Treatment Study for Cognitive Deficits in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2

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.
    

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.
    

Intervention name(s): MK-0777; MK-0777; placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): MK-0777 GEM, 8 mg BID; MK-0777 GEM, 3 mg BID; 2 tablets placebo BID
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Cognition; Schizophrenia