Intramuscular (IM) Olanzapine Versus IM Haloperidol Plus Lorazepam for Acute Agitation in Schizophrenia

• Sponsor: National Taiwan University Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT00797277
• Collaborator: Yu-Li Hospital (Other)
• Enrollment: 67
• Location: 1
• Arms: 2
• Duration (Months): 35
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Schizoaffective Disorder; Agitation	Drug: IM olanzapine; Drug: IM haloperidol plus lorazepam	Phase 3

Detailed Description

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

Study Design:

This is a randomized, 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 (SAS) and Barnes Akathisia Scales (BAS).

Statistical Procedures:

The efficacy analyses were based on intent to treat (ITT) population defined as consisting of all randomized subjects. The last observation carried forward (LOCF) dataset was used to estimate the missing data. Data were analysed using statistical program R Language version 2.8.0 (http://www.r-project.org/), with significance set at p < .05. Demographic characteristics and clinical parameters at baseline were compared by treatment group using the t-test for continuous variables and chi-square test for categorical variables. The primary treatment comparison was 2-hour PANSS-EC scores after first injection. Continuous efficacy and safety data were evaluated by multiple linear regression, adjusting for treatment group, 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. To compare the number difference in adverse events between two treatment groups, Fisher's exact test was used due to low cell counts.

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Randomized Trial of Intramuscular (IM) Olanzapine Versus Intramuscular Combination of Haloperidol and Lorazepam in the Treatment of Acute Agitation in Schizophrenia
• Study Start Date: Jul 1, 2006
• Actual Primary Completion Date: Jun 1, 2009
• Actual Study Completion Date: Jun 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IM olanzapine Patients of this arm received 10 mg IM olanzapine after randomization	Drug: IM olanzapine; 10mg olanzapine IM; Other Names: zyprexa
Active Comparator: IM haloperidol plus lorazepam Patients of this arm received 5 mg IM haloperidol plus 2 mg IM lorazepam after randomization	Drug: IM haloperidol plus lorazepam; IM 5 mg haloperidol plus IM 2 mg lorazepam; Other Names: haldol and ativan

Outcome Measures

Primary Outcome Measures

1. The Change of the Positive and Negative Symptom Scale Excited Component (PANSS-EC) Score From Baseline to 120 Minutes After First Injection [from baseline to 120 minutes after first injection]

   The primary efficacy measure was PANSS-EC, which was derived from the PANSS by its originators using a principal-components factor analysis, and includes the items of tension, uncooperativeness, hostility, poor impulse control and excitement.22 The score of each item ranges from 1 (normal) to 7 (most severe), with a total sum score ranging from 5 to 35. The changes in PANSS-EC from baseline to 2 hours after the first injection were compared.

Secondary Outcome Measures

1. Change of the Agitation-Calmness Evaluation Scale (ACES) Score From Baseline to 120 Minutes After 1st Injection [from baseline to 120 minutes after first injection]

   Agitation was further assessed by the Agitation Calmness Evaluation Scale (ACES) (Copyright 1998, Eli Lilly and Company), a single-item scale developed by Eli Lilly and Company on which 1 indicates marked agitation; 2, moderate agitation; 3, mild agitation; 4, normal; 5, mild calmness; 6, moderate calmness; 7, marked calmness; 8, deep sleep; and 9, unable to be aroused.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Psychiatry, National Taiwan University Hospital	Taipei		Taiwan	100

Sponsors and Collaborators

• National Taiwan University Hospital
• Yu-Li Hospital

Investigators

• Study Director: Tzung-Jeng Hwang, MD, MPH, PhD, Department of Psychiatry, National Taiwan University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Breier A, Meehan K, Birkett M, David S, Ferchland I, Sutton V, Taylor CC, Palmer R, Dossenbach M, Kiesler G, Brook S, Wright P. A double-blind, placebo-controlled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry. 2002 May;59(5):441-8.

• Responsible Party: National Taiwan University Hospital
• ClinicalTrials.gov Identifier: NCT00797277
• Other Study ID Numbers: 950107
• First Posted: Nov 25, 2008
• Last Update Posted: Sep 15, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by National Taiwan University Hospital: schizophrenia; schizoaffective disorder; olanzapine; haloperidol; lorazepam; agitation
• Additional relevant MeSH terms: Psychomotor Agitation; Schizophrenia; Psychotic Disorders; Lorazepam; Haloperidol; Olanzapine; Haloperidol decanoate

Study Results

Participant Flow

Recruitment Details	The study was conducted at 3 psychiatric centers from September 2006 to February 2009.
Pre-assignment Detail	A total of 294 patients were assessed initially. Before randomization, 47 patients were excluded, including "no signed informed consent" (n=20), "having received recent depot injection" (n=24), "no overt agitation after admission" (n=180)" and "newly added benzodiazepine or antipsychotics" (n=3).

