Efficacy and Safety Study of Clozapine Augmented by Atomoxetine Versus Clozapine Augmented by Placebo in Patients With Chronic Resistant Schizophrenia
This is a randomized, placebo-controlled study to assess the efficacy and safety of ATX augmentation of CLZ as a treatment for the cognitive symptoms of schizophrenia. A total sample size of 126 subjects diagnosed with schizophrenia and being treated with the antipsychotic clozapine will undergo genotyping. These subjects will have an initial assessment at four weeks and regular follow-up assessments for a total period of 52 weeks. These subjects will be randomized to continued treatment with CLZ and augmentation with ATX or Placebo.
Drug: Clozapine augmented with atomoxetine up to 40 mg or placebo
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Correlation of Phenotype, Genotype and Clinical Efficacy/Toxicity of Clozapine Augmented by Atomoxetine for Treatment Refractory Schizophrenia (CAPG Study)|
- Impact of treatment will be based on clinical examination, laboratory values, and rating scales including, PANSS, CGI, AIMS, BAS, SAS, cognitive measures, NOSIE. [ Time Frame: 375 days ] [ Designated as safety issue: No ]Via rating scales and cognitive measures, effects of CLZ and ATZ on congitive function will be assessed. A total of 126 suybjets diagnosed with Schizophrenia will be recruited, consented, and treated with CLZ and ATZ. They will undergo genetic testing for 31 mutations of CYP2D6 including gene duplication and deletion as well as, two mutations in CYP2C19.
- Concentrations [ Time Frame: week 1 and week 4 ] [ Designated as safety issue: No ]Determine the concentration of atomozetine and its two prominent metabolites
- blood cell counts [ Time Frame: week 1 and week 4 ] [ Designated as safety issue: Yes ]Obtain complete blood counts and CLZ levels on screening and at week 1 and 4
- adverse events [ Time Frame: day one forward ] [ Designated as safety issue: Yes ]clincal evaluation for adverse drug interactions that occur with the start of atomoxetine
- symptom measure [ Time Frame: screen, day 1 and all f/u visits ] [ Designated as safety issue: Yes ]Panss, MADRS and CGI scales completed at each visit
- social cognition [ Time Frame: screening, day 1 and f/u visits ] [ Designated as safety issue: No ]assessment of cognitive function via Penn Emotional REcognition and facial memory tests.
- weight change [ Time Frame: day one and follow up visits ] [ Designated as safety issue: Yes ]measures of weight change from baseline.
- daily functioning [ Time Frame: baseline through f/u visits ] [ Designated as safety issue: Yes ]measure of daily functioning via the NOSIE and extrapyraminal/motor signs via the BARS and AIMS scales
- adverse events 2 [ Time Frame: baseline forward ] [ Designated as safety issue: Yes ]evaluation via vital signs, clinical labs and ECG for safety
|Study Start Date:||September 2005|
|Study Completion Date:||September 2008|
|Primary Completion Date:||October 2006 (Final data collection date for primary outcome measure)|
Active Comparator: clozapine with AZT added
Clozapine augmented with Atomoxitine up to 40mg
|Drug: Clozapine augmented with atomoxetine up to 40 mg or placebo|
Placebo Comparator: placebo
Subjects will have a placebo pill added to their clozapine regimen.
|Drug: Clozapine augmented with atomoxetine up to 40 mg or placebo|
The purpose of this study is to scientifically explore the potential of pharmacogenetic applications as a means of predicting the clinical efficacy and safety of treatment with clozapine and atomoxetine in a treatment resistant schizophrenic population.
The principle enzyme involved in the metabolism of clozapine is CYP1A2 with minor contributions from CYP2D6. However, all the subjects will be on a stable dose of clozapine and will continue on the same dosage throughout the study. On the other hand, half the number of subjects will be randomized to augmentation with atomoxetine and since atomoxetine is predominantly metabolized by CYP2D6 with contributions from CYP2C19, we will focus on genetic variations for CYP2D6 and CYP2C19.
The goal of this study is to associate atomoxetine and metabolite drug concentrations with clinical efficacy and the development of any clinical adverse drug reactions and to determine whether clinical outcome (efficacy and ADRs) experienced following drug ingestion are more likely to be seen in patients who manifest CYP2D6 and/or CYP2C19 polymorphism(s). Other indications for pharmacogenetics in patient care, relevance of therapeutic drug monitoring, augmentation strategies and dosage guidelines may be generated from the experience and results of this study.
- To compare the effects of the combination of CLZ+ATX on cognitive function in patients with schizophrenia, as measured by change in a Composite Cognitive index derived from a battery composed of standardized cognitive tests, the Brief Assessment of Cognition in Schizophrenia..
- A total sample of 126 subjects diagnosed with schizophrenia and being treated with the antipsychotic clozapine, will be recruited to participate in the study. All 126 subjects will undergo genetic testing after obtaining informed consent, for 31 known mutations in CYP2D6 including gene duplication and deletion as well as, two mutations in CYP2C19.
- Determine the concentration of atomoxetine and its two prominent metabolites (4-hydroxyatomoxetine, and N-desmethylatomoxetine) at the end of week one and four weeks after initiating therapy by LC/MS/MS analysis.
- Obtain weekly complete blood counts and CLZ levels on screening, at the end of week one and week four.
- Clinically evaluate patients and document any adverse drug reactions that occur after starting treatment with atomoxetine
- To examine the effects of the combination of CLZ+ATX on psychopathology as measured by the Positive and Negative Syndrome Scale (PANSS) scores (PANSS Total, PANSS Positive, PANSS Negative), the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impressions-Improvement Scale
- To examine the effects of the combination of CLZ+ATX on measures of social cognition: Penn Emotional Recognition and Facial Memory Tests.
- To compare the effects of the combination of CLZ+ATX on weight change from baseline.
- To examine the effects of the combination of CLZ+ATX on daily functioning as measured by the NOSIE.
- To examine the effects of the combination of CLZ+ATX on extrapyramidal signs and motor symptoms as measured by the Barnes Akathesia Rating Scale (BARS), the Abnormal Involuntary Movement Scale (AIMS), and the Simpson-Angus Scale (SAS).
- To evaluate the safety of the combination of CLZ+ATX as measured by treatment-emergent adverse events and changes in vital signs, clinical laboratory analytes, and electrocardiogram.
|United States, Indiana|
|LaRue Carter Hospital|
|Indianapolis, Indiana, United States, 46222|
|Principal Investigator:||Anantha Shekhar, MD, PhD||Indiana University School of Medicine|