Siltuximab in Schizophrenia

Summary

This study is a Phase 1 clinical trial to determine the safety, tolerability, and efficacy of Siltuximab (Sylvant) as an adjunct to antipsychotic medications in stable outpatients with schizophrenia. Siltuximab (structural formula C6450H9932N1688O2016S50) is a recombinant chimeric (human-murine) anti-human interleukin-6 (IL-6) monoclonal antibody. Siltuximab is formulated as a concentrate for solution for infusion, and will be administered by intravenous infusion. The investigators propose a 9-week randomized controlled trial of siltuximab, given in adjunct to antipsychotics, in N=30 stable outpatients with schizophrenia or schizoaffective disorder and evidence of increased inflammation in the peripheral blood (high-sensitivity C-reactive protein \[hsCRP\] \>0.5 mg/dL). The investigators hypothesize that adjunctive treatment with siltuximab will be associated with significant improvement in cognition compared to placebo in patients with schizophrenia, baseline IL-6 levels are higher in siltuximab-treated responders versus non-responders, and there will be greater decreases in hsCRP from baseline to week 6 in siltuximab-treated versus placebo-treated responders, with response defined as ≥0.5 SD improvement in cognition. Siltuximab is administered as an intravenous infusion every 3 weeks. Following a screening evaluation, participants will receive three infusions of siltuximab, one at baseline, another at week 3 of the study, and another at week 6. The investigators will measure changes in cognitive function and symptoms over a 9-week period. Complementing previous positive clinical trials of non-steroidal anti-inflammatory drugs, this would be a "proof-of-concept" study that targeting specific cytokines is a viable treatment for schizophrenia. Interleukin 6 and its receptor were discovered and cloned at Osaka University, Japan, by Tadamitsu Kishimoto in the 1980s. Janssen Pharmaceuticals, Inc. began the clinical development of siltuximab for the treatment of multicentric Castleman's disease, a rare blood disorder. Other clinical studies with siltuximab have been conduced for patients with B-cell non-Hodgkin's lymphoma, multiple myeloma, and ovarian cancer. In April 2014,siltuxiumab was approved by the U.S. Food and Drug Administration (US FDA) as Sylvant for human immunodeficiency virus (HIV)-negative and human herpesvirus-8 (HHV-8)-negative multicentric Castleman's disease.

