstract available.
• Background Blamire AM, Anthony DC, Rajagopalan B, Sibson NR, Perry VH, Styles P. Interleukin-1beta -induced changes in blood-brain barrier permeability, apparent diffusion coefficient, and cerebral blood volume in the rat brain: a magnetic resonance study. J Neurosci. 2000 Nov 1;20(21):8153-9. doi: 10.1523/JNEUROSCI.20-21-08153.2000.
• Background Hoffman WH, Burek CL, Waller JL, Fisher LE, Khichi M, Mellick LB. Cytokine response to diabetic ketoacidosis and its treatment. Clin Immunol. 2003 Sep;108(3):175-81. doi: 10.1016/s1521-6616(03)00144-x.
• Background Glaser N. Cerebral injury and cerebral edema in children with diabetic ketoacidosis: could cerebral ischemia and reperfusion injury be involved? Pediatr Diabetes. 2009 Dec;10(8):534-41. doi: 10.1111/j.1399-5448.2009.00511.x. Epub 2009 Oct 10. No abstract available.
• Background Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA. Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol. 2003 Oct;140(3):471-6. doi: 10.1038/sj.bjp.0705462. Epub 2003 Aug 26.
• Background Banwell V, Sena ES, Macleod MR. Systematic review and stratified meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke. J Stroke Cerebrovasc Dis. 2009 Jul-Aug;18(4):269-76. doi: 10.1016/j.jstrokecerebrovasdis.2008.11.009.
• Background Clark SR, McMahon CJ, Gueorguieva I, Rowland M, Scarth S, Georgiou R, Tyrrell PJ, Hopkins SJ, Rothwell NJ. Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations. J Cereb Blood Flow Metab. 2008 Feb;28(2):387-94. doi: 10.1038/sj.jcbfm.9600537. Epub 2007 Aug 8.
• Background Emsley HC, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ; Acute Stroke Investigators. A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005 Oct;76(10):1366-72. doi: 10.1136/jnnp.2004.054882.
• Background Leslie KS, Lachmann HJ, Bruning E, McGrath JA, Bybee A, Gallimore JR, Roberts PF, Woo P, Grattan CE, Hawkins PN. Phenotype, genotype, and sustained response to anakinra in 22 patients with autoinflammatory disease associated with CIAS-1/NALP3 mutations. Arch Dermatol. 2006 Dec;142(12):1591-7. doi: 10.1001/archderm.142.12.1591.
• Background Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, Gitton X, Widmer A, Patel N, Hawkins PN; Canakinumab in CAPS Study Group. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009 Jun 4;360(23):2416-25. doi: 10.1056/NEJMoa0810787.
• Background Kitley JL, Lachmann HJ, Pinto A, Ginsberg L. Neurologic manifestations of the cryopyrin-associated periodic syndrome. Neurology. 2010 Apr 20;74(16):1267-70. doi: 10.1212/WNL.0b013e3181d9ed69.
• Background Mandrup-Poulsen T, Bendtzen K, Nerup J, Dinarello CA, Svenson M, Nielsen JH. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia. 1986 Jan;29(1):63-7. doi: 10.1007/BF02427283.
• Background Atkinson MA, Wilson SB. Fatal attraction: chemokines and type 1 diabetes. J Clin Invest. 2002 Dec;110(11):1611-3. doi: 10.1172/JCI17311. No abstract available.
• Background Mandrup-Poulsen T, Pickersgill L, Donath MY. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat Rev Endocrinol. 2010 Mar;6(3):158-66. doi: 10.1038/nrendo.2009.271.
• Background Kaas A, Pfleger C, Hansen L, Buschard K, Schloot NC, Roep BO, Mortensen HB; Hvidore Study Group on Childhood Diabetes. Association of adiponectin, interleukin (IL)-1ra, inducible protein 10, IL-6 and number of islet autoantibodies with progression patterns of type 1 diabetes the first year after diagnosis. Clin Exp Immunol. 2010 Sep;161(3):444-52. doi: 10.1111/j.1365-2249.2010.04193.x.
• Background Pickersgill LM, Mandrup-Poulsen TR. The anti-interleukin-1 in type 1 diabetes action trial--background and rationale. Diabetes Metab Res Rev. 2009 May;25(4):321-4. doi: 10.1002/dmrr.960.
• Background Kindt S, Vanden Berghe P, Boesmans W, Roosen L, Tack J. Prolonged IL-1beta exposure alters neurotransmitter and electrically induced Ca(2+) responses in the myenteric plexus. Neurogastroenterol Motil. 2010 Mar;22(3):321-e85. doi: 10.1111/j.1365-2982.2009.01414.x. Epub 2009 Oct 1.
• Background Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: a sensor for metabolic danger? Science. 2010 Jan 15;327(5963):296-300. doi: 10.1126/science.1184003.
• Background Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med. 2007 Apr 12;356(15):1517-26. doi: 10.1056/NEJMoa065213.
• Background Larsen CM, Faulenbach M, Vaag A, Ehses JA, Donath MY, Mandrup-Poulsen T. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care. 2009 Sep;32(9):1663-8. doi: 10.2337/dc09-0533. Epub 2009 Jun 19.
