SEAMS: Systematic Evaluation of Antiviral Medication in Schizophrenia

• Sponsor: Konasale Prasad (Other)
• Overall Status: Completed
• CT.gov ID: NCT00514449
• Collaborator: Stanley Medical Research Institute (Other), Wayne State University (Other)
• Enrollment: 31
• Locations: 2
• Arms: 2
• Duration (Months): 111
• Patients Per Site: 15.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to examine whether antiviral medication will help improve psychotic symptoms and cognition in individuals early in the course of schizophrenia or schizoaffective disorder who are exposed to herpes simplex virus, type 1 (HSV 1), a virus that causes commonly occurring and recurrent cold sores.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia; Schizoaffective Disorder	Drug: Valacyclovir; Drug: Placebo	Phase 2

Detailed Description

The main objective of the study is to evaluate the efficacy of add-on treatment of Valacyclovir (VAV), an antiviral medication, in the treatment of early course schizophrenia/schizoaffective disorder patients. Our main hypothesis is that the VAV add-on treatment will improve positive, negative and cognitive symptoms in herpes simplex virus (HSV) positive schizophrenia or schizoaffective disorder patients. We hypothesize that the grey matter reductions in specific brain regions (such as prefrontal regions) will improve in patients on VAV + antipsychotic compared to those on placebo + antipsychotic and the improvements in positive, negative and cognitive symptoms will be correlated with the grey matter changes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 31 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized Double-blind Controlled Trial of Valacyclovir Add-on Treatment of HSV Positive Early Course Schizophrenia Patients
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Sep 1, 2016
• Actual Study Completion Date: Sep 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Valacyclovir 1 gram pill taken twice a day for 2 weeks, after 2 weeks it increased to 1.5 gram pill taken twice a day for 16 weeks.	Drug: Valacyclovir; 1 g PO BID x 2 weeks after 2 weeks it goes up to 1.5 g PO BID x 16 weeks along with antipsychotic
Placebo Comparator: Sugar pill 2 placebo pills taken twice a day for 2 weeks, after 2 weeks 3 pills taken twice a day for 16 weeks.	Drug: Placebo; 2 pills twice a day x 2 weeks, after 2 weeks 3 pills twice a day x 16 weeks along with antipsychotic

Outcome Measures

Primary Outcome Measures

1. PANSS Positive and Negative Syndrome Scale for Schizophrenia [Baseline, Weeks 2, 4, 6, 10, 14, 18]

   This is a structured measure of severity of psychopathology that includes both positive and negative symptoms. The range is a minimum score of 30 and the maximum is 210. The lower scores suggest milder severity of illness domains.

2. Cognitive Function Neuropsychological Battery (Gur Battery) [Baseline, Week 18]

   All results are given as the mean difference between an 18 week follow-up and the baseline battery administrations.This is a computerized test that measures both accuracy and response times. A range for response times is not available because of individual variabilities. Accuracy scores can vary for each test: Working memory accuracy range was 0-16. Verbal memory accuracy range was 0-20. For both, the higher the score the better. No cut offs are available

Secondary Outcome Measures

1. Changes in Grey Matter Deficit [Baseline, Week 18]

   Gray matter volume changes (in cc) were measured using structural MRI. Changes were reported as gray matter volume in cc. Note: Assessment of blood oxygenation level dependent (BOLD) changes using fMRI were erroneously included in the original study record.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Both genders between the ages of 18-50 years

• Schizophrenia or schizoaffective disorder as defined in DSM-IV

• Duration of illness 10 years or less

• On a stable dose of an antipsychotic medication for at least a month

• Should score 4 or more on at least one of the subscales of PANSS

• Positive for HSV1

• Written informed consent

Exclusion Criteria:

• Substance abuse in the last month/dependence 6 months prior to the study

• History of, or current medical/neurological illnesses which affects CNS function e.g., epilepsy, head injury with prolonged loss of consciousness

• Pregnancy

• History of immune disorders, HIV infection or currently receiving immunosuppressants

