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Trial record 1 of 1 for:    11086983 [PUBMED-IDS]
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Treatment Study for Cognitive Deficits in Schizophrenia (TURNS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00505076
Recruitment Status : Completed
First Posted : July 20, 2007
Results First Posted : October 31, 2014
Last Update Posted : October 31, 2014
Sponsor:
Collaborators:
University of Maryland, College Park
Washington University School of Medicine
Massachusetts General Hospital
Nathan Kline Institute for Psychiatric Research
Columbia University
Duke University
Beth Israel Deaconess Medical Center
Information provided by (Responsible Party):
Stephen R. Marder, University of California, Los Angeles

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.


Condition or disease Intervention/treatment Phase
Schizophrenia Drug: MK-0777 Drug: placebo Phase 2

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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 (P.I.: Jeffrey Lieberman, M.D.); Duke University School of Medicine (P.I.: Joseph McEvoy, M.D.); Harvard University School of Medicine (P.I.: Donald Goff, M.D.); Maryland Psychiatric Research Center (MPRC) (P.I.: Robert W. Buchanan, M.D.); Nathan Kline Institute (P.I.: Daniel Javitt, M.D.) University of California Los Angeles School of Medicine (P.I.: Steve Marder, M.D.); and Washington University School of Medicine (P.I.: John Csernansky, M.D.). The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia (HHSN 27820044 1003C; P.I.: Steve Marder, M.D.). Data management will be performed by the Clinical Trials Data Management Unit of the Nathan Kline Institute under the direction of Jim Robinson, M.S., 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) BPRS(Brief 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) attention/vigilance; 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 (i.e., CBC (complete blood count), liver function tests, electrolytes, glucose, BUN/Creatinine, 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 and/or in a group setting about the study.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 63 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: MK-0777 for the Treatment of Cognitive Impairments in Patients With Schizophrenia
Study Start Date : July 2007
Actual Primary Completion Date : September 2009
Actual Study Completion Date : September 2009

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Schizophrenia

Arm Intervention/treatment
Experimental: MK-0777 8 mg
MK-0777 8 mg tablet by mouth twice daily for 4 weeks
Drug: MK-0777
MK-0777 GEM, 8 mg BID

Experimental: MK-0777 3 mg
MK-0777 3 mg tablet by mouth twice daily for 4 weeks
Drug: MK-0777
MK-0777 GEM, 3 mg BID

Placebo Comparator: Placebo
Placebo tablet by mouth twice daily for 4 weeks
Drug: placebo
2 tablets placebo BID




Primary Outcome Measures :
  1. Composite MATRICS Consensus Cognitive Battery Score [ Time Frame: 4 weeks ]
    The primary outcome measure is the composite score on the Matrics Consensus Cognitive Battery (MCCB). The MCCB composite score is a standardized mean of the seven domain scores. T-scores are standardized to normative data, and have an estimated mean of 50 and SD of 10 in the general healthy population. Data reduction for analysis of neurocognitive testing used the following steps: i) individual neurocognitive test scores at baseline and follow-up were converted to t-scores; ii) t-scores within the pre-specified cognitive domains measured by more than one test were averaged to obtain a domain-specific t-score; and iii) domain-specific t-scores were averaged to create the MCCB composite score.


Secondary Outcome Measures :
  1. UPSA(UCSD Performance-Based Skills Assessment) Summary Score [ Time Frame: Baseline and end of treatment, a total of four weeks. ]
    The UCSD Performance-Based Skills Assessment assessed functional capacity. The UPSA Summary Score has a range from 0 to 120. A higher score indicates less impairment.

  2. Schizophrenia Cognition Rating Scale (SCoRS) Score [ Time Frame: 4 Weeks (Baseline to End of Treatment) ]
    The Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. The SCoRS Interviewer Global Rating of function has a range 1 to 10. Higher ratings indicate greater impairment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis: DSM IV/DSM IV TR schizophrenia (including disorganized, paranoid, undifferentiated, and catatonic subtypes)
  • Capable of providing informed consent
  • Duration of illness equal to or greater than one year
  • Treated with one or two of the following second generation antipsychotics: risperidone, paliperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole for the previous two months, with no change in dose in the last month.
  • Meet the following symptom criteria:

    • Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior, Unusual Thought Content or Conceptual Disorganization item score ≤ 4
    • All Scale for the Assessment of Negative Symptoms global items ≤ 3
    • Simpson-Angus Scale total score ≤ 6
    • Calgary Depression Scale total score ≤ 10
  • Meet the following cognitive performance criteria:

    • Performance less than the maximum cutoff (in parentheses) for ONE of the following MCCB tests: i.) Letter-number span (20); ii.) HVLT total (31); and iii.) CPT d-prime (3.47)
    • Able to complete the baseline MCCB validly
    • Raw score ≥6 on the WTAR

Exclusion Criteria:

  • Current treatment (within 4 weeks) with conventional antipsychotics (e.g. fluphenazine, haloperidol) or clozapine
  • Current treatment with psychotropic agents known to act at the GABAA receptor, including benzodiazepines; sedative-hypnotics other than trazadone and chloral hydrate; carbamazepine, gabapentin, lamotrigine, and valproic acid
  • Current treatment with a drug that inhibits CYP3A4, including: cimetidine; cyclosporine; erythromycin or erythromycin-like drugs (e.g., azithromycin, clarithromycin); diltiazem; fluoxetine, fluovoxamine; itraconazole, ketoconazole or other systemic antifungal agents in the azole class; nefazodone; or induce CYP3A4, including: carbamazepine, modafinil; phenobarbital; phenytoin; rifampin; St. Johns wort; and troglitazone.
  • Current treatment with psychotropic agents known to effect cognition: amphetamine; barbiturates; lithium; MAOIs; methylphenidate
  • Current treatment with herbal preparations with possible psychotropic effects (e.g., St. Johns wort, kava-kava, Valerian, S-Adenosyl Methionine [SAMe])
  • Current treatment with systemic steroids
  • DSM-IV diagnosis of alcohol or substance abuse (other than nicotine) within the last month or a DSM-IV diagnosis of alcohol or substance dependence within the last 6 months
  • Presence of PI or greater posterior subcapsular cataracts
  • Uveitis with 1+ or greater flare or cells
  • Nuclear or cortical cataracts
  • History of significant head injury/trauma, as defined by one or more of the following: loss of consciousness (LOC) for more than 1 hour, seizures from the head injury, clear cognitive sequellae of the injury, or cognitive rehabilitation following the injury
  • History of clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorders.
  • Clinically significant abnormalities in physical examination, ECG, or laboratory assessments
  • A positive test for Hepatitis C antibody with concurrent evidence of impaired hepatic function (increased AST or ALT greater than 2 times the upper limit of normal) or positive tests for Hepatitis A antibody IgM fraction or Hepatitis B surface antigen, irrespective of the AST or ALT values.
  • Pregnant women or women of child-bearing potential, either not surgically-sterile or using appropriate methods of birth control
  • Women who are breast-feeding
  • History of severe symptoms of benzodiazepine withdrawal (e.g., history of seizures or delirium associated with withdrawal)
  • Received ECT treatment within the last 3 months
  • Participated in a clinical trial of any other psychotropic medication within 2 months

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00505076


Locations
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United States, California
UCLA
Los Angeles, California, United States, 90073
United States, Maryland
Maryland Psychiatric Research Center
Catonsville, Maryland, United States, 21228
United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Harvard Medical School
Boston, Massachusetts, United States, 02115
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
United States, New York
Columbia University Medical Center
New York, New York, United States, 10032
Nathan Kline Institute
Orangeburg, New York, United States, 10962
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27509
Sponsors and Collaborators
University of California, Los Angeles
University of Maryland, College Park
Washington University School of Medicine
Massachusetts General Hospital
Nathan Kline Institute for Psychiatric Research
Columbia University
Duke University
Beth Israel Deaconess Medical Center
Investigators
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Principal Investigator: Robert W Buchanan, M.D. University of Maryland, College Park

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Stephen R. Marder, Principal Investigator, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT00505076     History of Changes
Other Study ID Numbers: TURNS02
HHSN278200441003C ( Other Grant/Funding Number: NIMH grant )
First Posted: July 20, 2007    Key Record Dates
Results First Posted: October 31, 2014
Last Update Posted: October 31, 2014
Last Verified: October 2014
Keywords provided by Stephen R. Marder, University of California, Los Angeles:
Cognition
Schizophrenia
Additional relevant MeSH terms:
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Schizophrenia
Schizophrenia Spectrum and Other Psychotic Disorders
Mental Disorders