Arm/Group Title	1. IM Olanzapine	2. IM Haloperidol Plus Lorazepam
Arm/Group Description	Patients of this arm received 10 mg IM olanzapine after randomization. The patients could receive a maximum of 3 injections within the 24-hour period. Second and third injections were prescribed at the discretion of the clinical investigators. A second injection was allowed after 2 hours had elapsed since the first injection. A third injection was allowed after 4 hours had passed since the second injection.	Patients of this arm received 5 mg IM haloperidol plus 2 mg IM lorazepam after randomization. The patients could receive a maximum of 3 injections within the 24-hour period. Second and third injections were prescribed at the discretion of the clinical investigators. A second injection was allowed after 2 hours had elapsed since the first injection. A third injection was allowed after 4 hours had passed since the second injection.
Period Title: Overall Study
STARTED	37	30
COMPLETED	37	30
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	1. IM Olanzapine	2. IM Haloperidol Pus Lorazepam	Total
Arm/Group Description	Patients of this arm received 10 mg IM olanzapine after randomization	Patients of this arm received 5 mg IM haloperidol plus 2 mg IM lorazepam after randomization	Total of all reporting groups
Overall Participants	37	30	67
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.1 (10.8)	41.3 (11.3)	39.0 (11.0)
Sex: Female, Male (Count of Participants)
Female	15 40.5%	11 36.7%	26 38.8%
Male	22 59.5%	19 63.3%	41 61.2%

Outcome Measures

1. Primary Outcome

Title	The Change of the Positive and Negative Symptom Scale Excited Component (PANSS-EC) Score From Baseline to 120 Minutes After First Injection
Description	The primary efficacy measure was PANSS-EC, which was derived from the PANSS by its originators using a principal-components factor analysis, and includes the items of tension, uncooperativeness, hostility, poor impulse control and excitement.22 The score of each item ranges from 1 (normal) to 7 (most severe), with a total sum score ranging from 5 to 35. The changes in PANSS-EC from baseline to 2 hours after the first injection were compared.
Time Frame	from baseline to 120 minutes after first injection

Outcome Measure Data

Analysis Population Description

Those receiving at least one IM injection

Arm/Group Title	1. IM Olanzapine	2. IM Haloperidol Plus Lorazepam
Arm/Group Description	10 mg olanzapine IM injection	5 mg haloperidol plus 2 mg lorazepam IM injection
Measure Participants	37	30
Mean (Standard Deviation) [units on a scale]	-10.2 (6.5)	-9.9 (5.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1. IM Olanzapine, 2. IM Haloperidol Plus Lorazepam
	Comments	we hypothesized that there would be no statistical significant difference between the 2 groups in the primary outcome.
	Type of Statistical Test	Non-Inferiority or Equivalence
	Comments	There was no previous study comparing these 2 treatments. We hypothesized that the mean difference between the 2 treatments would be small.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.0
	Confidence Interval	() %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change of the Agitation-Calmness Evaluation Scale (ACES) Score From Baseline to 120 Minutes After 1st Injection
Description	Agitation was further assessed by the Agitation Calmness Evaluation Scale (ACES) (Copyright 1998, Eli Lilly and Company), a single-item scale developed by Eli Lilly and Company on which 1 indicates marked agitation; 2, moderate agitation; 3, mild agitation; 4, normal; 5, mild calmness; 6, moderate calmness; 7, marked calmness; 8, deep sleep; and 9, unable to be aroused.
Time Frame	from baseline to 120 minutes after first injection

Outcome Measure Data

Analysis Population Description

Those receiving at least one IM injection

Arm/Group Title	1. IM Olanzapine	2. IM Haloperidol Pus Lorazepam
Arm/Group Description	10 mg olanzapine IM injection	5 mg haloperidol plus 2 mg lorazepam IM injection
Measure Participants	37	30
Mean (Standard Deviation) [units on a scale]	2.14 (1.80)	2.23 (1.65)

Adverse Events

Time Frame	24 hours
Adverse Event Reporting Description	collect the adverse event that occur from baseline to 24 hours after the first injection
Arm/Group Title	1. IM Olanzapine		2. IM Haloperidol Pus Lorazepam
Arm/Group Description	Patients of this arm received 10 mg IM olanzapine after randomization		Patients of this arm received 5 mg IM haloperidol plus 2 mg IM lorazepam after randomization
All Cause Mortality
	1. IM Olanzapine		2. IM Haloperidol Pus Lorazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	1. IM Olanzapine		2. IM Haloperidol Pus Lorazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/30 (0%)
Other (Not Including Serious) Adverse Events
	1. IM Olanzapine		2. IM Haloperidol Pus Lorazepam
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/37 (10.8%)		7/30 (23.3%)
Nervous system disorders
dizziness	1/37 (2.7%)	1	2/30 (6.7%)	2
drowsiness	3/37 (8.1%)	3	5/30 (16.7%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.