A Double-Blind Trial of Adjunctive Valacyclovir to Improve Cognition in Early Phase Schizophrenia

Study Overview
=================
Brief Summary
-----------------
The primary aim of the study is to determine the efficacy of adjunctive valacyclovir, in comparison to placebo, to improve visual (Brief Visuospatial Memory Test) and working (composite score of the Spatial Span and Letter Number Span tests) memory in individuals who are HSV-1 positive and early in the course of schizophrenia. We hypothesize that individuals who are HSV-1 positive, but not those who are HSV-1 negative, will demonstrate significant valacyclovir efficacy for visual and working memory.

Detailed Description
-----------------
One hundred and seventy-five participants (N=70 HSV-1 seropositive and N=105 HSV-1 seronegative) will be randomized 1:1 to receive adjunctive valacyclovir or adjunctive placebo for a 16 week period. The primary outcome that will be assessed is improvement in changes in visual and working memory scores in HSV-1 positive and negative participants over the course of the study. We will also measure the overall cognitive functioning and the severity of psychiatric symptoms over the course of the study and will evaluate the tolerability and safety of valacyclovir treatment in this population. In addition, we will explore the relationship between changes in the levels of inflammatory markers (HSV2, CMV, EBV, CRP, and Toxoplasmosis) and treatment response over the course of the study.

Official Title
-----------------
A Double-Blind Trial of Adjunctive Valacyclovir to Improve Cognition in Early Phase Schizophrenia

