Ignite Creation Date:
2024-05-05 @ 6:32 PM
Last Modification Date:
2024-10-26 @ 9:34 AM
Study NCT ID:
NCT00505076
Status:
COMPLETED
Last Update Posted:
2014-10-31
First Post:
2007-07-19
Brief Title:
Treatment Study for Cognitive Deficits in Schizophrenia
Sponsor:
University of California Los Angeles
Organization:
University of California Los Angeles
Study Overview
Official Title:
MK-0777 for the Treatment of Cognitive Impairments in Patients With Schizophrenia
Status:
COMPLETED
Status Verified Date:
2014-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
TURNS
Brief Summary:
Patients with schizophrenia are characterized by a broad range of neurocognitive abnormalities These include impairments in attention including abnormalities in sensory gating executive function visual and verbal learning and memory working memory processing speed and social cognition Nuechterlein et al 2004 These impairments are major determinants of poor functional outcome in patients with schizophrenia Green 1996 Green et al 2004 Conventional antipsychotics have limited effects on these impairments Second generation antipsychotics may have modest benefits for cognitive function but whether this represents a direct cognitive enhancing effect has not been established Regardless patients continue to exhibit pronounced cognitive impairments despite adequate second generation antipsychotic treatment Adjunctive pharmacotherapy may offer a viable approach for the treatment of cognitive impairments Adjunctive agents can be used to modulate specific neurotransmitter systems that are hypothesized to be involved in the pharmacology of cognitive functions
The standard of care for schizophrenia is antipsychotic medications to treat psychotic symptoms However cognitive impairments remain and these impairments have been found to be significantly associated with the poor psychosocial function observed in patients with schizophrenia There is a considerable preclinical rationale for the use of drugs that act at the Gamma-amino-buyric acid GABA α2 subunit as adjunctive treatments to target cognitive impairments MK-0777 GEM Merck-0777 Gel Extrusion Module formulation provides an opportunity to directly test this mechanism
The purpose of the proposed study is to examine the efficacy and safety of two doses of MK Merck -0777 GEM 3 mg BID twice daily and 8 mg BID twice daily in the treatment of cognitive impairments in patients with schizophrenia Secondary goals are to determine whether MK-0777 has beneficial effects on measures of functional capacity and patient self-report of cognitive function
The standard of care for schizophrenia is antipsychotic medications to treat psychotic symptoms However cognitive impairments remain and these impairments have been found to be significantly associated with the poor psychosocial function observed in patients with schizophrenia There is a considerable preclinical rationale for the use of drugs that act at the Gamma-amino-buyric acid GABA α2 subunit as adjunctive treatments to target cognitive impairments MK-0777 GEM Merck-0777 Gel Extrusion Module formulation provides an opportunity to directly test this mechanism
The purpose of the proposed study is to examine the efficacy and safety of two doses of MK Merck -0777 GEM 3 mg BID twice daily and 8 mg BID twice daily in the treatment of cognitive impairments in patients with schizophrenia Secondary goals are to determine whether MK-0777 has beneficial effects on measures of functional capacity and patient self-report of cognitive function
Detailed Description:
The proposed study is a multicenter randomized double blind comparison of MK-0777 GEM 3 mg BID MK-0777 GEM 8 mg BID and placebo The total sample will consist of 90 clinically stable patients with DSM IV TR schizophrenia with 30 subjects randomized to each group A best estimate diagnostic approach will be utilized in which information from the Structured Clinical Interview for DSM-IV Diagnostic and Statistical Manual of Mental Disorders Fourth Edition First et al 1997 is supplemented by information from family informants previous psychiatrists and medical records to generate a diagnosis The projected number of subjects to be recruited from each site is 12-13 There will be a 2 week placebo lead-in evaluation phase in which subjects will undergo baseline diagnostic medical including a physical examination EKG electrocardiogram CBC Complete Blood Count complete metabolic panel urine toxicology and UA urinalysis psychiatric and neurocognitive symptom level and functional capacity and patient self-report of cognitive function assessments In addition all subjects will receive a slit-lamp eye examination At the end of the evaluation phase subjects will be randomized to one of two MK-0777 doses or placebo The double-blind treatment phase will be 4 weeks Subjects will receive