Varenicline Adjunctive Treatment in Schizophrenia

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT00492349
• Collaborator: Stanley Medical Research Institute (Other)
• Enrollment: 91
• Locations: 3
• Arms: 2
• Duration (Months): 47
• Patients Per Site: 30.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The principal aim of the project is to conduct an off-label adjunctive clinical trial evaluating varenicline as a treatment for core neurobiological and clinical deficits in schizophrenia, in addition to evaluating for smoking cessation in schizophrenia patients.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Schizoaffective Disorder; Schizophreniform Disorder	Drug: Varenicline; Drug: Placebo	Phase 4

Detailed Description

This is a double-blind, placebo controlled clinical trial in schizophrenia patients. Outcome measures include biomarkers and clinical symptoms and functions, and smoking cessation. Neurobiological and cognitive markers will be measured for short term (2 weeks) and longer-term (8 weeks). Current schizophrenia treatments are mostly ineffective against primary negative symptoms and the cognitive and information processing deficits associated with the disorder. Previous research has identified several neurophysiological deficits in schizophrenia that are enduring, frequently occurring before psychosis, and mark the disease liability. These schizophrenia endophenotypes provide important targets for novel treatment development as they represent the core deficits of the disorder. We hypothesize that sustained nicotinic and dopaminergic modulation by varenicline may ameliorate the core neurobiological deficits seen in schizophrenia patients, which would lead to subsequent clinical improvement. Neurobiological and neurocognitive markers and clinical and functional measures will be obtained to determine 1) short-term effect of varenicline on biomarkers; and 2) longer-term improvement in clinical symptoms, smoking cessation, and functions; and how biomarker changes predict these improvements.

Study Design

• Study Type: Interventional
• Actual Enrollment: 91 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Varenicline Adjunctive Treatment in Schizophrenia
• Study Start Date: May 1, 2007
• Actual Primary Completion Date: May 1, 2010
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Varenicline	Drug: Varenicline; Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks; Other Names: Chantix
Placebo Comparator: 2 Placebo	Drug: Placebo; Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks

Outcome Measures

Primary Outcome Measures

1. Hamilton Depression Rating Scale (Ham-D) [Week 8]

   Ham-D Total Score (range 0 to 54, higher score is worse). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

2. Memory Saccadic Positional Error, Degrees [Week 8]

   A saccade is a quick eye movement. Spatial working memory was assessed by memory saccade. Participants were asked to focus on a target while a peripheral cue was flashed. Participants were signaled to look in the direction of the peripheral cue when the central target was removed, and the positional error was calculated as the distance between the saccadic and peripheral target positions. Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

3. Predictive Pursuit Gain [Week 8]

   Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Participants are asked to track a target with their eyes. Participants may use a predictive mechanism to perform the tracking. The pursuit gain using the predictive mechanism is calculated. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

4. Maintenance Pursuit Gain [Week 8]

   Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Eye velocity during the regular eye-tracking period (without foveal stabilization) divided by target velocity was used to calculate the maintenance pursuit gain. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

5. Digit Symbol Test [Week 0, Week 2 and Week 8]

   Digit symbol test score (0 to no definite upper range, higher score is better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

6. Conner's Continuous Performance Test (CPT) Detectability Score [Week 0, Week 2 and Week 8]

   Conner's CPT Detectability Score (no set normal range, higher is generally better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

7. Antisaccade Error Rates [Week 0, Week 2 and Week 8]

   In antisaccade, participants were asked to focus on a central target. When a peripheral cue was presented, participants were asked to look in an equidistant and opposite direction of the peripheral cue. The error rate is calculated as the number of trials in which the participant looked toward the cue, rather than in the opposite direction, divided by the total number of trials. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

8. P50 [Week 0, Week 2 and Week 8]

   P50 response is a measure of the amplitude of the brain wave in response to a sound, where the positive going amplitude of the brain wave occurring at about 50 milliseconds after the sound. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18-60

• DSM-IV Diagnosis of schizophrenia, schizoaffective disorder, or schizophreniform disorder

• Clinically stable with no change in antipsychotic medications and increase of daily dose for 4 weeks prior to enrollment

• Sufficient understanding of the study and risks (ESC score 10 or above)

