Clinical trial NCT02796859: Siltuximab in Schizophrenia
Official title: A Randomized Controlled Trial of Adjunctive Siltuximab in Schizophrenia
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Schizophrenia
Psychotic Disorders
Keywords: Inflammation
Psychosis
Schizophrenia
Lead sponsor: Augusta University
Sponsor class: OTHER
Collaborators: name: Stanley Medical Research Institute
First posted: 2016-06-13
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: A pathophysiological role for inflammation in schizophrenia has been one of the more enduring findings in the field. Recently, increased understanding of complex interactions between inflammation and the brain in other chronic diseases has better informed this relationship in schizophrenia. Several trials have found that treatment with non-steroidal anti-inflammatory drugs (NSAIDs), in adjunct to antipsychotics, was associated with significant improvement in psychopathology in schizophrenia. Cytokines are key regulators of inflammation that exert effects in the periphery and the brain. Serum cytokine levels predicted response in two studies , and another study found a trend for improved cognition with adjunctive NSAID treatment. These findings provide important empirical support for a pathophysiological role for inflammation in some patients with schizophrenia. Two important limitations of these trials are that: a) the agents investigated have relevant off-target (i.e., non-immune) effects, and b) evidence of inflammation in the peripheral blood was not an inclusion criterion, which may have decreased the signal-to-noise ratio.

Schizophrenia is associated with impaired cognition, which persists despite current treatments, and is an important determinant of quality of life and overall function. Converging lines of evidence suggest that interleukin-6 (IL-6) is a promising therapeutic target for cognitive impairment in schizophrenia. IL-6 is a cytokine produced by peripheral blood leukocytes, and central nervous system (CNS) microglia and astrocytes. The IL-6 gene is a risk factor for schizophrenia and may impact on serum IL-6 levels. Blood and cerebrospinal fluid (CSF) IL-6 levels are altered in schizophrenia. IL-6 levels are associated with psychopathology and cognition in schizophrenia. Serum IL-6 levels are also increased in prodromal psychosis, drug-naïve first-episode psychosis (FEP) and first-degree relatives of patients with schizophrenia. In populations outside of schizophrenia, higher serum IL-6 levels are associated with poorer cognition, cognitive decline, and smaller hippocampal volume. In FEP and chronic schizophrenia, IL-6 levels are a significant predictor of smaller left hippocampal volume.

Evidence from animal studies also supports a putative role for IL-6 in the pathophysiology of schizophrenia. A single maternal injection of IL-6 during mouse pregnancy caused prepulse and latent inhibition deficits in the adult offspring. In rat prenatal immune activation models, adult offspring have increased serum IL-6 levels, at an age with homology to the usual age of onset of schizophrenia, that are modulated by antipsychotics. Ketamine-induced neuronal production of IL-6 is responsible for the activation of brain N=nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase and dysfunction of fast-spiking parvalbumin-expressing interneurons.

Along with our other previous work, our preliminary studies provide strong evidence that IL-6 is a novel therapeutic target for cognitive impairment in schizophrenia, and demonstrate the feasibility of the proposed trial. Briefly, in 64 patients with schizophrenia, the investigators found higher blood IL-6 levels were a significant predictor of greater impairment on the Brief Assessment of Cognition in Schizophrenia (BACS) after controlling for multiple potential confounding factors. In an 8-week open-label trial in 6 subjects, tocilizumab (an anti-IL-6 receptor monoclonal antibody), given in adjunct to antipsychotics, was well tolerated and associated with significant improvement in BACS verbal fluency at 4 weeks, BACS digit symbol coding at 2, 4, and 8 weeks, and BACS composite score at 4 and 8 weeks.

In the first year following the submission, one clinical trial is planned. The investigators will conduct a 9-week randomized, double-blind, placebo-controlled trial to determine the safety, tolerability, and efficacy of siltuximab as an adjunct to antipsychotic medications in 30 stable outpatients with schizophrenia.

Siltuximab has not been used before in the treatment of schizophrenia, and using it this way is experimental. The risks that have been found in people with multicentric Castleman's disease are known, but there may be unknown risks when used in schizophrenia. Clinically significant adverse drug reactions include anaphylaxis, renal failure, and pneumonia. Known side effects of siltuximab that are common include: swelling of the extremities, fatigue, itching, rash, weight gain, diarrhea, abdominal pain, and joint or limb pain. The most common side effect of the drug is nasopharyngitis, which occurs in 63% of subjects with long-term exposure to Siltuximab.

Subjects with schizophrenia and schizoaffective disorder will be accessed from outpatient psychiatry clinic at Augusta University or other satellite collaborative sites. The study has 5 visits: screening, baseline, and weeks 3, 6, and 9. Subjects will be randomized equally to either siltuximab (n=15) or placebo (n=15), in adjunct to their current antipsychotic and other psychotropic medications. The study has 5 visits: screening, baseline, and weeks 3, 6, and 9. Subjects will be randomized equally to either siltuximab (n=15) or placebo (n=15), in adjunct to their current antipsychotic and other psychotropic medications. 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. 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. Subjects will be monitored for an additional 30 minutes following the completion of the infusion. Dr. Miller will monitor the subject throughout the infusion and the 30 minute post-infusion period. The investigators will contact the subjects by phone on days 1 and 7 after each infusion to assess for any infusion-related events. The investigators will assess cognition and psychopathology at baseline, and at weeks 3, 6, and 9. The investigators will also measure a multiplex panel of blood cytokines (including IL-6) and tryptophan catabolites at baseline, and at weeks 3, 6, and 9. At Screening, all subjects will be administered the evaluation to sign consent, informed consent, and the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders (DSM) psychosis and affective disorders modules. The investigators will perform a medical history and physical exam, fasting labs (complete blood count \[CBC\], complete metabolic profile \[CMP\], hsCRP, lipid panel, urinalysis, and urine drug screen (UDS), hepatitis panel, HIV, rapid plasma reagin \[RPR\], and human chorionic gonadotropin \[hCG\] in females), a tuberculin skin test, and a 12-lead electrocardiogram. At Baseline, the investigators will perform the Positive And Negative Syndrome Scale (PANSS), BACS, and Clinical Global Impressions scale (CGI), Calgary Depression Scale (CDS) and Short Form Health Survey (SF-36) and draw blood for IL-6 and high-sensitivity c-reactive protein (hsCRP). At Week 3, 6, and 9, the investigators will perform an interval history, physical exam, PANSS, BACS, CGI, CDS, SF-36, and obtain fasting labs (CBC, CMP, lipid panel, hsCRP, urinalysis, UDS, and hCG in females). Different versions of the BACS will be used to avoid practice effects. Patients will be withdrawn if they meet any exclusion criterion at any time point.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in Cognition
timeFrame: Baseline and 9 weeks
Secondary outcomes:
measure: Change in Total Psychotic Symptoms
timeFrame: Baseline and 9 weeks
Other outcomes:
Locations:
city: Augusta
country: United States
facility: Augusta University
state: Georgia
Study officials:
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