An Open-Label Trial of Tocilizumab in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 1

Summary: 
      This study is a Phase 1 clinical trail 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
      (Ig) gamma-1 subclass. Tocilizumab is formulated as a concentrate for solution for infusion,
      and will be administered by intravenous infusion.

      The investigators propose an 8-week trial to determine the safety, tolerability, and
      effectiveness of tocilizumab, given in addition to antipsychotic medications, in 10 stable
      outpatients with schizophrenia. The investigators hypothesize that tocilizumab will be
      associated with clinically significant improvement in cognition and total psychotic symptoms
      over the course of the trial. Tocilizumab is administered as an intravenous infusion every 4
      weeks. Following a screening evaluation, participants will receive two infusions of
      tocilizumab, one at baseline and another at week 4 of the study. The investigators will
      measure changes in cognitive function and symptoms over an 8-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.

      Data presented in 2008 showed the effectiveness of tocilizumab in combination therapy with
      methotrexate for rheumatoid arthritis treatment. In further studies, it was effective and
      generally well tolerated when administered either as monotherapy or in combination with
      conventional disease-modifying antirheumatic drugs in adult patients with moderate to severe
      rheumatoid arthritis.
    

Detailed description: 
      Schizophrenia is a chronic, debilitating disorder with life-long consequences on affected
      individuals and families. Schizophrenia is also associated with impaired cognition or
      thinking, which persists despite currently available treatments, and is an important
      determinant of quality of life and overall function. Associations between immune system
      abnormalities and schizophrenia, in particular increased inflammation, are one of the more
      enduring findings in the field. Four of six trials found that treatment with non-steroidal
      anti-inflammatory drugs (NSAIDs) was associated with significant improvement in
      psychopathology (Muller et al., 2010a; Muller et al., 2010b). Serum cytokine levels predicted
      response in two studies (Laan et al., 2010; Muller et al., 2004), and another study found a
      trend for improved cognition (Muller et al., 2005) with adjunctive NSAID treatment. These
      findings provide important empirical support for a pathophysiological role for inflammation
      in a subset of patients with schizophrenia.

      Cytokines are key regulators of inflammation that exert effects in the periphery and the
      brain. IL-6 is a cytokine produced by peripheral blood leukocytes, and central nervous system
      microglia and astrocytes. Serum IL-6 levels are increased in patients with schizophrenia, and
      two studies reported significant positive correlations between IL-6 and total psychopathology
      at baseline and following antipsychotic treatment (Miller et al., 2011). Schizophrenia is
      associated with impaired cognition, which persists despite current treatments, and is an
      important determinant of quality of life and overall function. In populations outside of
      schizophrenia, higher serum IL-6 levels are associated with poorer cognition, cognitive
      decline, and smaller hippocampal gray matter volume (Marsland et al., 2006; Marsland et al.,
      2008). In a first-episode psychosis sample, IL-6 messenger ribonucleic acid expression was a
      significant predictor of smaller left hippocampal volume (Mondelli et al., 2011).

      Several other lines of evidence provide a theoretical background for targeting IL-6 in
      schizophrenia. Polymorphisms of the gene for IL-6 (Paul-Samojedny et al., 2010) and its
      receptor (Sun et al., 2008) have been associated with schizophrenia. In mice, a single
      maternal injection of IL-6 during pregnancy caused prepulse and latent inhibition deficits in
      the adult offspring (Smith et al., 2007). Prenatal maternal infections are a replicated risk
      factor for schizophrenia (Brown and Derkits, 2010). In a rat prenatal immune activation
      model, adult offspring have increased serum IL-6 levels, at an age with homology to the usual
      age of onset of schizophrenia, that are significantly decreased following treatment with
      haloperidol (Romero et al., 2007; Romero et al., 2010). Another animal study found that
      ketamine-induced neuronal production of IL-6 is responsible for the activation of brain
      NADPH-oxidase and subsequent dysfunction of fast-spiking parvalbumin-expressing interneurons
      (Behrens et al., 2008). These findings provide further support for a potential role of IL-6
      in the pathophysiology of schizophrenia.