Exclusion Criteria:

• Major medical illness history including, but not limited to, history of heart attack, stroke, TIA (transient ischemic attack)

• History of organic brain disorders that may affect neurophysiological measurements, including seizure disorder, brain tumor, head injury with evidence of significant cognitive deterioration

• DSM-IV diagnosis of substance dependence within 6 months except nicotine and marijuana

• On nicotine replacement therapy (nicotine patch, gum, or nasal spray)

• Uncontrolled blood pressure (persistent systolic above 155 or diastolic above 95)

• EKG of second or third degree atrioventricular (AV) block

• Renal insufficiency with estimated creatinine clearance <40 ml/min

• Women who have positive urine pregnancy tests

• Women who are pregnant, plan to become pregnant, or in breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UMB School of Medicine	Baltimore	Maryland	United States	21201
2	University of Maryland Medical System	Baltimore	Maryland	United States	21201
3	Maryland Psychiatric Research Center	Baltimore	Maryland	United States	21228

Sponsors and Collaborators

• University of Maryland, Baltimore
• Stanley Medical Research Institute

Investigators

• Principal Investigator: L. Elliot Hong, M.D., Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for more information about the study: Varenicline Adjunctive Treatment in Schizophrenia

Publications

None provided.

• Responsible Party: L. Elliot Hong, Principal Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT00492349
• Other Study ID Numbers: HP-00040322
• First Posted: Jun 27, 2007
• Last Update Posted: Jan 5, 2022
• Last Verified: Dec 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by L. Elliot Hong, Principal Investigator, University of Maryland, Baltimore: Varenicline; Neurobiology; clinical trial; cognitive deficits; Schizophreniform Disorder
• Additional relevant MeSH terms: Disease; Schizophrenia; Psychotic Disorders; Varenicline

Study Results

Participant Flow

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline Treatment Group	Placebo Control Group
Period Title: Overall Study
STARTED	35	34
Week 2	32	33
Week 8	32	27
COMPLETED	32	27
NOT COMPLETED	3	7

Baseline Characteristics

Arm/Group Title	Varenicline	Placebo	Total
Arm/Group Description	Total of all reporting groups
Overall Participants	35	34	69
Age (years) [Mean (Standard Deviation) ]
Smoker	43.0 (2.5)	41.5 (2.5)	42.2 (2.5)
Non-Smoker	45.7 (2.6)	42.1 (3.2)	43.9 (2.8)
Sex: Female, Male (Count of Participants)
Female	12 34.3%	10 29.4%	22 31.9%
Male	23 65.7%	24 70.6%	47 68.1%
Region of Enrollment (participants) [Number]
United States	35 100%	34 100%	69 100%
BPRS Total (units on a scale) [Mean (Standard Deviation) ]
Smoker	36.2 (1.9)	35.0 (2.0)	35.6 (1.9)
Non-Smoker	31.2 (2.0)	34.0 (2.5)	32.6 (2.2)
Ham-D Total Score (units on a scale) [Mean (Standard Deviation) ]
Smoker	5.0 (0.9)	5.76 (1.15)	5.38 (1.0)
Nonsmoker	5.2 (0.7)	6.6 (1.0)	5.8 (0.8)

Outcome Measures

1. Primary Outcome

Title	Hamilton Depression Rating Scale (Ham-D)
Description	Ham-D Total Score (range 0 to 54, higher score is worse). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline: Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks	Placebo: Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Measure Participants	32	27
Smoker	22.9 (3.2)	20.6 (3.4)
Nonsmoker	19.4 (3.2)	18.6 (2.2)

2. Primary Outcome

Title	Memory Saccadic Positional Error, Degrees
Description	A saccade is a quick eye movement. Spatial working memory was assessed by memory saccade. Participants were asked to focus on a target while a peripheral cue was flashed. Participants were signaled to look in the direction of the peripheral cue when the central target was removed, and the positional error was calculated as the distance between the saccadic and peripheral target positions. Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline: Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks	Placebo: Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Measure Participants	32	27
Smoker	1.6 (0.2)	1.7 (0.2)
Nonsmoker	1.7 (0.1)	1.8 (0.2)

