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Tocilizumab in Schizophrenia

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ClinicalTrials.gov Identifier: NCT02874573
Recruitment Status : Recruiting
First Posted : August 22, 2016
Last Update Posted : July 9, 2018
Sponsor:
Collaborator:
Brain & Behavior Research Foundation
Information provided by (Responsible Party):
Brian Miller, Augusta University

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.


Condition or disease Intervention/treatment Phase
Schizophrenia Psychotic Disorders Drug: Tocilizumab Drug: Normal saline Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Adjunctive Tocilizumab in Schizophrenia
Study Start Date : September 2016
Estimated Primary Completion Date : June 2019
Estimated Study Completion Date : September 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Tocilizumab

Arm Intervention/treatment
Active Comparator: Treatment Group
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
Investigational agent
Other Name: Actemra

Placebo Comparator: Control Group
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
Placebo
Other Name: 0.9% NS




Primary Outcome Measures :
  1. Change in Cognition [ Time Frame: Baseline and 12 weeks ]
    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.


Secondary Outcome Measures :
  1. Change in Total Psychotic Symptoms [ Time Frame: Baseline and 12 weeks ]
    The Positive and Negative Symptoms Scale (PANSS) is the metric used to characterize psychotic symptoms in this study. The PANSS consists of 30 items, each scored 1-7. The range for the PANSS total score is 30-210. There are 3 subscales - PANSS positive score (range 7-49), PANSS negative score (range 7-49), and PANSS general score (range 16-112). PANSS total score is the summation of these 3 subscales. Higher values for the total and subscale scores reflect more severe psychopathology. A positive change in PANSS total score reflects an increase in psychopathology. A negative change in PANSS total score reflects a decrease in psychopathology.



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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02874573


Contacts
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Contact: Brian J Miller, MD 706-721-4445 brmiller@augusta.edu
Contact: Elizabeth Matznick, BS 706-721-3048 ematznick@augusta.edu

Locations
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United States, Georgia
Augusta University Recruiting
Augusta, Georgia, United States, 30912
Contact: Brian J Miller, MD    706-721-4445    brmiller@augusta.edu   
Contact: Elizabeth Matznick, BS    706-721-3048    ematznick@augusta.edu   
Sponsors and Collaborators
Brian Miller
Brain & Behavior Research Foundation
Investigators
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Principal Investigator: Brian J Miller, MD Augusta University

Publications:
Miller B, Mellor A, Buckley PF. Interleukin-6 and Cognition in Non-Affective Psychosis. Schizophr Bull 2013; 39: S242-S243.
Miller BJ, Timonen M, Isohanni M. Cytokine abnormalities, inflammation and psychosis in the northern finland 1966 birth cohort. European Psychiatry 2014; 29: S519.

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Responsible Party: Brian Miller, Associate Professor, Augusta University
ClinicalTrials.gov Identifier: NCT02874573     History of Changes
Other Study ID Numbers: 944642
First Posted: August 22, 2016    Key Record Dates
Last Update Posted: July 9, 2018
Last Verified: July 2018
Keywords provided by Brian Miller, Augusta University:
Inflammation
Schizophrenia
Additional relevant MeSH terms:
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Schizophrenia
Mental Disorders
Psychotic Disorders
Schizophrenia Spectrum and Other Psychotic Disorders