• Positive and Negative Symptom Scale Excited Component (PANSS-EC) [ Time Frame: 15, 30, 60, 120 minutes after first injection ] [ Designated as safety issue: Yes ]
  

• Agitation-Calmness Evaluation Scale (ACES) [ Time Frame: 15, 30, 60, 120 minutes after first injection ] [ Designated as safety issue: Yes ]
  

To date, there have been no published reports of clinical studies of IM olanzapine versus IM haloperidol plus lorazepam in patients with schizophrenia. The latter combination is used quite often as a traditional way to treat agitated schizophrenia patients.

Study Design:

This is a randomized, single-blind, active-controlled, parallel-group study, consisting of screening and treatment phase. Patients completing the screening phase would be randomized to receive either 10mg olanzapine IM or 5 mg haloperidol plus 2 mg lorazepam IM . The ratio of randomization was 1:1. Treatment assignments are based on a computer-generated randomization code supplied by central unit with block designs. Patients can receive a maximum of 3 injections within the first 24-hour period. Second and third injections are used under the clinical judgment of investigators. The second injection is allowed after 2-hour has elapsed since first injection. The third injection is allowed after 4-hour have passed since the second injection. Prohibited medications include antiarrythmics, antipsychotics, antidepressants, anticonvulsants, antiemetics, and other psychotropic drugs.

Efficacy Assessments:

Patients are assessed by the study investigators at the screening visit and at 15, 30, 60, 120 minutes after first injection. The primary efficacy measure is PANSS-EC, which includes the items tension, uncooperativeness, hostility, poor impulse control, excitement and is derived from the PANSS by its originators using a principal-components factor analysis. Agitation is further assessed by the Agitation-Calmness Evaluation Scale (ACES) (Copyright 1998, Eli Lilly and Company; all rights reserved). Clinical Global Impression-Severity（CGI-S）scale37 is used to assess general psychiatric condition. For each patient, the same rater conducted the assessment throughout the study.

Safety assessments:

During the 24-hour treatment period, safety is assessed by clinical examination and laboratory investigations, recording spontaneously reported adverse events, completing the Simpson-Angus Scale (SAS3) and Barnes Akathisia Scales (BAS).

Statistical Procedures:

The efficacy analyses are based on intent-to treat (ITT) population defined as consisting of all randomized subjects. The last observation carried forward (LOCF) dataset is used to estimate the missing data. The primary treatment comparisons are 2-hour PANSS-EC scores after first injection. Continuous efficacy data (eg, change from baseline) are evaluated by analysis of covariance (ANCOVA), adjusting for baseline values and the fixed factors treatment, center, and treatment-by-center interaction. The treatment-by-center interaction was tested at the 0.10 significant levels and dropped from the model if it was not statistically significant. The 95% confidence interval is used to provide the test of hypothesis of efficacy of olanzapine is superior to haloperidol plus lorazepam. Categorical efficacy data are analysed using the Cochran-Mantel-Haenszel test with center control. For primary efficacy analyses, the hypothesis was one-sided and evaluated at the 0.025 significant levels. For other analyses, the test was two-sided and evaluated at the 0.05 significant levels.

Response is defined a priori as a 40% reduction or more in PANSS-EC scores. Response rate is also analysed using the Cochran-Mantel-Haenszel test with center control, and the Breslow-Day test to investigate the homogeneity of odds ratio across sites.