• Background Donath, M. Y., Weder, C., and Brunner, A. XOMA 052, a potential disease modifying anti-ILbeta antibody, shows sustained HbA1c reductions 3 months after a single injection with no increases in safety parameters in subjects with type 2 diabetes. Diabetes 58[Suppl. 1], A30. 2009. Ref Type: Abstract
• Background Rewers, A Klingensmith G Brown A Rewers M. Children presenting in DKA at diagnosis have higher HbA1cduring initial 8 years of type 1 diabetes independently of access to care and ethnicity. Pediatric Diabetes 8[Suppl. 7], 32. 2007. Ref Type: Abstract
• Background Glaser NS, Marcin JP, Wootton-Gorges SL, Buonocore MH, Rewers A, Strain J, DiCarlo J, Neely EK, Barnes P, Kuppermann N. Correlation of clinical and biochemical findings with diabetic ketoacidosis-related cerebral edema in children using magnetic resonance diffusion-weighted imaging. J Pediatr. 2008 Oct;153(4):541-6. doi: 10.1016/j.jpeds.2008.04.048. Epub 2008 Jun 27.
• Background Quiros JA, Marcin JP, Kuppermann N, Nasrollahzadeh F, Rewers A, DiCarlo J, Neely EK, Glaser N. Elevated serum amylase and lipase in pediatric diabetic ketoacidosis. Pediatr Crit Care Med. 2008 Jul;9(4):418-22. doi: 10.1097/PCC.0b013e318172e99b.
• Background Rewers A, McFann K, Chase HP. Bedside monitoring of blood beta-hydroxybutyrate levels in the management of diabetic ketoacidosis in children. Diabetes Technol Ther. 2006 Dec;8(6):671-6. doi: 10.1089/dia.2006.8.671.
• Background Galea J, Ogungbenro K, Hulme S, Greenhalgh A, Aarons L, Scarth S, Hutchinson P, Grainger S, King A, Hopkins SJ, Rothwell N, Tyrrell P. Intravenous anakinra can achieve experimentally effective concentrations in the central nervous system within a therapeutic time window: results of a dose-ranging study. J Cereb Blood Flow Metab. 2011 Feb;31(2):439-47. doi: 10.1038/jcbfm.2010.103. Epub 2010 Jul 14.
• Background Gueorguieva I, Clark SR, McMahon CJ, Scarth S, Rothwell NJ, Tyrrell PJ, Hopkins SJ, Rowland M. Pharmacokinetic modelling of interleukin-1 receptor antagonist in plasma and cerebrospinal fluid of patients following subarachnoid haemorrhage. Br J Clin Pharmacol. 2008 Mar;65(3):317-25. doi: 10.1111/j.1365-2125.2007.03026.x. Epub 2007 Sep 13.
• Background DKA TREATMENT PROTOCOL Barbara Davis Center for Childhood Diabetes, University of Colorado & The Children's Hospital Denver. http://www.ucdenver.edu/academics/colleges/medicalschool/centers/BarbaraDavis/Pages/contact.aspx . 2010.
• Background Erlich H, Valdes AM, Noble J, Carlson JA, Varney M, Concannon P, Mychaleckyj JC, Todd JA, Bonella P, Fear AL, Lavant E, Louey A, Moonsamy P; Type 1 Diabetes Genetics Consortium. HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families. Diabetes. 2008 Apr;57(4):1084-92. doi: 10.2337/db07-1331. Epub 2008 Feb 5.
• Background Soldatos T, Chatzimichail K, Papathanasiou M, Gouliamos A. Optic nerve sonography: a new window for the non-invasive evaluation of intracranial pressure in brain injury. Emerg Med J. 2009 Sep;26(9):630-4. doi: 10.1136/emj.2008.058453.
• Background Karakitsos D, Soldatos T, Gouliamos A, Armaganidis A, Poularas J, Kalogeromitros A, Boletis J, Kostakis A, Karabinis A. Transorbital sonographic monitoring of optic nerve diameter in patients with severe brain injury. Transplant Proc. 2006 Dec;38(10):3700-6. doi: 10.1016/j.transproceed.2006.10.185.
• Background Tayal VS, Neulander M, Norton HJ, Foster T, Saunders T, Blaivas M. Emergency department sonographic measurement of optic nerve sheath diameter to detect findings of increased intracranial pressure in adult head injury patients. Ann Emerg Med. 2007 Apr;49(4):508-14. doi: 10.1016/j.annemergmed.2006.06.040. Epub 2006 Sep 25.
• Background Le A, Hoehn ME, Smith ME, Spentzas T, Schlappy D, Pershad J. Bedside sonographic measurement of optic nerve sheath diameter as a predictor of increased intracranial pressure in children. Ann Emerg Med. 2009 Jun;53(6):785-91. doi: 10.1016/j.annemergmed.2008.11.025. Epub 2009 Jan 23.
• Background Auron PE, Webb AC, Rosenwasser LJ, Mucci SF, Rich A, Wolff SM, Dinarello CA. Nucleotide sequence of human monocyte interleukin 1 precursor cDNA. Proc Natl Acad Sci U S A. 1984 Dec;81(24):7907-11. doi: 10.1073/pnas.81.24.7907.

Drugs

Indications