      In our Preliminary Study, patients with schizophrenia, age 18-70 and taking non-clozapine
      antipsychotics, had a fasting blood draw for serum cytokines, and assessment of
      psychopathology, including cognition. Subjects were not taking NSAIDs, and had no history of
      immune disorders, illicit drug use in the past month, or antibiotic use in the past 2 weeks.
      In 39 patients, after controlling for potential confounding effects of age, sex, race,
      smoking, BMI, socioeconomic status, serum cortisol, psychotropic medications, intelligence
      quotient, and severity of psychopathology, higher serum IL-6 levels predicted greater
      cognitive impairment, measured by the Brief Assessment of Cognition in Schizophrenia (BACS)
      composite score, in a linear regression model (p=0.002, Figure 1). Higher IL-6 levels were
      also associated with significantly lower scores on the Verbal Memory (r=-0.40, p<0.01) and
      Motor Speed (r=-0.42, p<0.01) subtests of the BACS.

      In the first year, one clinical trial is planned. We will conduct an 8-week open-label trial
      to determine the safety, tolerability, and efficacy of tocilizumab as an adjunct to
      antipsychotic medications in 10 stable outpatients with schizophrenia.

      Tocilizumab 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 rheumatoid arthritis are
      known, but there may be unknown risks when used in schizophrenia. Clinically significant
      adverse drug reactions include anaphylaxis (0.4%), infections (0.1-7.8%), intestinal
      perforation, neutropenia (7.0%), and cardiac failure. Known side effects of tocilizumab that
      are common include: increase in hepatic enzymes (AST, ALT), hypertension, headache,
      neutropenia, infusion-related reactions, upper respiratory tract infections, and
      nasopharyngitis.

      Less common side effects include: peripheral edema, dizziness, rash, increased total
      cholesterol and LDL, hypothyroidism, diarrhea, abdominal pain, mouth ulcerations, gastric
      ulcer, stomatitis, weight gain, gastritis, thrombocytopenia, leukopenia, increased bilirubin,
      conjunctivitis, nephrolithiasis, bronchitis, cough, dyspnea, herpes simplex. Rare side
      effects include: cellulitis, fungal infections, diverticulitis, gastroenteritis, herpes
      zoster, hypertriglyceridemia, malignancy (including breast and colon), multiple sclerosis,
      otitis media, pneumonia, sepsis, tuberculosis, urinary tract infections, and varicella.

      Subjects with schizophrenia will be accessed from outpatient psychiatry clinic at Georgia
      Health Sciences University or other satellite collaborative sites. The study has 5 visits:
      screening, baseline, and 2, 4, and 8 weeks. At Screening, all subjects will be administered
      the evaluation to sign consent, informed consent, and the structured clinical interview for
      Diagnostic and Statistical Manual psychosis and affective disorders modules. We will perform
      a medical history and physical exam, fasting labs (CBC, Complete Metabolic Panel, lipid
      panel, urinalysis, and urine drug screen (UDS)), a tuberculin skin test, and a 12-lead
      electrocardiogram. At Baseline, we will perform the Positive and Negative Syndrome Scale,
      BACS, and Clinical Global Impressions scale (CGI), and draw blood for IL-6 and
      high-sensitivity c-reactive protein (hsCRP). All subjects will receive a 4 mg/kg infusion of
      tocilizumab, the recommended starting dose for adults with rheumatoid arthritis. We will
      contact the subjects by phone on day 1 and 7 after the infusion to assess for any
      infusion-related events. At Week 2 and 4, we will perform an interval history, physical exam,
      Positive and Negative Syndrome Scale, BACS, and CGI. Different versions of the BACS will be
      used to avoid practice effects. At Week 4, we will obtain fasting labs (CBC, Complete
      Metabolic Panel, lipid panel, IL-6, hsCRP, and UDS), and subjects will receive a 4 mg/kg
      infusion of tocilizumab, We will contact the subjects by phone day 1 and 7 after the second
      infusion to assess for any infusion-related events. At Week 8, we will perform an interval
      history, physical exam, and administer the Positive and Negative Syndrome Scale, BACS, CGI,
      and obtain fasting labs (CBC, Complete Metabolic Panel, lipid panel, IL-6, hsCRP, and UDS).
      Patients will be withdrawn if they meet any exclusion criterion at any time point.
    

Intervention name(s): Tocilizumab
Intervention type(s): Drug
Intervention description(s): Therapeutic/Pharmacologic Class of Drug:
Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) gamma-1 subclass.
Type of Dosage Form:
Concentrate for solution for infusion.
Route of Administration:
Intravenous (i.v.) infusion.
Other intervention name(s): Brand Name: Actemra; NDA/Serial Number: STN 125276/S022 (Cross ref: IND 11972)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: tocilizumab; safety; tolerability; efficacy; schizophrenia; improvement; cognition; psychotic symptoms; baseline IL-6 levels