Efficacy of Pimozide Augmentation for Clozapine Partial Response

• ClinicalTrials.gov Identifier: NCT00374244
• Recruitment Status: Completed
• First Posted: September 11, 2006
• Results First Posted: March 4, 2016
• Last Update Posted: March 4, 2016
• Sponsor: Yale University
• Collaborator: Stanley Medical Research Institute
• Information provided by (Responsible Party): Yale University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Schizophrenia
• Interventions: Drug: Pimozide; Drug: placebo
• Enrollment: 28

Participant Flow

Recruitment Details	This clinical trial was conducted at the outpatient clinics of the West Haven VA, Connecticut Mental Health Center of Yale Department of Psychiatry, and the Zucker-Hillside Hospital of Long Island Jewish Health Care System, and approved by the respective Institutional Review Boards.
Pre-assignment Details	Prior to randomization, a stable dose of clozapine for the past 2 weeks with a blood level of at least 350 ng/ml was targeted. Subjects were stratified as to whether they were receiving psychoactive medications such as mood stabilizers, to ensure that about equal numbers of subjects were randomized based on this treatment profile.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Period Title: Overall Study
Started	14	14
Completed	14	14
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		Placebo Pimozide	Active Pimozide	Total
Arm/Group Description		Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.	Total of all reporting groups
Overall Number of Baseline Participants		14	14	28
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	14 participants	14 participants	28 participants
		41.5 (2.8)	44.3 (2.0)	43.0 (9.0)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	14 participants	14 participants	28 participants
	Female	4 28.6%	4 28.6%	8 28.6%
	Male	10 71.4%	10 71.4%	20 71.4%

Outcome Measures

1. Primary Outcome

Title	Brief Psychiatric Rating Scale (BPRS) Total Score
Description	The Brief Psychiatric Rating Scale (BPRS) is an 18-item instrument. The items are anchored on a 7-point scale (higher rating: greater severity). Total scores range from 18 to 126 (higher score: greater severity). The instrument covers areas including: somatic concerns, anxiety, emotional withdrawal, conceptual disorganization, guilt feelings, tension, mannerisms and posturing, grandiosity, depressive mood, hostility, suspiciousness, hallucinatory behavior, motor retardation, uncooperativeness, unusual thought content, blunted affect, excitement and disorientation.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Subjects were analyzed intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	44.1 (2.0)	44.3 (2.0)

2. Primary Outcome

Title	Brief Psychiatric Rating Scale (BPRS) Total Score
Description	The Brief Psychiatric Rating Scale (BPRS) is an 18-item instrument. The items are anchored on a 7-point scale (higher rating: greater severity). Total scores range from 18 to 126 (higher score: greater severity). The instrument covers areas including: somatic concerns, anxiety, emotional withdrawal, conceptual disorganization, guilt feelings, tension, mannerisms and posturing, grandiosity, depressive mood, hostility, suspiciousness, hallucinatory behavior, motor retardation, uncooperativeness, unusual thought content, blunted affect, excitement and disorientation.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Subjects were analyzed intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	37.9 (2.1)	39.6 (2.1)

3. Primary Outcome

Title	Scale for the Assessment of Negative Symptoms (SANS)
Description	The Scale for the Assessment of Negative Symptoms (SANS) is a rating scale to measure negative symptoms in schizophrenia. The scale has 25 items (20 individual and 5 global) rated on scale of 0-5 (higher rating: greater severity). SANS is split into 5 domains, and within each domain separate symptoms are rated from 0 (absent) to 5 (severe). Domains include: Affective Flattening or Blunting, Alogia, Avolition - Apathy, Anhedonia - Asociality, Attention. The total range of the SANS is from 0 to 120.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Analyzed intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	44.3 (5.9)	38.5 (5.8)

4. Primary Outcome

Title	Scale for the Assessment of Negative Symptoms (SANS)
Description	The Scale for the Assessment of Negative Symptoms (SANS) is a rating scale to measure negative symptoms in schizophrenia. The scale has 25 items (20 individual and 5 global) rated on scale of 0-5 (higher rating: greater severity). SANS is split into 5 domains, and within each domain separate symptoms are rated from 0 (absent) to 5 (severe). Domains include: Affective Flattening or Blunting, Alogia, Avolition - Apathy, Anhedonia - Asociality, Attention. The total range of the SANS is from 0 to 120.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Analyzed intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	36.3 (5.9)	37.3 (5.9)

5. Secondary Outcome

Title	CGI Severity of Illness Scale (CGI-S)
Description	CGI Severity of Illness Scale (CGI-S) assesses severity of illness on 1-7 scale. Clinicians' experience is used to gauge the severity of illness from 'normal' (value=1) to 'among the most extremely ill patients' (value=7). The higher rating correlates with more severely ill.
Time Frame	baseline

