A Study Comparing Rapid Acting Intramuscular Olanzapine and Placebo in Agitated Patients With Schizophrenia

Study Overview
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Brief Summary
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The primary objectives of the study is to confirm if the efficacy of IM olanzapine in patients with schizophrenia is greater than IM placebo by comparing changes from baseline to 2 hours post first IM injection of agitation.

Official Title
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A Placebo-Controlled, Double-Blind Confirmatory Study of Rapid-Acting Intramuscular Olanzapine in Agitated Patients With Schizophrenia

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Rapid Acting Intramuscular Olanzapine
* Drug: Isotonic sodium chloride solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients have met Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision (DSM-IV-TR) criteria for schizophrenia. Male or female, at least 20 years and less than 65 years old. Inpatients during the study. Each patient, or a proxy consenter, understand the nature of the study and must sign an informed consent document. The patient is able to cooperate with all study procedures in the view of the investigator. Patients are considered, by the investigator or subinvestigator, to be clinically agitated and appropriate candidates for treatment with intramuscular (IM) medication. The investigator must believe that it is safe to administer IM olanzapine to the patients with respect to the safety profile, including the anticholinergic properties of Olanzapine IM. Patients have a minimum total score of ≧ 20 on the five items of the Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) using the 1-7 scoring system prior to the first injection of study drug. Patients have a score of 1 or 2 on the Agitation-Calmness Evaluation Scale (ACES) prior to the first injection of study drug. Exclusion Criteria: Patients who were previously treated with oral olanzapine and are considered to be treatment-resistant to oral olanzapine, in the opinion of the investigator. Patients who have a history of allergic reaction or intolerance to study medication. Patients who show evidence of clinically significant bradycardia or arrhythmia obtained either from a physical exam or an electrocardiogram (ECG). Patients who require concomitant treatment with any other medication with primary central nervous system activity, other than those allowed as specified in section concomitant treatment. Patients who have acute, serious or unstable medical conditions, including (but not limited to) hepatic insufficiency (specifically any degree of jaundice), recent cerebrovascular accidents, uncontrolled seizure disorders, serious acute systemic infection or immunologic disease, unstable cardiovascular disorders (including ischemic heart disease), renal, gastroenterologic, respiratory, endocrinologic, neurologic, or hematologic diseases. Patients with inadequately controlled diabetes, or patients whose treatment for diabetes were changed within 4 weeks prior to the first injection of the study drug. The investigator's discretion will supersede even if the patients do not meet the above criteria for concurrent diabetes. Patients who have a known neutrophil count or total of segmented cell and band cell counts of <1,500 /millimeter cubed (mm3). Patients who have a known alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) values ≧2 times the normal upper limit of the performing laboratory (ULN) or aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) values ≧3 times the ULN or total bilirubin values ≧1.5 times the ULN. Patients who have a known serum triglycerides ≧500 milligrams/deciliter (mg/dL). Electrocardiogram abnormalities considered clinically significant by the investigator. Patients who have had treatment with injectable depot antipsychotics within one injection interval prior to study drug administration. Patients who have received treatment with antipsychotics or other prohibited concomitant medicines showing in the section prohibited concomitant medicines within 2 hours prior to the first IM study drug administration. Patients who have had treatment with benzodiazepines within 4 hours prior to first IM study drug administration. Patients who have been administered epinephrine within 24 hours prior to the first IM study drug administration. Patients who have received treatment with psychostimulants or reserpine within 7 days prior to the first IM study drug administration. Patients who have received beta blockers or calcium channel blockers previously, must have been taking the same medication at the same dose for 28 days prior to the first IM study drug administration. No beta blockers or calcium channel blockers may be administered within 24 hours of the first IM study drug injection, or any time during the double blind phase.

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IM olanzapine 10mg<br>Patients will receive at least one injection of Intramuscular (IM) olanzapine 10mg. If patients do not respond to the study medication or if patients do not have enough improvement based on the investigator's judgment, and in addition, if the investigator judges it is reasonable, the patient will receive a second injection at the same dose strength as the first injection after 2 hours following the first injection (no later than 8 hours after the first injection). | Drug: Rapid Acting Intramuscular Olanzapine<br>* 10mg/injection, IM. If patients do not respond to the first study medication or if patients do not have enough improvement based on the investigator's judgment, and in addition, if the investigator judges it is reasonable, the patient will receive a second injection at the same dose strength as the first injection after 2 hours following the first injection (no later than 8 hours after the first injection).<br>* Other names: RAIM;|
| Placebo Comparator: IM placebo<br>Patients will receive at least one injection of Intramuscular placebo. If patients do not respond to the study medication or if patients do not have enough improvement based on the investigator's judgment, and in addition, if the investigator judges it is reasonable, the patient will receive a second injection at the same dose strength as the first injection after 2 hours following the first injection (no later than 8 hours after the first injection). | Drug: Isotonic sodium chloride solution<br>* 0.9% sodium chloride (NaCl) solution. If patients do not respond to the first study medication or if patients do not have enough improvement based on the investigator's judgment, and in addition, if the investigator judges it is reasonable, the patient will receive a second injection at the same dose strength as the first injection after 2 hours following the first injection (no later than 8 hours after the first injection).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 2 Hours Post the First Intramuscular (IM) Injection in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Measures excitability and consists of the following 5 items from the PANSS: Excitement, Hostility, Tension, Uncooperativeness, and Poor Impulse Control. Each item is rated on a scale from 1 (Absent) to 7 (Extreme). The sum of the 5 items is defined as the PANSS-EC total score which ranges from 5 to 35. | 2 hours post first intramuscular (IM) injection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Measures excitability and consists of the following 5 items from the PANSS: Excitement, Hostility, Tension, Uncooperativeness, and Poor Impulse Control. Each item is rated on a scale from 1 (Absent) to 7 (Extreme). The sum of the 5 items is defined as the PANSS-EC total score which ranges from 5 to 35. | 15 min, 30 min, 60 min, 90 min post first IM injection | 
| Number of Responders at 2 Hours After First Intramuscular (IM) Injection | A responder was defined ast he patient with ≥ 40% decrease in the PANSS-EC total score at 2 hours after the first IM injection in comparison with baseline. (See outcome measure 1 for description of PANSS-EC). | 2 hours post first IM injection | 
| Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | The ACES differentiates agitation, calmness, and sleep-state, using a 9-point scale: 1 (Marked Agitation) to 9 (Unarousable). Scores of 4 (Normal) to 7 (Marked Calmness) were used for this outcome measure. | 30 min, 60 min, 90 min and 2 hours post first IM injection |