Schizoaffective Disorder, Schizophrenia
Conditions
Brief summary
Randomized, double-blind clinical trial of tocilizumab vs. placebo as add-on treatment for residual positive, negative, and cognitive symptoms in schizophrenia. The primary study hypothesis is that individuals receiving tocilizumab will show greater improvements in their PANSS total scores than those taking placebo.
Detailed description
One of the main mediators of the effects of infection/inflammation in the human body is cytokines. Recent data suggest that cytokines, and in particular IL-6, may mediate the effects of lifetime or prenatal infection on schizophrenia risk. Preclinical models of schizophrenia support a convergence between a role for IL-6 in the pathophysiology of schizophrenia and the major neurochemical hypotheses of schizophrenia-the dopamine and glutamate hypotheses. Namely, IL-6 dysfunction or excess promotes schizophrenia-like behaviors and schizophrenia-like biochemical and electrophysiological profiles, while IL-6 knockout or neutralization mitigates these abnormalities. Furthermore, plasma IL-6 levels are elevated in acutely psychotic but not treated patients, and Positron Emission Tomography (PET) studies have shown active inflammation in the brains of individuals with psychosis. Finally, treatment of individuals with schizophrenia with non-specific anti-inflammatory agents, such as celecoxib and aspirin, has suggested a role for anti-inflammatory agents in schizophrenia. These data also suggest that studies of immunologic agents that more specifically target the underlying pathophysiology of schizophrenia may be more efficacious. Tocilizumab (Actemra®) is an FDA-approved humanized monoclonal antibody against the IL-6 receptor used for treatment of rheumatoid arthritis in individuals who have not responded to at least one TNF-alpha therapy and for juvenile idiopathic arthritis
Interventions
DRUGTocilizumab
8mg/kg intravenously via iv drip over 60 min
DRUGPlacebo
intravenously via iv drip over 60 min
Sponsors
Stanley Medical Research Institute
New York State Psychiatric Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
* Fulfill DSM-IV criteria for schizophrenic illness, schizoaffective disorder * Negative urine toxicology * Capacity to understand the study and give written informed consent * Must be on a stable dose of antipsychotic medications, up to two medications, except for clozapine, for at least 4 weeks if oral or 2 cycles if depot. Mood stabilizers, benzodiazepines and antidepressants are allowed as long as no change for 4 weeks. * Moderate level of symptomatology
Exclusion criteria
* Pregnancy or lactation, lack of effective birth control during the 15 days before the initial day of the study and for the duration of the drug trial * Unstable medical or neurological condition (including chronic rashes other than mild eczema, ANC \< 2000, platelet count \< 120,000, severe liver disease or AST/ALT greater than 1.5 times the ULN at baseline, or any chronic inflammatory or immunologic disorder that impairs the immune system, a current severe infection, intestinal diverticula, or tuberculosis (latent or active-patients with a positive ppd but negative chest x ray may participate) or a live vaccine within one month of receiving study drug * Any current non medicinal use of amphetamines, opiates, cocaine, sedative-hypnotics, cannabis, or other psychoactive drugs (other than nicotine) * Currently taking a medication known to cause neutropenia (clozapine, carbamazepine), or another disease modifying anti-rheumatic drugs (DMARD) * Any history of substance dependence (other than nicotine or cannabis) within the previous 6 months or a history of substance abuse within the previous 1 month (other than nicotine) * Impaired intellectual functioning * Major surgery (including joint surgery) within 8 weeks prior to screening or planned major surgery within 6 months following randomization * Treatment with any investigational agent within 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) * Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-CD19 and anti-CD20 * Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline * Previous treatment with tocilizumab (an exception to this criterion may be granted for single dose exposure upon application to the sponsor on case-by-case basis * Any previous treatment with alkylating agents such as chlorambucil, or with a total lymphoid irradiation * History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies * Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease) * Current liver disease * Known active current or history of recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds). * Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks or oral antibiotics within 2 weeks * Active