Conditions
-----------------
Schizophrenia

Intervention / Treatment
-----------------
* Drug: Valacyclovir HCI 500 mg tablets
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18 to 40 years of age at study entry. Able to give written informed consent. DSM IV-TR Diagnosis of schizophrenia, schizophreniform, or schizoaffective disorder as confirmed by Structured Clinical Interview for DSM-IV-TR (SCID) Onset of schizophreniform disorder, schizophrenia, or schizoaffective disorder within the past eight years as defined by first medical records documentation of these conditions Outpatient or inpatient. Clinical stability as defined by: CGI-S score of less than or equal to 4 (moderately ill) at randomization AND Participants must not have experienced an exacerbation of their illness within 4 weeks prior to randomization leading to an intensification of psychiatric care in the opinion of the investigator. Examples of intensification of care include, but are not limited to: inpatient hospitalization, day/partial hospitalization, outpatient crisis management, or psychiatric treatment in an emergency room AND Antipsychotic treatment stability for at least 4 weeks prior to randomization (no change in antipsychotic dosing, addition of any new antipsychotic medication, or discontinuing an antipsychotic medication) Fluent in English. Female participants of childbearing potential must test negative for pregnancy at screening visit and agree to use a single, effective, medically acceptable method of birth control for the duration of the study. Exclusion Criteria: Known IQ less than 70 as determined by medical history. IV drug use within previous three month prior to study entry. Any serious active medical condition that affects brain or cognitive functioning (e.g., epilepsy, serious head injury, brain tumor or other neurological disorder) in the investigator's opinion. Known medical history of Human Immunodeficiency Virus (HIV) Receipt of valacyclovir or chemically-related medication within 2 weeks prior to randomization. History of hypersensitivity to valacyclovir or acyclovir as determined by self-report and medical history. DSM-IV diagnosis of substance dependence within 3 months of study entry (with the exception of nicotine or caffeine dependence). Participants who have participated in a clinical trial with any pharmacological treatment intervention for which they received study-related medication in the 4 weeks prior to screening AND participants currently receiving treatment (within 1 dosing interval plus 4 weeks) with an investigational depot formulation of an antipsychotic medication. Females who are pregnant or planning to become pregnant or breastfeeding or planning to do so during the study period. Participants with current acute, serious, or unstable medical conditions, including, but not limited to: inadequately controlled diabetes, asthma, COPD, recent cerebrovascular accidents, acute systemic infection or immunologic disease, unstable cardiovascular disorders, malnutrition, or hepatic or renal disease, renal including renal failure, gastroenterologic, respiratory, endocrinologic, neurologic, hematologic including thrombotic thrombocytopenia purpura/hemolytic uremic syndrome, or infectious diseases Participants who require concomitant treatment with any other medication other than those allowed as specified in Attachment 2, or with any other medication specifically excluded in Attachment 2. Clinically significant electrocardiogram (ECG) abnormality prior to randomization as defined by: participants with a corrected QT interval (Bazett's; QTcB) >450 msec (male) or >470 msec (female) prior to randomization. Repeat ECGs will be conducted at the discretion of the principal investigator or medical designee. Test positive for (1) Hepatitis C virus antibody, (2) Hepatitis B surface antigen (HBsAg) with or without positive Hepatitis B core total antibody. Participants with moderate to severe renal impairment as defined by creatinine clearance (CrCl) < 60 ml/min (measured by the Cockcroft-Gault equation) at screening. Participants with hepatic impairment as defined by liver transaminases or total bilirubin > 3 × upper limit of normal (ULN). Participants considered a high risk for suicidal acts - active suicidal ideation as determined by clinical interview OR any suicide attempt in 90 days prior to screening. Participants who demonstrate overtly aggressive behavior or who are deemed to pose a homicidal risk in the investigator's opinion. Participants currently receiving cognitive remediation therapy at time of study entry Participants who have had electroconvulsive therapy (ECT) within 12 months of study entry or who will have ECT at any time during the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: valacyclovir<br>3000mg daily oral 16 weeks | Drug: Valacyclovir HCI 500 mg tablets<br>* Valacyclovir HCI 500 mg capsules 6/day oral for 16 weeks<br>|
| Placebo Comparator: placebo<br>placebo 6 capsules daily oral 16 weeks | Drug: placebo<br>* placebo capsules 6/day oral for 16 weeks<br>* Other names: placebo capsules;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Visual Memory | To determine the efficacy of adjunctive valacyclovir, in comparison to placebo, to improve visual memory (Brief Visuospatial Memory Test) in individuals who are HSV-1 positive and early in the course of schizophrenia. The Brief Visuospatial Memory Test is a subscale of the MATRICS Consensus Cognitive Battery (MCCB) and was used to assess visual memory. The BVMT consists of three trials in which participants must recall shapes by drawing figures on a blank page after being given the opportunity to memorize the figures for 10 seconds. Each page consists of six figures. Points are awarded based on the accuracy of the drawn figure and by correct placement on the page. A minimum of 0 to 12 points are awarded per trial, so a participant can score between 0 and 36 points for all three trials. The raw score is then converted to a t-score, normed by age and sex. The min and max t-scores are between 0-100, a higher t-score representing a better outcome. | Baseline, 8 weeks, and 16 weeks | 
| Working Memory | Determine the efficacy of adjunctive valacyclovir, in comparison to placebo, on working memory (composite score of the Wechsler Memory Scale-III: Spatial Span and Letter Number Span tests). WMS has 2 sections in which a subject recalls increasingly difficult sequences. The total raw score range for both sections is 0-32. The raw score is then converted to a tscore based on normative ranges by age and sex, ranging from 0-100. For both the raw and tscore a higher score reflects better performance. LNS consists of 24 increasingly difficult sequences of letters and numbers that a subject is to recall and repeat back in Numeric-Alpha sequential order. The total raw score range is 0-24. The raw score is then converted to a tscore based on normative ranges by age and sex, ranging from 0-100. For both the raw and tscore a higher score reflects better performance. The Working Memory composite score is calculated by summing the WMS and LNS tscores, a higher tscore reflects better performance. | Baseline, 8 weeks, and 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Performance | To evaluate the efficacy of adjunctive valacyclovir, in comparison to placebo, to improve general cognitive performance as measured by the MATRICS Consensus Cognitive Battery composite score in HSV1 + and - participants. MCCB is comprised of 10 tests, Trail Making Test Part A; Brief Assessment in Cognition in Schizophrenia Symbol Coding; Hopkins Verbal Learning Test-Revised; Wechsler Memory Scale-III Spatial Span; Letter Number Sequencing; Neuropsychological Assessment Battery Mazes; Brief Visuospatial Memory Test-Revised; Category Fluency Animal Naming; Mayer-Salovey-Caruso Emotional Intelligence Test Managing Emotions; and Continuous Performance Test-Identical Pairs. For each test, a score is derived based on the raw item values. Each of the individual item raw scores is standardized to age and gender corrected tscores which are then summed to convert into a composite score ranging from <214->486 based on the MCCB scoring manual, with a higher score reflecting better performance. | Baseline, 8 Weeks, and 16 weeks | 
| Functional Performance | To evaluate the efficacy of adj. valacyclovir to improve functional performance and quality of life (QOL) as measured by the UCSD Performance-Based Skills Assessment, Version B (UPSA-B); QOL Enjoyment and Satisfaction Questionnaire Short Form (Q-LES); and Personal and Social Performance Scale (PSP). The UPSA-B is a performance-based assessment of improvement in functional capacity.Participants are asked to role-play communication and finance tasks. Scores are assigned for each of the 2 subscales and formula is used to calculate a total score (0-100). A higher score reflects better performance. The Q-LES, 16 item scale yields a raw total score, ranging from 14-70, with a higher score representing higher QOL. The PSP scale is a single item scale assessing 4 domains of functioning: personal&social relationships, socially useful activities, self-care, and disturbing&aggressive behaviors. An adjusted score from 0-100 is generated, a higher score reflects better functioning. | Baseline, 8 weeks, and 16 weeks | 
| Psychosis Symptoms | To evaluate the efficacy of adj. valacyclovir for general and positive symptoms (sxs) as measured by the PANSS total and factor scores and negative sxs as measured by the NSA-16.The PANSS contains 30 items that assess sxs of psychotic d/os.Positive sxs are rated on 7 items, negative sxs on 7 items, and general psych. on 16 items.Scores for each item range from 1-7.Positive total scores ranging from 7-49, negative total scores ranging from 7-49, and general psych. scores ranging from 16-112.Total scores for all items range from 30-210.Additionally a factor score can be derived for Cognition/Disorganization by using scores from 7 items and ranges from 7-49.For factor and total scores a lower score reflects fewer sxs.The NSA-16 is used to rate behaviors commonly associated with negative sxs of schizophrenia.The scale rates subjects on 16 anchors from 1 to 6.The total score is the sum of the 16 specific items and ranges from 16 to 96; a higher score indicates greater severity of illness. | Baseline, 4 weeks, 8 weeks, 12 weeks, and 16 weeks | 
| Functional Performance | To evaluate the efficacy of adjunctive valacyclovir, compared to placebo, to improve to improve global functional assessments as measured by the Clinical Global Impressions Severity Scale (CGI-S). The CGI-S is a single 7-point Likert scale rating severity of psychopathology on a scale of 1 (normal, not ill) to 7 (very severely ill). | Baseline, 8 weeks, and 16 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
schizophrenia, schizoaffective, schizophreniform, inflammatory markers, HSV1, cognition, early psychosis, valacyclovir