Official Title: “An Open-Label, Randomized Trial of Intramuscular Olanzapine Versus Intramuscular Combination of Haloperidol and Lorazepam in the Treatment of Acute Agitation in Schizophrenia”

The aim of this study was to compare the efficacy and safety of intramuscular 10 mg olanzapine versus intramuscular 5 mg haloperidol plus lorazepam 2 mg in the treatment of acute agitated schizophrenic patients of Taiwanese populations.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Subject), Active Control, Parallel Assignment, Efficacy Study

Study Primary Completion Date: February 2009

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.

Intervention(s) in this Clinical Trial

• Drug: IM olanzapine
  • 10mg olanzapine IM
• Drug: haloperidol plus lorazepam IM
  • 5 mg haloperidol plus 2 mg lorazepam, IM

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1. IM olanzapine
• Active Comparator: 2. IM haloperidol pus lorazepam

Primary Measures

• Positive and Negative Symptom Scale Excited Component (PANSS-EC)
  • Time Frame: 15, 30, 60, 120 minutes after first injection
    Safety Issue?: Yes

Secondary Measures

• Agitation-Calmness Evaluation Scale (ACES)
  • Time Frame: 15, 30, 60, 120 minutes after first injection
    Safety Issue?: Yes

Inclusion Criteria:

• Men and non-pregnant, non-lactating women aged 18 to 65 years with a primary diagnosis of schizophrenia (DSM-IV)
• were hospitalized due to an acute relapse
• were clinically agitated with a minimum total score of ≧ 14 on the five items of the PANSS-EC and at least one individual item score of ≧ 4 using the 1-7 scoring system prior to first IM injection of study drug.

Exclusion Criteria:

• female subjects who were either pregnant or breast-feeding;
• patients with acute, serious or unstable medical conditions;
• treatment with benzodiazepines within 4 hours prior to the first IM study drug administration;
• treatment with an injection depot neuroleptic within 1 injection interval prior to study drug administration;
• history of allergic reaction or intolerance to study medication(s);
• had a known diagnosis of dementia of any type, as defined in the DSM-IV.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Taiwan University Hospital

Overall Clinical Trial Officials and Contacts

Tzung-Jeng Hwang, MD Study Director Department of Psychiatry, National Taiwan University Hospital  

Overall Contact: Tzung-Jeng Hwang, MD 886-2-23123456 tjhwang@ntu.edu.tw

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00797277

Study ID Number: 950107

ClinicalTrials.gov Identifier: NCT00797277

Health Authority: Taiwan: Department of Health