• Subjects on regular antiviral therapy

• History of hypersensitivity to Valacyclovir

• Mental retardation as defined in DSM-IV

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wayne State University	Detroit	Michigan	United States	48201
2	Western Psychiatric Institute and Clinic	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Konasale Prasad
• Stanley Medical Research Institute
• Wayne State University

Investigators

• Principal Investigator: Konasale Prasad, MD, Western Psychiatric Institute and Clinic
• Principal Investigator: Vishwajit Nimgaonkar, MD, PhD, Western Psychiatric Institute and Clinic
• Principal Investigator: Matcheri Keshavan, MD, Wayne State University
• Principal Investigator: Rajaprabhakaran Rajarethinam, MD, Wayne State University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Prasad KM, Shirts BH, Yolken RH, Keshavan MS, Nimgaonkar VL. Brain morphological changes associated with exposure to HSV1 in first-episode schizophrenia. Mol Psychiatry. 2007 Jan;12(1):105-13, 1. Epub 2006 Oct 10.

• Responsible Party: Konasale Prasad, Assistant Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT00514449
• Other Study ID Numbers: 0602032
• First Posted: Aug 10, 2007
• Last Update Posted: Jun 14, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Schizophrenia; Psychotic Disorders; Valacyclovir

Study Results

Participant Flow

Recruitment Details	Subjects were recruited between 7/2007 and 8/2009 at two separate sites, Pittsburgh and Detroit. Recruitment took place through the local hospital and community mental health and school counseling centers, as well as other research studies and area mental health conferences.
Pre-assignment Detail	Patients first had a placebo run-in for two weeks along with the psychiatric medications they were on and then randomized at Week 2 to either VAV or placebo group. Enrolled subjects were excluded due to cannabis abuse, claustrophobia, and a duration of illness that was too long.

Arm/Group Title	Valacyclovir	Sugar Pill
Arm/Group Description	1 gram pill taken twice a day for 2 weeks, after 2 weeks it increased to 1.5 gram pill taken twice a day for 16 weeks.	2 placebo pills taken twice a day for 2 weeks, after 2 weeks 3 pills taken twice a day for 16 weeks.
Period Title: Overall Study
STARTED	12	12
COMPLETED	9	8
NOT COMPLETED	3	4

Baseline Characteristics

Arm/Group Title	Valacyclovir	Sugar Pill	Total
Arm/Group Description	1 gram pill taken twice a day for 2 weeks, after 2 weeks it increased to 1.5 gram pill taken twice a day for 16 weeks.	2 placebo pills taken twice a day for 2 weeks, after 2 weeks 3 pills taken twice a day for 16 weeks.	Total of all reporting groups
Overall Participants	12	12	24
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	12 100%	12 100%	24 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.6 (9.4)	28.7 (8.5)	29.2 (8.8)
Sex: Female, Male (Count of Participants)
Female	6 50%	5 41.7%	11 45.8%
Male	6 50%	7 58.3%	13 54.2%
Region of Enrollment (participants) [Number]
United States	12 100%	12 100%	24 100%

Outcome Measures

1. Primary Outcome

Title	PANSS Positive and Negative Syndrome Scale for Schizophrenia
Description	This is a structured measure of severity of psychopathology that includes both positive and negative symptoms. The range is a minimum score of 30 and the maximum is 210. The lower scores suggest milder severity of illness domains.
Time Frame	Baseline, Weeks 2, 4, 6, 10, 14, 18

Outcome Measure Data

Analysis Population Description

Comparative analysis of active drug versus placebo

Arm/Group Title	Valacyclovir	Sugar Pill
Arm/Group Description	1 gram pill taken twice a day for 2 weeks, after 2 weeks it increased to 1.5 gram pill taken twice a day for 16 weeks	2 placebo pills taken twice a day for 2 weeks, after 2 weeks 3 pills taken twice a day for 16 weeks.
Measure Participants	12	12
Scores at Baseline of the trial	70.08 (12.616)	83.92 (13.895)
Scores at week 2 of the trial	72.25 (11.450)	77 (14.917)
Scores at week 4 of the trial	67.36 (12.314)	75.2 (13.998)
Scores at week 6 of the trial	65.583 (9.228)	74.3 (16.275)
Scores at week 10 of the trial	65.2 (10.737)	73.2 (12.044)
Scores at week 14 of the trial	57.1 (12.511)	69.6 (14.886)
Scores at the end of the trial	56.5 (9.289)	67.125 (13.726)

