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Siltuximab in Schizophrenia

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ClinicalTrials.gov Identifier: NCT02796859
Recruitment Status : Recruiting
First Posted : June 13, 2016
Last Update Posted : July 29, 2021
Stanley Medical Research Institute
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 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.

Condition or disease Intervention/treatment Phase
Schizophrenia Psychotic Disorders Drug: Siltuximab Drug: normal saline Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized Controlled Trial of Adjunctive Siltuximab in Schizophrenia
Study Start Date : May 2016
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Siltuximab

Arm Intervention/treatment
Active Comparator: Treatment Group
Subjects in the siltuximab group will receive an 11 mg/kg infusion at baseline, and weeks 3 and 6, as per the recommended dosing for multicentric Castleman's disease
Drug: Siltuximab
Investigational agent
Other Name: Sylvant

Placebo Comparator: Control Group
Subjects in the placebo group will receive an infusion of normal saline (with the same packaging and volume as the siltuximab group) at baseline, and weeks 3 and 6.
Drug: normal saline
Other Name: 0.9% NS

Primary Outcome Measures :
  1. Change in Cognition [ Time Frame: Baseline and 9 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 9 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

Inclusion Criteria:

  • capable of giving informed consent
  • diagnosis of schizophrenia or schizoaffective disorder
  • stable based on clinical judgment
  • taking a non-clozapine antipsychotic
  • on the same psychotropic medications for >4 weeks
  • 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 exposure to tuberculosis
  • low absolute neutrophil (<2000) or platelet (<100,000) count
  • abnormal hepatic function (AST or ALT >1.5 times the upper limit of normal) or renal function (BUN or creatinine >1.5 times the upper limit of normal)
  • any abnormal lab test result judged to be clinically significant
  • active or chronic infections
  • pregnancy, breast feeding, or female 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): NCT02796859

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Contact: Brian J Miller, MD 706-721-4445 brmiller@augusta.edu
Contact: Rebecca Nichols, MBA 706-721-4605 rnichols@augusta.edu

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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: Rebecca Nichols, MBA    706-721-4605    RNichols@augusta.edu   
Principal Investigator: Brian J Miller, MD         
Sponsors and Collaborators
Brian Miller
Stanley Medical Research Institute
Miller B, Mellor A, Buckley PF. Interleukin-6 and Cognition in Non-Affective Psychosis. Schizophrenia Bulletin 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: NCT02796859    
Other Study ID Numbers: 15T-005
First Posted: June 13, 2016    Key Record Dates
Last Update Posted: July 29, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by Brian Miller, Augusta University:
Additional relevant MeSH terms:
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Mental Disorders
Psychotic Disorders
Schizophrenia Spectrum and Other Psychotic Disorders
Antineoplastic Agents