Outcome Measure Data

Analysis Population Description

Analyzes intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	4.1 (0.5)	4.0 (0.9)

6. Secondary Outcome

Title	CGI Severity of Illness Scale (CGI-S)
Description	CGI Severity of Illness Scale (CGI-S) assesses severity of illness on 1-7 scale. Clinicians' experience is used to gauge the severity of illness from 'normal' (value=1) to 'among the most extremely ill patients' (value=7). The higher rating correlates with more severely ill.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Analyzed intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	3.9 (0.8)	3.9 (0.5)

7. Secondary Outcome

Title	CGI Improvement Scale (CGI-I)
Description	CGI Improvement Scale (CGI-I) higher rating correlates with worsening of condition (vs. improvement with lower rating). The CGI-I is scored from 1 to 7 where 1 = 'very much improved' and 7 = 'very much worse'. Clinicians are asked to rate total improvement in the following manner: "...in your judgement, it is due entirely to drug treatment. Compared to his condition at admission to the project, how much has he changed?"
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Analyzed intent to treat.

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Least Squares Mean (Standard Error); Unit of Measure: units on a scale
	2.8 (1.0)	3.4 (0.5)

8. Secondary Outcome

Title	Verbal Fluency
Description	Verbal fluency was measured using the Controlled Word Association Test (COWAT). There is no range for this measure, as it is not a scale. The subjects can generate as many new words as they can, so there is no maximum. The greater the number of words one generates indicates better performance.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: words
	12.2 (1.4)	10.5 (1.5)

9. Secondary Outcome

Title	Verbal Fluency
Description	Verbal fluency was measured using the Controlled Word Association Test (COWAT). There is no range for this measure, as it is not a scale. The subjects can generate as many new words as they can, so there is no maximum. The greater the number of words one generates indicates better performance.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: words
	12.3 (1.5)	11.1 (1.5)

10. Secondary Outcome

Title	QTc
Description	The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart. ECG machines calculate a corrected QT (QTc). QTc is the corrected QT interval in the EKG. Normal range is from 430-470ms.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: ms
	408.8 (5.0)	412.3 (5.1)

11. Secondary Outcome

Title	QTc
Description	The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart. ECG machines calculate a corrected QT (QTc). QTc is the corrected QT interval in the EKG. Normal range is from 430-470ms.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intention to Treat

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: ms
	412.9 (5.0)	420.3 (5.2)

12. Secondary Outcome

Title	Processing Speed
Description	Processing speed was assessed using using Digit Symbol Coding from the Wechsler Adult Intelligence Scale, Revised (WAIS-R). The tool is used for the assessment of processing speed. The range of scores is 0 to 100- with the higher number indicating greater performance.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: units on a scale
	48.8 (4.6)	43.3 (4.9)

13. Secondary Outcome

Title	Processing Speed
Description	Processing speed was assessed using using Digit Symbol Coding from the Wechsler Adult Intelligence Scale, Revised (WAIS-R). The tool is used for the assessment of processing speed. The range of scores is 0 to 100- with the higher number indicating greater performance.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: units on a scale
	46.5 (4.7)	42.8 (5.0)

14. Secondary Outcome

Title	Verbal Learning and Memory: List A
Description	Verbal learning and memory were assessed by the Rey Auditory Verbal Learning Test (RAVLT) List A: Total Trials (1-5). This assessment consists of a list of words that the subject repeats back, it does not have an interpret-able range of scores like a traditional scale. Scores are based on number of words repeated back.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: words
	40.0 (3.3)	26.5 (2.8)

15. Secondary Outcome

Title	Verbal Learning and Memory: List A
Description	Verbal learning and memory were assessed by the Rey Auditory Verbal Learning Test (RAVLT) List A: Total Trials (1-5). This assessment consists of a list of words that the subject repeats back, it does not have an interpret-able range of scores like a traditional scale. Scores are based on number of words repeated back.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: words
	38.0 (4.8)	32.3 (4.2)

16. Secondary Outcome

Title	Verbal Learning and Memory: List B
Description	Verbal learning and memory were assessed by the Rey Auditory Verbal Learning Test (RAVLT) List B: Single Trial. This assessment consists of a list of words that the subject repeats back, it does not have an interpret-able range of scores like a traditional scale. Scores are based on number of words repeated back.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: words
	3.8 (0.4)	3.5 (0.4)

17. Secondary Outcome

Title	Verbal Learning and Memory: List B
Description	Verbal learning and memory were assessed by the Rey Auditory Verbal Learning Test (RAVLT) List B: Single Trial. This assessment consists of a list of words that the subject repeats back, it does not have an interpret-able range of scores like a traditional scale. Scores are based on number of words repeated back.
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: words
	3.4 (0.6)	3.9 (0.6)