3. Primary Outcome

Title	Predictive Pursuit Gain
Description	Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Participants are asked to track a target with their eyes. Participants may use a predictive mechanism to perform the tracking. The pursuit gain using the predictive mechanism is calculated. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline: Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks	Placebo: Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Measure Participants	32	27
Smoker	0.31 (0.03)	0.34 (0.04)
Nonsmoker	0.24 (0.04)	0.31 (0.04)

4. Primary Outcome

Title	Maintenance Pursuit Gain
Description	Pursuit gain is the averaged artifact-free eye velocity divided by target velocity. Eye velocity during the regular eye-tracking period (without foveal stabilization) divided by target velocity was used to calculate the maintenance pursuit gain. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline: Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks	Placebo: Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Measure Participants	32	27
Smoker	0.8 (0.1)	0.8 (0.04)
Nonsmoker	0.8 (0.1)	0.8 (0.1)

5. Primary Outcome

Title	Digit Symbol Test
Description	Digit symbol test score (0 to no definite upper range, higher score is better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 0, Week 2 and Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline Varenicline: Varenicline 0.5mg po qd x 7 days then titrated to Varenicline 0.5mg po bid x 7 weeks	Placebo Placebo: Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Measure Participants	28	28
Week 0	53.9 (19.3)	53.2 (19.1)
Week 2	55.9 (19.0)	53.8 (20.6)
Week 8	54.2 (20.3)	54.3 (21.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Varenicline, Placebo
	Comments	Mixed model ANCOVA in which baseline served as the covariate and Smoking status and measurement occasions were between and within-groups factors, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

6. Primary Outcome

Title	Conner's Continuous Performance Test (CPT) Detectability Score
Description	Conner's CPT Detectability Score (no set normal range, higher is generally better). Definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 0, Week 2 and Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline	Placebo
Measure Participants	30	26
Week 0	0.87 (0.38)	0.87 (0.50)
Week 2	0.89 (0.42)	0.97 (0.54)
Week 8	0.95 (0.48)	0.97 (0.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Varenicline, Placebo
	Comments	Mixed model ANCOVA in which baseline CPT Detectability served as the covariate and Smoking status and measurement occasions were between and within-groups factors, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	All treatment main and interaction effect p-values were > 0.05.
	Method	ANCOVA
	Comments

7. Primary Outcome

Title	Antisaccade Error Rates
Description	In antisaccade, participants were asked to focus on a central target. When a peripheral cue was presented, participants were asked to look in an equidistant and opposite direction of the peripheral cue. The error rate is calculated as the number of trials in which the participant looked toward the cue, rather than in the opposite direction, divided by the total number of trials. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 0, Week 2 and Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline	Placebo Placebo: Placebo 0.5mg po qd x 7 days then titrated to Placebo 0.5mg po bid x 7 weeks
Measure Participants	31	27
Week 0	0.61 (0.27)	0.54 (0.27)
Week 2	0.49 (0.27)	0.54 (0.26)
Week 8	0.45 (0.26)	0.53 (0.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Varenicline, Placebo
	Comments	Mixed model ANCOVA in which baseline Antisaccade Errors served as the covariate and Smoking status and measurement occasions were between and within-groups factors, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	ANCOVA
	Comments

8. Primary Outcome

Title	P50
Description	P50 response is a measure of the amplitude of the brain wave in response to a sound, where the positive going amplitude of the brain wave occurring at about 50 milliseconds after the sound. Further definition is fully described in a peer-review journal reported at Arch Gen Psychiatry 2011 Dec;68(12):1195-206.
Time Frame	Week 0, Week 2 and Week 8

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Varenicline	Placebo
Arm/Group Description	Varenicline	Placebo
Measure Participants	31	32
Week 0	3.2 (0.73)	3.1 (.71)
Week 2	3.2 (0.75)	3.0 (.72)
Week 8	3.2 (0.6)	2.5 (.77)

Adverse Events

Arm/Group Title	Varenicline		Placebo
Arm/Group Description	Varenicline		Placebo
All Cause Mortality
	Varenicline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Varenicline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Varenicline		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/35 (0%)		0/34 (0%)

Limitations/Caveats

The small number of nonsmokers in the placebo arm could have led to reduced power and false negatives.

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.