An Open-Label Trial of Tocilizumab in Schizophrenia - Full Text View

Purpose

This study is a Phase 1 clinical trail to determine the safety, tolerability, and efficacy of Tocilizumab (Actemra) as an adjunct to antipsychotic medications in stable outpatients with schizophrenia. Tocilizumab (structural formula C6428H9976N1720O2018S42) is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. Tocilizumab is formulated as a concentrate for solution for infusion, and will be administered by intravenous infusion.

The investigators propose an 8-week trial to determine the safety, tolerability, and effectiveness of tocilizumab, given in addition to antipsychotic medications, in 10 stable outpatients with schizophrenia. The investigators hypothesize that tocilizumab will be associated with clinically significant improvement in cognition and total psychotic symptoms over the course of the trial. Tocilizumab is administered as an intravenous infusion every 4 weeks. Following a screening evaluation, participants will receive two infusions of tocilizumab, one at baseline and another at week 4 of the study. The investigators will measure changes in cognitive function and symptoms over an 8-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. In 1997, Chugai Pharmaceuticals began the clinical development of tocilizumab for the treatment of rheumatoid arthritis. Clinical studies for Castleman's disease and systemic juvenile idiopathic arthritis started in 2001 and 2002, respectively. Hoffmann-La Roche co-developed the drug due to a license agreement in 2003.

Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with methotrexate for RA treatment. In further studies, it was effective and generally well tolerated when administered either as monotherapy or in combination with conventional DMARDs in adult patients with moderate to severe rheumatoid arthritis.

Condition	Intervention	Phase
Schizophrenia	Drug: Tocilizumab	Phase 1


Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open-Label Trial of Tocilizumab in Schizophrenia

Resource links provided by NLM:

MedlinePlus related topics: Mental Disorders Psychotic Disorders Schizophrenia

Drug Information available for: Tocilizumab

U.S. FDA Resources

Further study details as provided by Georgia Regents University:

Primary Outcome Measures:

Improvement in Cognition [ Time Frame: Change from baseline in Cognition at 8 weeks ] [ Designated as safety issue: No ]
The Brief Assessment of Cognition in Schizophrenia (BACS)is the metric used to characterize cognition in this study.

Secondary Outcome Measures:

Improvement in Total Psychotic Symptoms [ Time Frame: Change from baseline in Total Psychotic Symptoms at 8 weeks ] [ Designated as safety issue: No ]
The Clinical Global Impression (CGI) and Positive and Negative Symptoms Scale (PANSS)are the metrics used to characterize psychotic symptoms in this study.


Estimated Enrollment:	10
Study Start Date:	September 2012
Estimated Study Completion Date:	August 2015
Estimated Primary Completion Date:	August 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Tocilizumab Following a screening evaluation, participants will receive two infusions of tocilizumab, one at baseline and another at week 4 of the study. All subjects will receive a 4 mg/kg infusion of tocilizumab, the recommended starting dose for adults with RA.	Drug: Tocilizumab Therapeutic/Pharmacologic Class of Drug: Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. Type of Dosage Form: Concentrate for solution for infusion. Route of Administration: Intravenous (i.v.) infusion. Other Names: Brand Name: Actemra NDA/Serial Number: STN 125276/S022 (Cross ref: IND 11972)

Arms

Assigned Interventions

Experimental: Tocilizumab

Following a screening evaluation, participants will receive two infusions of tocilizumab, one at baseline and another at week 4 of the study. All subjects will receive a 4 mg/kg infusion of tocilizumab, the recommended starting dose for adults with RA.

Drug: Tocilizumab

Therapeutic/Pharmacologic Class of Drug:

Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass.

Type of Dosage Form:

Concentrate for solution for infusion.

Route of Administration:

Intravenous (i.v.) infusion.

Other Names:

Brand Name: Actemra
NDA/Serial Number: STN 125276/S022 (Cross ref: IND 11972)

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years to 50 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

male and female
age 18-50
capable of giving informed consent
diagnosis of schizophrenia
stable based on clinical judgement, no psychiatric hospitalizations in past 3 months, and on the same psychotropic medications for >4 weeks
taking a non-clozapine antipsychotic

Exclusion Criteria:

imminent danger to self/others
antibiotic use in the past 2 weeks
current scheduled use of immunomodulatory agents
history of an immune disorder
illicit drug use in the past 30 days
any unstable or untreated medical condition
history of gastrointestinal ulcers, diverticulitis, malignancy, CNS demyelinating disorder, seizure disorder, or tuberculosis
low absolute neutrophil (<2000) or platelet (<100,000) count
abnormal hepatic (AST or ALT >1.5 times the upper limit of normal) or renal (BUN or creatinine>1.5 times the upper limit of normal) function
any abnormal lab test result judged to be clinically significant
active, chronic or recurrent infections
pregnancy
breastfeeding
female and of child-bearing potential who is not using any contraception

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01696929

Contacts


Contact: Brian Miller, MD, PhD, MPH	706-721-4445	brmiller@georgiahealth.edu

Locations


United States, Georgia
Georgia Health Sciences University	Recruiting
Augusta, Georgia, United States, 30912
Contact: Brian Miller, MD, PhD, MPH 706-721-4445 brmiller@georgiahealth.edu
Contact 706-721-3048
Principal Investigator: Brian Miller, MD, PhD, MPH
Sub-Investigator: Peter F Buckley, MD

Sponsors and Collaborators

Brian Miller

Investigators


Principal Investigator:	Brian Miller, MD, PhD, MPH	Georgia Health Sciences University Department of Psychiatry and Health Behavior

More Information

Publications:

Müller N. COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Curr Opin Investig Drugs. 2010 Jan;11(1):31-42. Review.

Müller N, Krause D, Dehning S, Musil R, Schennach-Wolff R, Obermeier M, Möller 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.

Müller N, Ulmschneider M, Scheppach C, Schwarz MJ, Ackenheil M, Möller 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.

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.

Müller 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. Epub 2004 Nov 19.

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.

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.

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.

Mondelli V, Cattaneo A, Belvederi Murri M, 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):1677-84. doi: 10.4088/JCP.10m06745. Epub 2011 May 18.

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.

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.

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.

Brown AS, Derkits EJ. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry. 2010 Mar;167(3):261-80. doi: 10.1176/appi.ajp.2009.09030361. Epub 2010 Feb 1. Review.

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. Epub 2006 Dec 20.

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.

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.


Responsible Party:	Brian Miller, Assistant Professor, Georgia Regents University
ClinicalTrials.gov Identifier:	NCT01696929 History of Changes
Other Study ID Numbers:	Pro00000405
Study First Received:	September 24, 2012
Last Updated:	November 4, 2014
Health Authority:	United States: Institutional Review Board

Keywords provided by Georgia Regents University:


tocilizumab safety tolerability efficacy schizophrenia	improvement cognition psychotic symptoms baseline IL-6 levels

Additional relevant MeSH terms:


Schizophrenia Mental Disorders Schizophrenia and Disorders with Psychotic Features

ClinicalTrials.gov processed this record on February 26, 2015