bi-weekly symptom assessments and weekly side effect and vital sign assessments At week 4 subjects will undergo repeat administration of the neuropsychological test battery and the functional capacity and patient self-report of cognitive function measures These assessments will be done over a two-day period Subjects will have blood samples collected for antipsychotic and MK-0777 levels at week 4 An EKG electrocardiogram will be obtained at the end of the double-blind study Slit-lamp eye examinations will be conducted at study completion 6 months and 12 months after study completion After the completion of the 4-week double-blind phase there will be a 4-day follow-up phase during which subjects will be tapered off study medication
Study Locations The study will be conducted in the Treatment Units for Research on Neurocognition and Schizophrenia TURNS study network which is comprised of seven sites Columbia University School of Medicine PI Jeffrey Lieberman MD Duke University School of Medicine PI Joseph McEvoy MD Harvard University School of Medicine PI Donald Goff MD Maryland Psychiatric Research Center MPRC PI Robert W Buchanan MD Nathan Kline Institute PI Daniel Javitt MD University of California Los Angeles School of Medicine PI Steve Marder MD and Washington University School of Medicine PI John Csernansky MD The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia HHSN 27820044 1003C PI Steve Marder MD Data management will be performed by the Clinical Trials Data Management Unit of the Nathan Kline Institute under the direction of Jim Robinson MS and statistical analysis will be performed by Dr Robert McMahon of the Maryland Psychiatric Research Center Laboratory assays will be performed by Quest Diagnostics
Procedures
Clinical Assessments The symptom assessments will include the Brief Psychiatric Rating Scale Scale for the Assessment of Negative Symptoms SANS Calgary Depression Scale CDS and Clinical Global Impression Scale CGI
i BPRSBrief Psychiatric Rating Scale the four positive symptom items conceptual disorganization suspiciousness hallucinatory behavior and unusual thought content will be used to measure positive psychotic symptoms
ii SANS Scale for Assessment of Negative Symptoms the SANS total score minus the global items inappropriate affect poverty of content of speech and attention items will be used to measure negative symptoms The inappropriate affect poverty of content of speech and attention items are excluded as lacking construct validity and because factor analytic study results suggest that these items are not closely related to negative symptoms
iii CDS Calgary Depression Scale the CDS total score will be used to measure depressive symptoms
iv CGI Clinical Global Impressions the CGI severity of illness item will be used to assess global changes
Safety Assessments The safety assessments will include the Simpson Angus Extrapyramidal Symptom Rating Scale SAS Abnormal Involuntary Movement Scale AIMS and Side Effect Checklist SEC
i SAS a modified 11 item version of the SAS will be used to assess EPS ii AIMS is a 12 item scale with 7 items designed to assess abnormal facial oral extremity and trunk movements 3 global judgment items and 2 current dental status items
iii SEC is designed to assess vital signs commonly occurring antipsychotic side effects and side effects indicative of uveitis or cataracts
Subjects will be asked about adverse events at each visit and instructed to call the study site should they experience adverse events at any point in the study Any serious adverse event including death due to any cause which occurs to any subject entered into this study or within 14 days following cessation of treatment whether or not related to the investigational product will be reported to Merck Co Inc within 24 hours
Functional Assessments The functional assessments will include the UCSD Performance-Based Skills Assessment UPSA and the Schizophrenia Cognition Rating Scale SCoRS
i UPSA is designed to assess skills in five areas household chores communication finance transportation and planning recreational activities Subjects are asked to perform tasks in each of these areas and scored according to their ability to complete the task The UPSA takes 25 - 30 minutes to administer
ii SCoRS is a rating scale designed to elicit information from the subject and informant on the level of cognitive function of the subject The subject and informant versions both have 20 items Subject and informant interviews take from 10 - 15 minutes to complete
Neurocognitive Assessments The NIMH MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia Research Neuropsychological Battery the Wechsler Test of Adult Reading WTAR the N-Back test and the Continuous Performance Test CPT-AX will be used to assess cognitive function The NIMH MATRICS Neuropsychological Battery is comprised of measures of a working memory b attentionvigilance c verbal memory d visual memory e processing speed f problem solving and g social cognition The N-Back and CPT-AX are both computerized measures of prefrontal cortex dependent cognitive behavior