TB requiring treatment within the previous 3 years. * Primary or secondary immunodeficiency (history of or currently active) * Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured) or breast cancer diagnosed within the previous 20 years * Neuropathies or other conditions that might interfere with pain evaluation unless related to primary disease under investigation * Lack of peripheral venous access * Body weight of \>150 kg * Serum creatinine \> 1/6mg/dL (141 umol/L) in female patients and \> 1.9 mg/dL (168 umol/L) in male patients. Patients with serum creatinine values exceeding limits may be eligible for the study if their estimated glomerular filtration rates (GFR) are \> 30 * Total Bilirubin \>ULN * Hemoglobin \< 85g/L * White Blood Cells \<3.0 x 10\^9/L * Absolute Lymphocyte Count \< 0.5 x 10\^9/L * Positive Hepatitis BsAg or Hepatitis C antibody Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response to Tocilizumab | Baseline (start of tocilizumab) through 12 weeks. We present the change scores | To evaluate an anticipated clinical response to tocilizumab treatment including positive, negative and cognitive symptoms by the change in the Positive and Negative Syndrome Scale (PANSS) total score. Score ranges from 30 to 210 for PANSS total, 16-112 for General, 7-49 for positive and 7-49 for negative symptoms subscales. A lower score means less symptomatic. There is a total score and general psychopathology scores, a positive symptoms score and a negative symptom score. The unit of measure is units on a scale from 1-7, whole numbers only. Summed scores are simply added to each other |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cognitive Symptomatology - Overall MATRICS t Score Change | Baseline (start of tocilizumab) through 12 weeks | MATRICS cognitive consensus battery, overall t score change. The composite T-score at each time point (baseline and week 12) is a T-Score (ranging from 0 to 100) reflecting overall neuropsychological function, aggregated from the participant's T-scores on the MATRICS subscales for Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. The outcome is the difference between overall composite T-score at baseline and week 12, with higher difference score reflecting a greater improvement in neuropsychological performance. |
| Cognitive Symptomatology - UPSA-B Score Change | Baseline (start of tocilizumab) through 12 weeks | At Baseline and Week 12, participants are UPSA-B given items reflecting ability to complete tasks encountered in daily life, across two domains, Financial Skills and Communication Skills. % correct is calculated for each domain and converted to a standardized score from 0-50. These scores are summed to produce a total summary score ranging from 0-100. The outcome is the difference between this summary score at Baseline and Week 12, with a higher difference score reflecting a greater increase in functional capacity. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Relationship Between Baseline IL-6 Levels and Positive, Negative and Cognitive Symptoms and Impairment | Baseline (start of tocilizumab) through 12 weeks | Comparison of cytokines, in particular IL-6 levels and the positive, negative and cognitive symptoms and impairments in daily functioning in schizophrenia. These outcomes will be measured by Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), University of California Performance Skills Assessments (UPSA) and MATRICS. |
Countries
United States
Participant flow
Pre-assignment details
Of the 59 subjects who signed consent, 22 did not receive study drug. In addition, one of the 37 subjects who received study drug did not participate in any follow up assessments so was not included in the ITT analysis
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo-receiving group | 17 |
| Tocilizumab Tocilizumab-receiving group | 19 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | Tocilizumab | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants | 19 Participants | 36 Participants |
| Age, Continuous | 41.67 yrs STANDARD_DEVIATION 10.25 | 43.24 yrs STANDARD_DEVIATION 11.42 | 42.50 yrs STANDARD_DEVIATION 10.76 |
| chlorpromazine equivalents | 377 milligrams STANDARD_DEVIATION 346 | 257 milligrams STANDARD_DEVIATION 192 | 310 milligrams STANDARD_DEVIATION 396 |
| cigs /day | 8 cigarettes per day STANDARD_DEVIATION 3 | 10 cigarettes per day STANDARD_DEVIATION 5 | 9 cigarettes per day STANDARD_DEVIATION 4 |
| Clinical Global Impression - Severity Scale | 4 units on a scale STANDARD_DEVIATION 0.4 | 4 units on a scale STANDARD_DEVIATION 0.3 | 4 units on a scale STANDARD_DEVIATION 0.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 16 Participants | 14 Participants | 30 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| PANSS Total | 73.94 panss score STANDARD_DEVIATION 15.52 | 70.68 panss score STANDARD_DEVIATION 11.2 | 72.22 panss score STANDARD_DEVIATION 14.24 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 12 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 5 Participants | 14 Participants |
