Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT00056498
• Collaborator: National Institute of Mental Health (NIMH) (NIH), Ortho-McNeil Janssen Scientific Affairs, LLC (Industry)
• Enrollment: 65
• Location: 1
• Arms: 2
• Actual Duration (Months): 72
• Patients Per Site Per Month: 0.9

Study Details

Study Description

Brief Summary

This study will determine whether adding the drug risperidone (Risperdal®) is more effective than placebo in treating schizophrenic patients who are taking the drug clozapine.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Placebo; Drug: Risperdal	Phase 4

Detailed Description

Clozapine is the only antipsychotic drug that has been approved for treatment resistant patients with schizophrenia. However, up to 50% of patients treated with clozapine fail to respond and continue to exhibit clinically significant residual positive and negative symptoms and cognitive impairments. An emerging trend in treatment is the addition of a second antipsychotic drug. This study will determine if risperidone when given as adjunctive treatment is more effective than placebo in treating schizophrenic patients failing clozapine therapy.

Participants are randomly assigned to add either adjunctive risperidone or placebo to their current clozapine treatment in a single, daily dose for 16 weeks. Positive and negative symptoms, cognitive impairments, side effects of the treatment, anxiety, depression, hostility symptoms, and quality of life are assessed. Neurological tests, self administered questionnaires, and interviews are used to assess patients.

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Clozapine Treatment of Schizophrenic Patients
• Actual Study Start Date: Dec 1, 2001
• Actual Primary Completion Date: Dec 1, 2007
• Actual Study Completion Date: Dec 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Active Participants assigned to risperidone	Drug: Risperdal; Risperdal 4 mg per day for 16 weeks; Other Names: Risperidone
Placebo Comparator: Placebo Participants assigned to placebo	Drug: Placebo; Placebo capsule daily for 16 weeks

Outcome Measures

Primary Outcome Measures

1. Positive Symptom Item Scores by Week and Treatment Group [Baseline and every two weeks for 16 weeks.]

   The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating. A mixed model for unbalanced repeated measures analysis of covariance (ANCOVA), in which follow-up symptom score = baseline symptom score + treatment + week + treatment x week, and week is treated as a categorical, rather than a continuous measure. The treatment term estimates the average across weeks of the week-specific group differences, and is used as the main test for treatment effects on symptom change.

Secondary Outcome Measures

1. Neuropsychological Testing - Overall Composite Z-score [Baseline and Week 16]

   The neuropsychological testing measured attention, executive function/problem solving, motor speed, processing speed/response generation, and verbal, visual, and working memory. The individual test raw scores were converted to z-scores and an overall composite z-score was computed from the average of the individual test z-scores. Z-scores range from -3 standard deviations up to +3 standard deviations. Higher scores indicate better test performance.

2. Negative Symptom Total Score by Week and Treatment Group [Baseline and every two weeks for 16 weeks.]

   The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms. A mixed model for unbalanced repeated measures analysis of covariance (ANCOVA), in which follow-up symptom score = baseline symptom score + treatment + week + treatment x week, and week is treated as a categorical, rather than a continuous measure. The treatment term estimates the average across weeks of the week-specific group differences, and is used as the main test for treatment effects on symptom change.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• DSM-IV criteria for schizophrenia or schizoaffective disorder

• Current clozapine treatment

• Moderate illness severity and inadequate positive symptom response to clozapine treatment

• 6 month period of clozapine treatment with documented clozapine blood level greater than or equal to 350 ng/ml or clozapine and norclozapine blood level greater than or equal to 450 ng/ml

Exclusion Criteria:

• Organic brain disorder

• Mental retardation

• Medical condition whose pathology or treatment could alter the presentation or treatment of schizophrenia or significantly increase the risk associated with the proposed treatment protocol

• Pregnancy

• DSM-IV criteria for current alcohol or substance dependence within the last 6 months or DSM-IV criteria for alcohol or substance abuse within the last month

• Previously received adjunctive risperidone (at doses greater than or equal to 8 mg/day) with their clozapine treatment for greater than or equal to 6 weeks

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Maryland Psychiatric Research Center	Catonsville	Maryland	United States	21228

Sponsors and Collaborators

• University of Maryland, Baltimore
• National Institute of Mental Health (NIMH)
• Ortho-McNeil Janssen Scientific Affairs, LLC

Investigators

• Principal Investigator: Robert W Buchanan, MD, University of Maryland, College Park

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Robert Buchanan, Professor of Psychiatry, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT00056498
• Other Study ID Numbers: R01 MH045074 H-21270; R01MH045074; DSIR 83-ATAP
• First Posted: Mar 17, 2003
• Last Update Posted: Oct 1, 2019
• Last Verified: Sep 1, 2019

• Additional relevant MeSH terms: Schizophrenia; Risperidone

Study Results

Participant Flow

Recruitment Details	Though funding was in place beginning in 2001, recruitment took place from 2003 to 2008. Subjects were recruited from the Maryland Psychiatric Research Center Outpatient Reseach clinic, the Treatment Research Program, and community mental health centers.
Pre-assignment Detail	86 Participants signed informed consent. 15 were ineligible or excluded. 71 Participants entered the evaluation phase. Two were withdrawn prior to randomization. Four people withdrew after randomization but prior to starting study medications.