Screening The diagnosis of schizophrenia will be confirmed by a research psychiatrist using a modified version of the Structured Clinical Interview for DSM IV SCID The BPRS SANS CDRS and SAS will be administered to verify that inclusionary criteria are met Subjects will have a slit-lamp eye examination
2 Week Lead-in Evaluation Phase In the 2 week lead-in evaluation phase subjects will receive placebo They will undergo baseline symptom medical safety and neurocognitive assessments The subjects will undergo a physical examination including neurological exam an EKG and laboratory tests of major organ functions ie CBC complete blood count liver function tests electrolytes glucose BUNCreatinine Urinalysis UA urine toxicology and thyroid functions Baseline antipsychotic levels will be collected All women will have a pregnancy test unless they are either surgically or hormonally post menopausal
4-Week Double Blind Treatment Phase The study is a 4-week placebo controlled double blind study Subjects will be randomized to either MK-0777 GEM 3mg BID MK-0777 GEM 8mg BID or placebo The unblinded site pharmacist will be notified of the treatment assignment and will dispense study medication Subjects will receive biweekly symptom assessments and weekly side effect and vital sign assessments At week 4 subjects will undergo repeat administration of the neuropsychological test battery and the functional capacity and patient self-report of cognitive function measures These assessments will be done over a two-day period At week 4 subjects will also undergo a repeat slit lamp eye examination We will also attempt to contact and schedule subjects who dropped out of the study prior to week 4 for the week 4 slit lamp eye examination Finally subjects will have blood samples collected for antipsychotic and MK-0777 levels at week 4
6-Month and 12-Month Follow-up Evaluations All subjects regardless if they completed the 4-week double-blind treatment phase will be contacted and scheduled for follow-up slit lamp eye examinations
Randomization Subjects will be randomly assigned to placebo or one of two doses of experimental treatment within strata defined by site
Recruitment Recruitment for potential subjects will be performed by reviewing subject records to determine eligibility based on the inclusion and exclusion criteria Once qualifying records have been identified potential subjects will be informed individually andor in a group setting about the study
Study Locations The study will be conducted in the Treatment Units for Research on Neurocognition and Schizophrenia TURNS study network which is comprised of seven sites Columbia University School of Medicine PI Jeffrey Lieberman MD Duke University School of Medicine PI Joseph McEvoy MD Harvard University School of Medicine PI Donald Goff MD Maryland Psychiatric Research Center MPRC PI Robert W Buchanan MD Nathan Kline Institute PI Daniel Javitt MD University of California Los Angeles School of Medicine PI Steve Marder MD and Washington University School of Medicine PI John Csernansky MD The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia HHSN 27820044 1003C PI Steve Marder MD Data management will be performed by the Clinical Trials Data Management Unit of the Nathan Kline Institute under the direction of Jim Robinson MS and statistical analysis will be performed by Dr Robert McMahon of the Maryland Psychiatric Research Center Laboratory assays will be performed by Quest Diagnostics
Procedures
Clinical Assessments The symptom assessments will include the Brief Psychiatric Rating Scale Scale for the Assessment of Negative Symptoms SANS Calgary Depression Scale CDS and Clinical Global Impression Scale CGI
i BPRSBrief Psychiatric Rating Scale the four positive symptom items conceptual disorganization suspiciousness hallucinatory behavior and unusual thought content will be used to measure positive psychotic symptoms
ii SANS Scale for Assessment of Negative Symptoms the SANS total score minus the global items inappropriate affect poverty of content of speech and attention items will be used to measure negative symptoms The inappropriate affect poverty of content of speech and attention items are excluded as lacking construct validity and because factor analytic study results suggest that these items are not closely related to negative symptoms
iii CDS Calgary Depression Scale the CDS total score will be used to measure depressive symptoms
iv CGI Clinical Global Impressions the CGI severity of illness item will be used to assess global changes
