Schizophrenia
Conditions
Brief summary
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.
Interventions
DRUGRapid Acting Intramuscular Olanzapine
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).
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).
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 64 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 2 Hours Post the First Intramuscular (IM) Injection in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | 2 hours post first intramuscular (IM) injection | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | 15 min, 30 min, 60 min, 90 min post first IM injection | 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. |
| Number of Responders at 2 Hours After First Intramuscular (IM) Injection | 2 hours post first 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). |
| Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 30 min, 60 min, 90 min and 2 hours post first IM injection | 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. |
Countries
Japan
Participant flow
Pre-assignment details
One patient randomized to placebo was withdrawn from study by physician and is not included in the baseline demographic data table.
Participants by arm
| Arm | Count |
|---|---|
| IM Olanzapine 10mg Patients will receive at least one injection of Intramuscular 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). | 17 |
| IM Placebo 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). | 16 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | IM Olanzapine 10mg | IM Placebo | Total |
|---|---|---|---|
| Age at Onset | 22.6 years STANDARD_DEVIATION 6.4 | 21.3 years STANDARD_DEVIATION 6.1 | 22.0 years STANDARD_DEVIATION 6.2 |
| Age Continuous | 47.4 years STANDARD_DEVIATION 12.4 | 45.9 years STANDARD_DEVIATION 11.5 | 46.7 years STANDARD_DEVIATION 11.8 |
| Agitation-Calmness Evaluation Scale (ACES) | 1.8 units on a scale STANDARD_DEVIATION 0.4 | 1.8 units on a scale STANDARD_DEVIATION 0.4 | 1.8 units on a scale STANDARD_DEVIATION 0.4 |
| Body Mass Index (BMI) | 20.7 kilograms/square centimeters STANDARD_DEVIATION 2.9 | 22.8 kilograms/square centimeters STANDARD_DEVIATION 3.6 | 21.7 kilograms/square centimeters STANDARD_DEVIATION 3.3 |
| Diabetes Mellitus No | 15 participants | 14 participants | 29 participants |
| Diabetes Mellitus Yes | 2 participants | 2 participants | 4 participants |
| Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision Diagnosis Catatonic | 2 participants | 0 participants | 2 participants |
| Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision Diagnosis Disorganized | 7 participants | 7 participants | 14 participants |
| Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision Diagnosis Paranoid | 7 participants | 7 participants | 14 participants |
| Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision Diagnosis Residual | 0 participants | 2 participants | 2 participants |
| Diagnostic and Statistical Manual of Mental Disorders Fourth Edition, Text Revision Diagnosis Undifferentiated | 1 participants | 0 participants | 1 participants |
| Positive and Negative Syndrome Scale-Excited Component | 23.6 units on a scale STANDARD_DEVIATION 3.8 | 23.5 units on a scale STANDARD_DEVIATION 3.8 | 23.5 units on a scale STANDARD_DEVIATION 3.7 |
| Pre-Therapy Antipsychotic Usage No | 1 participants | 1 participants | 2 participants |
| Pre-Therapy Antipsychotic Usage Yes (<1000 milligrams/day) | 9 participants | 9 participants | 18 participants |
| Pre-Therapy Antipsychotic Usage Yes (>=1000 milligrams/day) | 7 participants | 6 participants | 13 participants |
| Region of Enrollment Japan | 17 participants | 16 participants | 33 participants |
| Sex: Female, Male Female | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 9 Participants | 10 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / — | 2 / — |
| serious Total, serious adverse events | 0 / — | 0 / — |
Outcome results
Primary
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.
Time frame: 2 hours post first intramuscular (IM) injection
Population: Number of randomized patients having the measures both at baseline and post-baseline. Last Observation Carried Forward.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| IM Olanzapine 10mg | Change From Baseline to 2 Hours Post the First Intramuscular (IM) Injection in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | -4.7 units on a scale | Standard Deviation 4.8 |
| IM Placebo | Change From Baseline to 2 Hours Post the First Intramuscular (IM) Injection in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | -4.6 units on a scale | Standard Deviation 4.5 |
Comparison: A sample size of at least 15 patients per group was necessary to verify that the decrease in PANSS-EC total score was significantly greater in the IM olanzapine group than the placebo group using Student's t-test with a power of 90% at a two-sided significance level of 5%.p-value: 0.94t-test, 2 sided
Secondary
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.
Time frame: 15 min, 30 min, 60 min, 90 min post first IM injection
Population: Number of patients having the measure both at baseline and post-baseline. Last Observation Carried Forward.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| IM Olanzapine 10mg | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 15 minutes | -1.2 units on a scale | Standard Deviation 1.3 |
| IM Olanzapine 10mg | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 30 minutes | -2.9 units on a scale | Standard Deviation 2.8 |
| IM Olanzapine 10mg | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 60 minutes | -3.8 units on a scale | Standard Deviation 3.6 |
| IM Olanzapine 10mg | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 90 minutes | -5.1 units on a scale | Standard Deviation 4.3 |
| IM Placebo | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 90 minutes | -4.6 units on a scale | Standard Deviation 4.7 |
| IM Placebo | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 15 minutes | -1.2 units on a scale | Standard Deviation 1.5 |
| IM Placebo | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 60 minutes | -3.4 units on a scale | Standard Deviation 4.1 |
| IM Placebo | Change From Baseline to Each Timepoint in Positive and Negative Syndrome Scale-Excited Component (PANSS-EC) | Change from Baseline to 30 minutes | -2.4 units on a scale | Standard Deviation 2.8 |
p-value: 1t-test, 2 sided
p-value: 0.62t-test, 2 sided
p-value: 0.784t-test, 2 sided
p-value: 0.756t-test, 2 sided
Secondary
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.
Time frame: 30 min, 60 min, 90 min and 2 hours post first IM injection
Population: Number of patients having the measure at post-baseline. Last Observation Carried Forward.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IM Olanzapine 10mg | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 30 Minutes | 1 participants |
| IM Olanzapine 10mg | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 60 Minutes | 1 participants |
| IM Olanzapine 10mg | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 90 Minutes | 2 participants |
| IM Olanzapine 10mg | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 2 Hours | 3 participants |
| IM Placebo | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 2 Hours | 2 participants |
| IM Placebo | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 30 Minutes | 1 participants |
| IM Placebo | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 90 Minutes | 2 participants |
| IM Placebo | Number of Participants With Scores of 4 to 7 in the Agitation-Calmness Evaluation Scale (ACES) at Each Timepoint | 60 Minutes | 1 participants |
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
p-value: 1Fisher Exact
Secondary
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).
Time frame: 2 hours post first IM injection
Population: Number of patients having the measures both at baseline and post-baseline. Last Observation Carried Forward.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IM Olanzapine 10mg | Number of Responders at 2 Hours After First Intramuscular (IM) Injection | 3 participants |
| IM Placebo | Number of Responders at 2 Hours After First Intramuscular (IM) Injection | 4 participants |
p-value: 1Fisher Exact