Pilot Trial of Valproate as Adjunctive Treatment for Toxoplasma Gondii Infection in Early Course Schizophrenia

Pilot Trial of Valproate as Adjunctive Treatment for Toxoplasma Gondii

This is an exploratory study in Egypt that will combine a treatment trial among early course schizophrenia (ECSZ) patients with key analyses suggested by rodent studies. Specifically, the study will test the provocative results from animal studies indicating an impact of Toxoplasma Gondii (TOX) exposure on novelty seeking. The study will also test whether exposure to TOX is associated with other cognitive and behavioral changes, as well as changes in overall social function. We will also explore the relative efficacy of Sodium Valproate (Depakote, DEP) in improving clinical and overall social function among TOX exposed and unexposed patients.

Hypotheses

1. At baseline, TOX exposure is associated with increased novelty seeking, clinical severity, and impaired cognitive and overall social function in patients with SZ.
2. Adjunctive DEP treatment improves clinical symptoms, cognitive and social function in SZ, particularly among TOX exposed SZ patients.
3. Exploratory hypothesis: adjunctive DEP reduces serological indices of TOX infection (VIP and TH levels).

Study Overview

• Status: Completed
• Conditions: Schizophrenia; Toxoplasmosis
• Intervention / Treatment: Drug: Sodium Valproate treatment; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 109
• Phase: Phase 4

Contacts and Locations

Study Locations

• Egypt
  • Mansourah, Egypt, 35516
    • Mansoura University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent
• Adult men or women (ages 18-50 years)
• Schizophrenia / schizoaffective disorder (DSM IV)
• Duration of illness < 5 years (since onset of psychosis)
• On a stable dose of an antipsychotic for at least a month
• Scores 4 or more on at least one item of the Positive and Negative Syndrome Scale.

Exclusion Criteria:

• Substance abuse in the past month/dependence past 6 months
• History of / or current medical/neurological illnesses e.g. mental retardation (DSM-IV) or epilepsy;
• Medical conditions that are judged by the consulting internist and research staff to be unstable
• Pregnant or breast-feeding women
• Known allergy or serious adverse event to DEP, Received Chlorpromazine, Trimethoprim or DEP for up to 6 months prior to study entry.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Sodium Valproate treatment; Sodium Valproate treatment:During the entry period, all patients will have a placebo run-in for two weeks after which they will be evaluated for the outcome variables and then randomized to either Sodium Valproate (Depakote, DEP) or placebo (PLA) group in a 1:1 proportion. For the Sodium Valproate treatment grou, this will be followed by a two week period to adjust the dose of DEP and attain therapeutic levels (50-100 µg/mL). Then DEP treatment will continue for 16 more weeks, after which DEP will be discontinued. Subject will be followed up for four weeks post-DEP discontinuation to monitor delayed adverse side effects.	Drug: Sodium Valproate treatment; Sodium Valproate treatment:During the entry period, all patients will have a placebo run-in for two weeks after which they will be evaluated for the outcome variables and then randomized to either Sodium Valproate (Depakote, DEP) or placebo (PLA) group in a 1:1 proportion. For the Sodium Valproate treatment group, this will be followed by a two week period to adjust the dose of DEP and attain therapeutic levels (50-100 µg/mL). Then DEP treatment will continue for 16 more weeks, after which DEP will be discontinued. Subject will be followed up for four weeks post-DEP discontinuation to monitor delayed adverse side effects.; Other Names: Depakote; Drug: Placebo; Placebo: During the entry period, all patients will have a placebo run-in for two weeks after which they will be evaluated for the outcome variables and then randomized to either the experimental Sodium Valproate (Depakote, or DEP) or placebo (PLA) group in a 1:1 proportion. For the PLA group, this will be followed by a two week period of placebo during which members of the experimental Sodium Valproate (Depakote/DEP) will have DEP dose adjusted to attain therapeutic levels (50-100 µg/mL). Then PLA treatment will continue for 16 more weeks. Subjects will be followed up for four weeks post PLA-discontinuation to monitor for delayed adverse side effects.
PLACEBO_COMPARATOR: Placebo; Placebo Comparator: During the entry period, all patients will have a placebo run-in for two weeks after which they will be evaluated for the outcome variables and then randomized to either the experimental Sodium Valproate (Depakote, or DEP) or placebo (PLA) group in a 1:1 proportion. For the PLA group, this will be followed by a two week period of placebo during which members of the experimental Sodium Valproate (Depakote/DEP) will have DEP dose adjusted to attain therapeutic levels (50-100 µg/mL). Then PLA treatment will continue for 16 more weeks. Subjects will be followed up for four weeks post PLA-discontinuation to monitor for delayed adverse side effects.	Drug: Placebo; Placebo: During the entry period, all patients will have a placebo run-in for two weeks after which they will be evaluated for the outcome variables and then randomized to either the experimental Sodium Valproate (Depakote, or DEP) or placebo (PLA) group in a 1:1 proportion. For the PLA group, this will be followed by a two week period of placebo during which members of the experimental Sodium Valproate (Depakote/DEP) will have DEP dose adjusted to attain therapeutic levels (50-100 µg/mL). Then PLA treatment will continue for 16 more weeks. Subjects will be followed up for four weeks post PLA-discontinuation to monitor for delayed adverse side effects.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Severity	Clinical Severity will be measured by the Positive and Negative Syndrome Scale (PANSS),a 7 point rating scale for 30 psychopathological items based on interviews or reports.	Clinical severity will be assessed during week 20 of the study.
Cognitive Domains assessed via the Arabic version of the Penn CNB	Cognitive domains will be assessed using the Arabic version of the Penn Computerized Neuropsychological Battery (CNB), which includes cognitive measures that distinguish SZ cases and relatives from controls. Accuracy and response time are recorded.	Cognitive domains wil be measured in week 16 of the study
Social Function assessed via the Quality of Life Scale	Overall Social function will be measured by the Quality of Life Scale, which measures interpersonal, social and occupational functioning.	Social functioing will be assessed during week during week 16.
Cognitive domains assessed via Trails Making Test	Cognitive domains will be assessed using the Trails Making Test, a neuropsychological test of attention and task switching.	Cognitive domains will be assessed in week 16 of the study
Social Function -assessed via the GAF scale	Social functioning will be assessed using the Global Assessment of Functioning (GAF), a global measure of function and symptom severity.	Social functioning will be assessed during week 16
Social Functioning assessed via the Short Form	Social functioning will be assessed via the Short Form, a multi-item scale that consists of 8 scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight.	Social functioning will be assessed during week 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Side effects	Participants will be monitored for adverse reactions to study medication through week 20.	Side effects will be measured during week 20 of the study.

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: Stanley Medical Research Institute; Mansoura University
• Investigators: Principal Investigator: Hader Mansour, MD, University of Pittsburgh

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 1, 2013
• Primary Completion (ACTUAL): October 30, 2017
• Study Completion (ACTUAL): December 31, 2017

Study Registration Dates

• First Submitted: June 21, 2013
• First Submitted That Met QC Criteria: December 9, 2013
• First Posted (ESTIMATE): December 13, 2013

Study Record Updates

• Last Update Posted (ACTUAL): February 14, 2018
• Last Update Submitted That Met QC Criteria: February 13, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: schizophrenia; toxoplasmosis
• Additional Relevant MeSH Terms: Mental Disorders; Infections; Schizophrenia Spectrum and Other Psychotic Disorders; Parasitic Diseases; Coccidiosis; Protozoan Infections; Schizophrenia; Toxoplasmosis; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: PRO12020320