Safety Assessments The safety assessments will include the Simpson Angus Extrapyramidal Symptom Rating Scale SAS Abnormal Involuntary Movement Scale AIMS and Side Effect Checklist SEC
i SAS a modified 11 item version of the SAS will be used to assess EPS ii AIMS is a 12 item scale with 7 items designed to assess abnormal facial oral extremity and trunk movements 3 global judgment items and 2 current dental status items
iii SEC is designed to assess vital signs commonly occurring antipsychotic side effects and side effects indicative of uveitis or cataracts
Subjects will be asked about adverse events at each visit and instructed to call the study site should they experience adverse events at any point in the study Any serious adverse event including death due to any cause which occurs to any subject entered into this study or within 14 days following cessation of treatment whether or not related to the investigational product will be reported to Merck Co Inc within 24 hours
Functional Assessments The functional assessments will include the UCSD Performance-Based Skills Assessment UPSA and the Schizophrenia Cognition Rating Scale SCoRS
i UPSA is designed to assess skills in five areas household chores communication finance transportation and planning recreational activities Subjects are asked to perform tasks in each of these areas and scored according to their ability to complete the task The UPSA takes 25 - 30 minutes to administer
ii SCoRS is a rating scale designed to elicit information from the subject and informant on the level of cognitive function of the subject The subject and informant versions both have 20 items Subject and informant interviews take from 10 - 15 minutes to complete
Neurocognitive Assessments The NIMH MATRICS Measurement and Treatment Research to Improve Cognition in Schizophrenia Research Neuropsychological Battery the Wechsler Test of Adult Reading WTAR the N-Back test and the Continuous Performance Test CPT-AX will be used to assess cognitive function The NIMH MATRICS Neuropsychological Battery is comprised of measures of a working memory b attentionvigilance c verbal memory d visual memory e processing speed f problem solving and g social cognition The N-Back and CPT-AX are both computerized measures of prefrontal cortex dependent cognitive behavior
Screening The diagnosis of schizophrenia will be confirmed by a research psychiatrist using a modified version of the Structured Clinical Interview for DSM IV SCID The BPRS SANS CDRS and SAS will be administered to verify that inclusionary criteria are met Subjects will have a slit-lamp eye examination
2 Week Lead-in Evaluation Phase In the 2 week lead-in evaluation phase subjects will receive placebo They will undergo baseline symptom medical safety and neurocognitive assessments The subjects will undergo a physical examination including neurological exam an EKG and laboratory tests of major organ functions ie CBC complete blood count liver function tests electrolytes glucose BUNCreatinine Urinalysis UA urine toxicology and thyroid functions Baseline antipsychotic levels will be collected All women will have a pregnancy test unless they are either surgically or hormonally post menopausal
4-Week Double Blind Treatment Phase The study is a 4-week placebo controlled double blind study Subjects will be randomized to either MK-0777 GEM 3mg BID MK-0777 GEM 8mg BID or placebo The unblinded site pharmacist will be notified of the treatment assignment and will dispense study medication Subjects will receive biweekly symptom assessments and weekly side effect and vital sign assessments At week 4 subjects will undergo repeat administration of the neuropsychological test battery and the functional capacity and patient self-report of cognitive function measures These assessments will be done over a two-day period At week 4 subjects will also undergo a repeat slit lamp eye examination We will also attempt to contact and schedule subjects who dropped out of the study prior to week 4 for the week 4 slit lamp eye examination Finally subjects will have blood samples collected for antipsychotic and MK-0777 levels at week 4
6-Month and 12-Month Follow-up Evaluations All subjects regardless if they completed the 4-week double-blind treatment phase will be contacted and scheduled for follow-up slit lamp eye examinations
Randomization Subjects will be randomly assigned to placebo or one of two doses of experimental treatment within strata defined by site
Recruitment Recruitment for potential subjects will be performed by reviewing subject records to determine eligibility based on the inclusion and exclusion criteria Once qualifying records have been identified potential subjects will be informed individually andor in a group setting about the study
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| HHSN278200441003C | OTHER_GRANT | NIMH grant | None |