Tocilizumab in Schizophrenia

NCT02874573 | Unknown Phase 1 DMC

• 1 other identifier: 944642
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This study is a Phase 1 clinical trial 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 G1 (IgG1) subclass. Tocilizumab is formulated as a concentrate for solution for infusion, and will be administered by intravenous infusion. The investigators propose a 12-week randomized controlled trial of tocilizumab, given in adjunct to antipsychotics, in N=20 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 tocilizumab will be associated with significant improvement in cognition compared to placebo in patients with schizophrenia, and baseline IL-6 levels are higher in tocilizumab-treated responders versus non-responders, and there will be greater decreases in hsCRP from baseline to week 12 in tocilizumab-versus placebo-treated responders, with response defined as ≥0.5 standard deviation (SD) improvement in cognition. Tocilizumab is administered as an intravenous infusion every 4 weeks. Following a screening evaluation, participants will receive three infusions of siltuximab, one at baseline, another at week 4 of the study, and another at week 8. The investigators will measure changes in cognitive function and symptoms over a 12-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. On 11 January 2010, Tocilizumab was approved by the U.S. Food and Drug Administration (US FDA) as Actemra for the treatment of rheumatoid arthritis. The FDA approved tocilizumab for the treatment of systemic juvenile idiopathic arthritis for children from two years of age in April 2011.

Conditions

Schizophrenia; Psychotic Disorders

Keywords

Inflammation; Schizophrenia

Outcome Measures

Primary Outcomes (1)

• Change in Cognition

  The Brief Assessment of Cognition in Schizophrenia (BACS) is the metric used to characterize cognition in this study. The BACS consists of 6 subscales: Verbal Memory (range 0-75), Working Memory (range 0-28), Motor Speed (range 0-100), Verbal Fluency (measure is total number of words generated in two 60 second trials), Attention and Processing speed (range 0-110), and Executive Function (range 0-22). For each subscale, higher scores reflect better cognition. For each subscale, a Standard Deviation Score was calculated based on normative data (Keefe et al. Norms and standardization of the Brief Assessment of Cognition in Schizophrenia (BACS). Schizophrenia Research 102 (2008) 108-115). The BACS composite score is calculated as the average Standard Deviation Score of the 6 subscale scores. The change in BACS composite score will be calculated as the BACS composite score at 9 weeks minus the BACS composite score at baseline.

  Baseline and 12 weeks

Secondary Outcomes (1)

• Change in Total Psychotic Symptoms

  Baseline and 12 weeks

Study Arms (2)

Treatment Group

ACTIVE COMPARATOR

Subjects in the tocilizumab group will receive a 4 mg/kg infusion at baseline, and weeks 4 and 8, as per the recommended starting dosing for rheumatoid arthritis

Drug: Tocilizumab

Control Group

PLACEBO COMPARATOR

Subjects in the placebo group will receive an infusion of normal saline (with the same packaging and volume as the tocilizumab group) at baseline, and weeks 4 and 8.

Drug: Normal saline

Interventions

Tocilizumab DRUG

Investigational agent

Also known as: Actemra

Treatment Group

Normal saline DRUG

Placebo

Also known as: 0.9% NS

Control Group

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• male and female
• age 18-55
• capable of giving informed consent
• Diagnostic and Statistical Manual of Mental Disorders (DSM)-V diagnosis of schizophrenia or schizoaffective disorder
• stable based on clinical judgment, no psychiatric hospitalizations in past 3 months, and on the same psychotropic medications for \>4 weeks
• taking a non-clozapine antipsychotic
• hsCRP \>0.3 mg/dL at the screening visit

You may not qualify if:

• 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
• breast feeding
• female and of child-bearing potential who is not using any contraception

Sponsors & Collaborators

• Brian Miller: lead
• Brain & Behavior Research Foundation: collaborator

Study Sites (1)

Augusta University

Augusta, Georgia, 30912, United States

RECRUITING

Related Publications (10)

• 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.

  PMID: 23720576 BACKGROUND

• Sasayama D, Wakabayashi C, Hori H, Teraishi T, Hattori K, Ota M, Ishikawa M, Arima K, Higuchi T, Amano N, Kunugi H. Association of plasma IL-6 and soluble IL-6 receptor levels with the Asp358Ala polymorphism of the IL-6 receptor gene in schizophrenic patients. J Psychiatr Res. 2011 Nov;45(11):1439-44. doi: 10.1016/j.jpsychires.2011.06.003. Epub 2011 Jun 22.

  PMID: 21700295 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.

  PMID: 21641581 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.

  PMID: 23290488 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.

  PMID: 25214388 BACKGROUND

• Miller B, Mellor A, Buckley PF. Interleukin-6 and Cognition in Non-Affective Psychosis. Schizophr Bull 2013; 39: S242-S243.

  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.

  PMID: 17132839 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.

  PMID: 24787542 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

• 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.

  PMID: 26930525 BACKGROUND

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders; Inflammation

Interventions

tocilizumab; Saline Solution

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Brian J Miller, MD

  Augusta University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Brian J Miller, MD

CONTACT

706-721-4445; brmiller@augusta.edu

Rebecca Nichols, MBA

CONTACT

706-721-4605; rnichols@augusta.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: August 17, 2016
• First Posted: August 22, 2016
• Study Start: September 1, 2016
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2023
• Last Updated: July 21, 2023

Record last verified: 2023-07

Locations

US (1)