A Randomized Controlled Trial of Adjunctive Tocilizumab in Schizophrenia

944642

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.

2016-09-01

2023-12-31

2023-12-31

Recruiting

Early phase I

20

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

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2023-07-21