| Region of Enrollment United States | 17 Participants | 19 Participants | 36 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 11 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants |
| Smoker | 7 Participants | 8 Participants | 15 Participants |
| weight | 203.24 pounds STANDARD_DEVIATION 51.95 | 218.63 pounds STANDARD_DEVIATION 45.24 | 211.36 pounds STANDARD_DEVIATION 44.01 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 17 | 0 / 19 |
| other Total, other adverse events | 4 / 17 | 5 / 19 |
| serious Total, serious adverse events | 0 / 17 | 1 / 19 |
Outcome results
Primary
Clinical Response to Tocilizumab
To evaluate an anticipated clinical response to tocilizumab treatment including positive, negative and cognitive symptoms by the change in the Positive and Negative Syndrome Scale (PANSS) total score. Score ranges from 30 to 210 for PANSS total, 16-112 for General, 7-49 for positive and 7-49 for negative symptoms subscales. A lower score means less symptomatic. There is a total score and general psychopathology scores, a positive symptoms score and a negative symptom score. The unit of measure is units on a scale from 1-7, whole numbers only. Summed scores are simply added to each other
Time frame: Baseline (start of tocilizumab) through 12 weeks. We present the change scores
Population: 17 placebo patients and 19 tocilizumab patients were included in the ITT analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Clinical Response to Tocilizumab | -5.33 Units on a scale (PANSS) | Standard Deviation 17.96 |
| Tocilizumab | Clinical Response to Tocilizumab | -0.5 Units on a scale (PANSS) | Standard Deviation 12.62 |
Secondary
Cognitive Symptomatology - Overall MATRICS t Score Change
MATRICS cognitive consensus battery, overall t score change. The composite T-score at each time point (baseline and week 12) is a T-Score (ranging from 0 to 100) reflecting overall neuropsychological function, aggregated from the participant's T-scores on the MATRICS subscales for Speed of Processing, Attention/Vigilance, Working Memory, Verbal Learning, Visual Learning, Reasoning and Problem Solving, and Social Cognition. The outcome is the difference between overall composite T-score at baseline and week 12, with higher difference score reflecting a greater improvement in neuropsychological performance.
Time frame: Baseline (start of tocilizumab) through 12 weeks
Population: These subjects were included in the ITT analysis and received the MATRICS. We will present total composite change scores from baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cognitive Symptomatology - Overall MATRICS t Score Change | 2.83 T Score Difference | Standard Deviation 5.59 |
| Tocilizumab | Cognitive Symptomatology - Overall MATRICS t Score Change | 1.47 T Score Difference | Standard Deviation 8.53 |
Secondary
Cognitive Symptomatology - UPSA-B Score Change
At Baseline and Week 12, participants are UPSA-B given items reflecting ability to complete tasks encountered in daily life, across two domains, Financial Skills and Communication Skills. % correct is calculated for each domain and converted to a standardized score from 0-50. These scores are summed to produce a total summary score ranging from 0-100. The outcome is the difference between this summary score at Baseline and Week 12, with a higher difference score reflecting a greater increase in functional capacity.
Time frame: Baseline (start of tocilizumab) through 12 weeks
Population: These subjects were included in the ITT analysis and received the UPSA at both baseline and week 12.We will present total composite change scores from baseline to week 12
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cognitive Symptomatology - UPSA-B Score Change | 1.12 Change in score on a scale | Standard Deviation 0.23 |
| Tocilizumab | Cognitive Symptomatology - UPSA-B Score Change | 1.12 Change in score on a scale | Standard Deviation 0.17 |
Other Pre-specified
Relationship Between Baseline IL-6 Levels and Positive, Negative and Cognitive Symptoms and Impairment
Comparison of cytokines, in particular IL-6 levels and the positive, negative and cognitive symptoms and impairments in daily functioning in schizophrenia. These outcomes will be measured by Positive and Negative Syndrome Scale (PANSS), Global Assessment of Functioning (GAF), Clinical Global Impression (CGI), University of California Performance Skills Assessments (UPSA) and MATRICS.
Time frame: Baseline (start of tocilizumab) through 12 weeks