Arm/Group Title	Risperidone	Placebo
Arm/Group Description	Participants assigned to risperidone	Participants assigned to placebo
Period Title: Overall Study
STARTED	30	35
COMPLETED	25	28
NOT COMPLETED	5	7

Baseline Characteristics

Arm/Group Title	Risperidone	Placebo	Total
Arm/Group Description	Participants assigned to risperidone	Participants assigned to placebo	Total of all reporting groups
Overall Participants	30	35	65
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	30 100%	35 100%	65 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.3 (7.2)	44.1 (9.3)	46.1 (8.6)
Sex: Female, Male (Count of Participants)
Female	11 36.7%	10 28.6%	21 32.3%
Male	19 63.3%	25 71.4%	44 67.7%
Region of Enrollment (participants) [Number]
United States	30 100%	35 100%	65.0 100%

Outcome Measures

1. Primary Outcome

Title	Positive Symptom Item Scores by Week and Treatment Group
Description	The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from "1=Not Present" to "7=Very Severe". The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating. A mixed model for unbalanced repeated measures analysis of covariance (ANCOVA), in which follow-up symptom score = baseline symptom score + treatment + week + treatment x week, and week is treated as a categorical, rather than a continuous measure. The treatment term estimates the average across weeks of the week-specific group differences, and is used as the main test for treatment effects on symptom change.
Time Frame	Baseline and every two weeks for 16 weeks.

Outcome Measure Data

Analysis Population Description

The intent to treat analysis included all participants who received at least one dose of study medication and completed the BPRS rating at the specified week.

Arm/Group Title	Risperidone	Placebo
Arm/Group Description	Participants assigned to risperidone	Participants assigned to placebo
Measure Participants	30	34
Week 0	15.5 (3.8)	15.5 (4.2)
Week 2	14.6 (3.7)	15.1 (4.0)
Week 4	13.3 (4.0)	14.4 (3.5)
Week 6	13.9 (3.9)	14.7 (3.8)
Week 8	13.5 (4.2)	14.9 (3.9)
Week 10	13.9 (4.2)	14.9 (4.2)
Week 12	13.8 (3.7)	15.3 (4.6)
Week 14	13.4 (3.5)	14.2 (3.8)
Week 16	13.2 (3.5)	14.1 (3.6)
Change Score	-2.6 (3.1)	-1.5 (3.4)

2. Secondary Outcome

Title	Neuropsychological Testing - Overall Composite Z-score
Description	The neuropsychological testing measured attention, executive function/problem solving, motor speed, processing speed/response generation, and verbal, visual, and working memory. The individual test raw scores were converted to z-scores and an overall composite z-score was computed from the average of the individual test z-scores. Z-scores range from -3 standard deviations up to +3 standard deviations. Higher scores indicate better test performance.
Time Frame	Baseline and Week 16

Outcome Measure Data

Analysis Population Description

Two participants completed 9 or fewer of the 13 individual tests in the neurocognitive battery, and were omitted from calculation of the overall composite score

Arm/Group Title	Risperidone	Placebo
Arm/Group Description	Participants assigned to risperidone	Participants assigned to placebo
Measure Participants	24	27
Baseline	0.02 (0.66)	-0.03 (0.46)
Week 16	0.12 (0.66)	0.07 (0.47)

3. Secondary Outcome

Title	Negative Symptom Total Score by Week and Treatment Group
Description	The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms. A mixed model for unbalanced repeated measures analysis of covariance (ANCOVA), in which follow-up symptom score = baseline symptom score + treatment + week + treatment x week, and week is treated as a categorical, rather than a continuous measure. The treatment term estimates the average across weeks of the week-specific group differences, and is used as the main test for treatment effects on symptom change.
Time Frame	Baseline and every two weeks for 16 weeks.

Outcome Measure Data

Analysis Population Description

The intent to treat analysis included all participants who received at least one dose of study medication and completed the SANS rating at the specified treatment week.

Arm/Group Title	Risperidone	Placebo
Arm/Group Description	Participants assigned to risperidone	Participants assigned to placebo
Measure Participants	30	34
Week 0	32.3 (11.6)	33.0 (13.3)
Week 2	30.8 (11.5)	34.0 (12.1)
Week 4	29.8 (11.6)	32.9 (13.3)
Week 6	31.2 (10.3)	33.0 (12.7)
Week 8	30.4 (11.3)	34.0 (14.1)
Week 10	30.6 (10.9)	33.1 (13.3)
Week 12	31.6 (10.7)	32.4 (12.5)
Week 14	31.7 (11.0)	34.4 (14.1)
Week 16	31.3 (11.9)	34.4 (14.8)
Change Score	-2.6 (5.6)	1.1 (10.8)

Adverse Events

Arm/Group Title	Risperidone		Placebo
Arm/Group Description	Participants assigned to risperidone		Participants assigned to placebo
All Cause Mortality
	Risperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Risperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/30 (3.3%)		2/35 (5.7%)
Gastrointestinal disorders
gastrointestinal symptoms	0/30 (0%)		1/35 (2.9%)
Psychiatric disorders
increased auditory hallucinations	1/30 (3.3%)		0/35 (0%)
Panic attack	0/30 (0%)		1/35 (2.9%)
Other (Not Including Serious) Adverse Events
	Risperidone		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/30 (0%)		0/35 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.