Timeline

Start

2016-05

Primary completion

2023-12-31

Completion

2023-12-31

Publications

• Background Muller N. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs. 2010 Jan;11(1):31-42.
• Background Muller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, Moller HJ, Klauss V, Schwarz MJ, Riedel M. Celecoxib treatment in an early stage of schizophrenia: results of a randomized, double-blind, placebo-controlled trial of celecoxib augmentation of amisulpride treatment. Schizophr Res. 2010 Aug;121(1-3):118-24. doi: 10.1016/j.schres.2010.04.015. Epub 2010 May 31.
• Background Nitta M, Kishimoto T, Muller N, Weiser M, Davidson M, Kane JM, Correll CU. Adjunctive use of nonsteroidal anti-inflammatory drugs for schizophrenia: a meta-analytic investigation of randomized controlled trials. Schizophr Bull. 2013 Nov;39(6):1230-41. doi: 10.1093/schbul/sbt070. Epub 2013 May 29.
• Background Sommer IE, van Westrhenen R, Begemann MJ, de Witte LD, Leucht S, Kahn RS. Efficacy of anti-inflammatory agents to improve symptoms in patients with schizophrenia: an update. Schizophr Bull. 2014 Jan;40(1):181-91. doi: 10.1093/schbul/sbt139. Epub 2013 Oct 8.
• Background Muller N, Ulmschneider M, Scheppach C, Schwarz MJ, Ackenheil M, Moller HJ, Gruber R, Riedel M. COX-2 inhibition as a treatment approach in schizophrenia: immunological considerations and clinical effects of celecoxib add-on therapy. Eur Arch Psychiatry Clin Neurosci. 2004 Feb;254(1):14-22. doi: 10.1007/s00406-004-0478-1.
• Background Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H. Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010 May;71(5):520-7. doi: 10.4088/JCP.09m05117yel.
• Background Muller N, Riedel M, Schwarz MJ, Engel RR. Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur Arch Psychiatry Clin Neurosci. 2005 Apr;255(2):149-51. doi: 10.1007/s00406-004-0548-4. Epub 2004 Nov 19.
• Background Paul-Samojedny M, Kowalczyk M, Suchanek R, Owczarek A, Fila-Danilow A, Szczygiel A, Kowalski J. Functional polymorphism in the interleukin-6 and interleukin-10 genes in patients with paranoid schizophrenia--a case-control study. J Mol Neurosci. 2010 Sep;42(1):112-9. doi: 10.1007/s12031-010-9365-6.
• Background Sun S, Wang F, Wei J, Cao LY, Qi LY, Xiu MH, Chen S, Li XH, Kosten TA, Kosten TR, Zhang XY. Association between interleukin-6 receptor polymorphism and patients with schizophrenia. Schizophr Res. 2008 Jul;102(1-3):346-7. doi: 10.1016/j.schres.2008.04.018. Epub 2008 May 27. No abstract available.
• Background Miller BJ, Buckley P, Seabolt W, Mellor A, Kirkpatrick B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol Psychiatry. 2011 Oct 1;70(7):663-71. doi: 10.1016/j.biopsych.2011.04.013. Epub 2011 Jun 8.
• Background Garver DL, Tamas RL, Holcomb JA. Elevated interleukin-6 in the cerebrospinal fluid of a previously delineated schizophrenia subtype. Neuropsychopharmacology. 2003 Aug;28(8):1515-20. doi: 10.1038/sj.npp.1300217. Epub 2003 Jun 11.
• Background Sasayama D, Hattori K, Wakabayashi C, Teraishi T, Hori H, Ota M, Yoshida S, Arima K, Higuchi T, Amano N, Kunugi H. Increased cerebrospinal fluid interleukin-6 levels in patients with schizophrenia and those with major depressive disorder. J Psychiatr Res. 2013 Mar;47(3):401-6. doi: 10.1016/j.jpsychires.2012.12.001. Epub 2013 Jan 3.
• Background Krause DL, Wagner JK, Wildenauer A, Matz J, Weidinger E, Riedel M, Obermeier M, Gruber R, Schwarz M, Muller N. Intracellular monocytic cytokine levels in schizophrenia show an alteration of IL-6. Eur Arch Psychiatry Clin Neurosci. 2012 Aug;262(5):393-401. doi: 10.1007/s00406-012-0290-2. Epub 2012 Jan 21.
• Background Frydecka D, Misiak B, Pawlak-Adamska E, Karabon L, Tomkiewicz A, Sedlaczek P, Kiejna A, Beszlej JA. Interleukin-6: the missing element of the neurocognitive deterioration in schizophrenia? The focus on genetic underpinnings, cognitive impairment and clinical manifestation. Eur Arch Psychiatry Clin Neurosci. 2015 Sep;265(6):449-59. doi: 10.1007/s00406-014-0533-5. Epub 2014 Sep 12.
• Background Miller B, Mellor A, Buckley PF. Interleukin-6 and Cognition in Non-Affective Psychosis. Schizophrenia Bulletin 2013(39): S242-S243.
• Background Stojanovic A, Martorell L, Montalvo I, Ortega L, Monseny R, Vilella E, Labad J. Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms. Psychoneuroendocrinology. 2014 Mar;41:23-32. doi: 10.1016/j.psyneuen.2013.12.005. Epub 2013 Dec 14.
• Background Nunes SO, Matsuo T, Kaminami MS, Watanabe MA, Reiche EM, Itano EN. An autoimmune or an inflammatory process in patients with schizophrenia, schizoaffective disorder, and in their biological relatives. Schizophr Res. 2006 May;84(1):180-2. doi: 10.1016/j.schres.2006.02.003. Epub 2006 Mar 10. No abstract available.