18. Secondary Outcome

Title	Trail Making Test: Trail A
Description	Working memory by Digit Span and Letter Number Sequencing, and attention/executive functions were measured by the Trail Making Test (Parts A and B). This is an assessment of attention/executive function, it does not have an interpret-able range of scores like a traditional scale. Subjects makes trails on paper against time.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: seconds
	3.7 (0.1)	3.8 (0.1)

19. Secondary Outcome

Title	Trail Making Test: Trail A
Description	The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy. ( Arnett, James A.; Seth S. Labovitz (1995). "Effect of physical layout in performance of the Trail Making Test". Psychological Assessment 7 (2): 220-221. doi:10.1037/1040-3590.7.2.220. Retrieved 2012-02-22.) Part A is used primarily to examine cognitive processing speed. Part B, in which the subject alternates between numbers and letters, is used to examine executive functioning. (Tombaugh, T.N.T.N (2004). "Trail Making test A and B: Normative Data Stratified by Age and Education". Archives of Clinical Neuropsychology : The Official Journal of the National Academy of Neuropsychologists 19 (2): 203-214. doi:10.1016/s0887-6177(03)00039-8. Retrieved 2012-01-10.)
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: seconds
	3.6 (0.1)	3.8 (0.1)

20. Secondary Outcome

Title	Trail Making Test: Trail B
Description	The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy. ( Arnett, James A.; Seth S. Labovitz (1995). "Effect of physical layout in performance of the Trail Making Test". Psychological Assessment 7 (2): 220-221. doi:10.1037/1040-3590.7.2.220. Retrieved 2012-02-22.) Part A is used primarily to examine cognitive processing speed. Part B, in which the subject alternates between numbers and letters, is used to examine executive functioning. (Tombaugh, T.N.T.N (2004). "Trail Making test A and B: Normative Data Stratified by Age and Education". Archives of Clinical Neuropsychology : The Official Journal of the National Academy of Neuropsychologists 19 (2): 203-214. doi:10.1016/s0887-6177(03)00039-8. Retrieved 2012-01-10.)
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: seconds
	4.6 (0.2)	4.9 (0.2)

21. Secondary Outcome

Title	Trail Making Test: Trail B
Description	The Trail Making Test is a neuropsychological test of visual attention and task switching. It consists of two parts in which the subject is instructed to connect a set of 25 dots as fast as possible while still maintaining accuracy. ( Arnett, James A.; Seth S. Labovitz (1995). "Effect of physical layout in performance of the Trail Making Test". Psychological Assessment 7 (2): 220-221. doi:10.1037/1040-3590.7.2.220. Retrieved 2012-02-22.) Part A is used primarily to examine cognitive processing speed. Part B, in which the subject alternates between numbers and letters, is used to examine executive functioning. (Tombaugh, T.N.T.N (2004). "Trail Making test A and B: Normative Data Stratified by Age and Education". Archives of Clinical Neuropsychology : The Official Journal of the National Academy of Neuropsychologists 19 (2): 203-214. doi:10.1016/s0887-6177(03)00039-8. Retrieved 2012-01-10.)
Time Frame	Endpoint (12 weeks)

Outcome Measure Data

Analysis Population Description

Intent to Treat Analysis

Arm/Group Title	Placebo Pimozide	Active Pimozide
Arm/Group Description:	Half of the subjects were randomized to placebo group.	Half of the subjects are randomized to the active drug.
Overall Number of Participants Analyzed	14	14
Mean (Standard Deviation); Unit of Measure: seconds
	4.6 (0.2)	4.9 (0.2)

Adverse Events

Time Frame	[Not Specified]
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Placebo Pimozide		Active Pimozide
Arm/Group Description	Half of the subjects were randomized to placebo group.		Half of the subjects are randomized to the active drug.
All-Cause Mortality
	Placebo Pimozide		Active Pimozide
	Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--
Serious Adverse Events
	Placebo Pimozide		Active Pimozide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0.00%)		0/14 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo Pimozide		Active Pimozide
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.14%)		1/14 (7.14%)
Cardiac disorders
QTc Prolongation	1/14 (7.14%)	1	1/14 (7.14%)	1

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

Results Point of Contact

• Name/Title: Handan Gunduz-Bruce MD
• Organization: Yale University School of Medicine, Dept of Psychiatry
• Phone: (203) 932-5711 ext 4130
• EMail: handan.gunduz-bruce@yale.edu

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT00374244
• Other Study ID Numbers: 02T-251
• First Submitted: September 7, 2006
• First Posted: September 11, 2006
• Results First Submitted: January 10, 2013
• Results First Posted: March 4, 2016
• Last Update Posted: March 4, 2016