Tocilizumab in Schizophrenia
| Status: | Recruiting |
|---|---|
| Conditions: | Schizophrenia, Psychiatric, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 55 |
| Updated: | 7/11/2018 |
| Start Date: | September 2016 |
| End Date: | September 2019 |
| Contact: | Brian J Miller, MD |
| Email: | brmiller@augusta.edu |
| Phone: | 706-721-4445 |
A Randomized Controlled Trial of Adjunctive Tocilizumab in Schizophrenia
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.
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.
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.1 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
psychopathology3 and cognition in schizophrenia. In populations outside of schizophrenia,
higher serum IL-6 levels are associated with poorer cognition. In first-episode and chronic
schizophrenia, IL-6 levels are a significant predictor of smaller left hippocampal volume.
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, we 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.5 In an 8-week open-label trial in 6 subjects, tocilizumab (a humanized
monoclonal antibody against the IL-6 receptor, approved by the US FDA in 2010 for the
treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had
an inadequate response to one or more tumor necrosis factor (TNF)-antagonist therapies,
administered as an intravenous infusion every 4 weeks), 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.10
In the first year following the submission, one clinical trial is planned. The investigators
will conduct a 12-week randomized, double-blind, placebo-controlled trial to determine the
safety, tolerability, and efficacy of tocilizumab as an adjunct to antipsychotic medications
in 20 stable outpatients with schizophrenia.
In our previous trial of Tocilizumab, no clinically significant adverse drug reactions
occurred. 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.
Subjects with schizophrenia and schizoaffective disorder will be accessed from outpatient
psychiatry clinic at Augusta University or other satellite collaborative sites. The study has
6 visits: screening, baseline, and weeks 2, 4, 8, and 12. Subjects will be randomized equally
to either tocilizumab (n=10) or placebo (n=10), in adjunct to their current antipsychotic and
other psychotropic medications. Tocilizumab will be obtained from the manufacturer,
Genentech, through our hospital pharmacy as per our previous trial. 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. 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. We will contact the subjects by phone on days 1 and 7
after each infusion to assess for any infusion-related events. We will assess cognition and
psychopathology at baseline, and at weeks 2, 4, 8, and 12. We will also measure a multiplex
panel of blood cytokines (including IL-6) at baseline, and at weeks 2m 4, 8, and 12. Patients
will be withdrawn if they meet any exclusion criterion at any time point.
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.1 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
psychopathology3 and cognition in schizophrenia. In populations outside of schizophrenia,
higher serum IL-6 levels are associated with poorer cognition. In first-episode and chronic
schizophrenia, IL-6 levels are a significant predictor of smaller left hippocampal volume.
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, we 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.5 In an 8-week open-label trial in 6 subjects, tocilizumab (a humanized
monoclonal antibody against the IL-6 receptor, approved by the US FDA in 2010 for the
treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had
an inadequate response to one or more tumor necrosis factor (TNF)-antagonist therapies,
administered as an intravenous infusion every 4 weeks), 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.10
In the first year following the submission, one clinical trial is planned. The investigators
will conduct a 12-week randomized, double-blind, placebo-controlled trial to determine the
safety, tolerability, and efficacy of tocilizumab as an adjunct to antipsychotic medications
in 20 stable outpatients with schizophrenia.
In our previous trial of Tocilizumab, no clinically significant adverse drug reactions
occurred. 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.
Subjects with schizophrenia and schizoaffective disorder will be accessed from outpatient
psychiatry clinic at Augusta University or other satellite collaborative sites. The study has
6 visits: screening, baseline, and weeks 2, 4, 8, and 12. Subjects will be randomized equally
to either tocilizumab (n=10) or placebo (n=10), in adjunct to their current antipsychotic and
other psychotropic medications. Tocilizumab will be obtained from the manufacturer,
Genentech, through our hospital pharmacy as per our previous trial. 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. 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. We will contact the subjects by phone on days 1 and 7
after each infusion to assess for any infusion-related events. We will assess cognition and
psychopathology at baseline, and at weeks 2, 4, 8, and 12. We will also measure a multiplex
panel of blood cytokines (including IL-6) at baseline, and at weeks 2m 4, 8, and 12. Patients
will be withdrawn if they meet any exclusion criterion at any time point.
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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