• Background Elderkin-Thompson V, Irwin MR, Hellemann G, Kumar A. Interleukin-6 and memory functions of encoding and recall in healthy and depressed elderly adults. Am J Geriatr Psychiatry. 2012 Sep;20(9):753-63. doi: 10.1097/JGP.0b013e31825d08d6.
• Background Sasayama D, Hori H, Teraishi T, Hattori K, Ota M, Matsuo J, Kawamoto Y, Kinoshita Y, Amano N, Kunugi H. Association of cognitive performance with interleukin-6 receptor Asp358Ala polymorphism in healthy adults. J Neural Transm (Vienna). 2012 Mar;119(3):313-8. doi: 10.1007/s00702-011-0709-3. Epub 2011 Aug 31.
• Background Frodl T, Carballedo A, Hughes MM, Saleh K, Fagan A, Skokauskas N, McLoughlin DM, Meaney J, O'Keane V, Connor TJ. Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: high IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder. Transl Psychiatry. 2012 Mar 13;2(3):e88. doi: 10.1038/tp.2012.14.
• Background Marsland AL, Petersen KL, Sathanoori R, Muldoon MF, Neumann SA, Ryan C, Flory JD, Manuck SB. Interleukin-6 covaries inversely with cognitive performance among middle-aged community volunteers. Psychosom Med. 2006 Nov-Dec;68(6):895-903. doi: 10.1097/01.psy.0000238451.22174.92.
• Background Marsland AL, Gianaros PJ, Abramowitch SM, Manuck SB, Hariri AR. Interleukin-6 covaries inversely with hippocampal grey matter volume in middle-aged adults. Biol Psychiatry. 2008 Sep 15;64(6):484-90. doi: 10.1016/j.biopsych.2008.04.016. Epub 2008 Jun 2.
• Background Kalmady SV, Venkatasubramanian G, Shivakumar V, Gautham S, Subramaniam A, Jose DA, Maitra A, Ravi V, Gangadhar BN. Relationship between Interleukin-6 gene polymorphism and hippocampal volume in antipsychotic-naive schizophrenia: evidence for differential susceptibility? PLoS One. 2014 May 2;9(5):e96021. doi: 10.1371/journal.pone.0096021. eCollection 2014.
• Background Miller BJ, Timonen M, Isohanni M. Cytokine abnormalities, inflammation and psychosis in the northern Finland 1966 birth cohort. European Psychiatry 2014 (29): S519.
• Background Mondelli V, Cattaneo A, Murri MB, Di Forti M, Handley R, Hepgul N, Miorelli A, Navari S, Papadopoulos AS, Aitchison KJ, Morgan C, Murray RM, Dazzan P, Pariante CM. Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: a pathway to smaller hippocampal volume. J Clin Psychiatry. 2011 Dec;72(12):1677-1684. doi: 10.4088/JCP.10m06745. Epub 2011 May 18.
• Background Smith SE, Li J, Garbett K, Mirnics K, Patterson PH. Maternal immune activation alters fetal brain development through interleukin-6. J Neurosci. 2007 Oct 3;27(40):10695-702. doi: 10.1523/JNEUROSCI.2178-07.2007.
• Background Basta-Kaim A, Szczesny E, Leskiewicz M, Glombik K, Slusarczyk J, Budziszewska B, Regulska M, Kubera M, Nowak W, Wedzony K, Lason W. Maternal immune activation leads to age-related behavioral and immunological changes in male rat offspring - the effect of antipsychotic drugs. Pharmacol Rep. 2012;64(6):1400-10. doi: 10.1016/s1734-1140(12)70937-4.
• Background Romero E, Ali C, Molina-Holgado E, Castellano B, Guaza C, Borrell J. Neurobehavioral and immunological consequences of prenatal immune activation in rats. Influence of antipsychotics. Neuropsychopharmacology. 2007 Aug;32(8):1791-804. doi: 10.1038/sj.npp.1301292. Epub 2006 Dec 20.
• Background Romero E, Guaza C, Castellano B, Borrell J. Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: implications for the etiopathology of schizophrenia. Mol Psychiatry. 2010 Apr;15(4):372-83. doi: 10.1038/mp.2008.44. Epub 2008 Apr 15.
• Background Behrens MM, Ali SS, Dugan LL. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J Neurosci. 2008 Dec 17;28(51):13957-66. doi: 10.1523/JNEUROSCI.4457-08.2008.
• Background Miller BJ, Culpepper N, Rapaport MH. C-reactive protein levels in schizophrenia: a review and meta-analysis. Clin Schizophr Relat Psychoses. 2014 Jan;7(4):223-30.
• Background Miller BJ, Mellor A, Buckley P. Total and differential white blood cell counts, high-sensitivity C-reactive protein, and the metabolic syndrome in non-affective psychoses. Brain Behav Immun. 2013 Jul;31:82-9. doi: 10.1016/j.bbi.2012.08.016. Epub 2012 Sep 11.
• Background Miller BJ, Kandhal P, Rapaport MH, Mellor A, Buckley P. Total and differential white blood cell counts, high-sensitivity C-reactive protein, and cardiovascular risk in non-affective psychoses. Brain Behav Immun. 2015 Mar;45:28-35. doi: 10.1016/j.bbi.2014.12.005. Epub 2014 Dec 24.
• Background Miller BJ, Dias JK, Lemos HP, Buckley PF. An open-label, pilot trial of adjunctive tocilizumab in schizophrenia. J Clin Psychiatry. 2016 Feb;77(2):275-6. doi: 10.4088/JCP.15l09920. No abstract available.

Drugs

Indications