2. Primary Outcome

Title	Cognitive Function Neuropsychological Battery (Gur Battery)
Description	All results are given as the mean difference between an 18 week follow-up and the baseline battery administrations.This is a computerized test that measures both accuracy and response times. A range for response times is not available because of individual variabilities. Accuracy scores can vary for each test: Working memory accuracy range was 0-16. Verbal memory accuracy range was 0-20. For both, the higher the score the better. No cut offs are available
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valacyclovir	Sugar Pill
Arm/Group Description	1 gram pill taken twice a day for 2 weeks, after 2 weeks it increased to 1.5 gram pill taken twice a day for 16 weeks.	2 placebo pills taken twice a day for 2 weeks, after 2 weeks 3 pills taken twice a day for 16 weeks.
Measure Participants	12	12
Working Memory: 2-Back Test Accuracy	2.13 (2.68)	0.13 (2.9)
Immediate Verbal Memory Reaction Accuracy	2.44 (2.62)	-0.49 (3.11)

3. Secondary Outcome

Title	Changes in Grey Matter Deficit
Description	Gray matter volume changes (in cc) were measured using structural MRI. Changes were reported as gray matter volume in cc. Note: Assessment of blood oxygenation level dependent (BOLD) changes using fMRI were erroneously included in the original study record.
Time Frame	Baseline, Week 18

Outcome Measure Data

Analysis Population Description

Analysis included on all participants on whom baseline and week 18 data were collected. Valacyclovir and placebo groups

Arm/Group Title	Valacyclovir	Sugar Pill
Arm/Group Description	A time by treatment group interaction showed increased gray matter volume estimated as number of voxels in a cluster with Valaclcovir compared to placebo	A time by treatment group interaction showed decreased or no significant change in the gray matter volume estimated as number of voxels in a cluster with Valaclcovir compared to placebo
Measure Participants	9	8
Mean (Standard Deviation) [cm^3]	26.83 (5.04)	24.22 (2.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valacyclovir, Sugar Pill
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p value is adjusted for multiple comparisons
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	number of voxels in a cluster
	Estimated Value	2037
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments	Time by treatment group interaction term

Adverse Events

Time Frame	2, 4, 6, 10, 14, and 18 weeks.
Arm/Group Title	Valacyclovir		Sugar Pill
Arm/Group Description	1 gram pill taken twice a day for 2 weeks, after 2 weeks it increased to 1.5 gram pill taken twice a day for 16 weeks.		2 placebo pills taken twice a day for 2 weeks, after 2 weeks 3 pills taken twice a day for 16 weeks.
All Cause Mortality
	Valacyclovir		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Valacyclovir		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Valacyclovir		Sugar Pill
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/12 (41.7%)		6/12 (50%)
Gastrointestinal disorders
Stomach Bloating	0/12 (0%)	0	1/12 (8.3%)	1
Constipation	1/12 (8.3%)	1	0/12 (0%)	0
Stomach Pain	1/12 (8.3%)	1	0/12 (0%)	0
General disorders
Fatigue	0/12 (0%)	0	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Pain in Elbow when Extended	0/12 (0%)	0	1/12 (8.3%)	1
Leg Cramps	0/12 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
Motion Sickness	1/12 (8.3%)	1	0/12 (0%)	0
Tongue Twitch	1/12 (8.3%)	1	0/12 (0%)	0
Slight Tremor	1/12 (8.3%)	1	0/12 (0%)	0
Psychiatric disorders
Mild Extrapyramidal Symptoms	0/12 (0%)	0	1/12 (8.3%)	1
Increased Sexual Drive	0/12 (0%)	0	1/12 (8.3%)	1
Insomnia	0/12 (0%)	0	1/12 (8.3%)	1

Limitations/Caveats

This was a small sample study designed as a proof of concept. A larger study will follow.

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.