Treatment Study for Cognitive Deficits in Schizophrenia (TURNS)

• Primary: MCCB: MATRICS Consensus Cognitive Battery [ Time Frame: Baseline (Wk #1) and end of treatment (Wk # 5), a total of five weeks. ] [ Designated as safety issue: No ]
  

• Secondary: UPSA: UCSD Performance-Based Skills Assessment; SCoRS: Schizophrenia Cognition Rating Scale [ Time Frame: Baseline (Wk #1) and end of treatment (Wk # 5), a total of five weeks. ] [ Designated as safety issue: No ]
  

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 (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, CBC, complete metabolic panel, urine toxicology, and UA; 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 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.

Subjects may be treated with any second generation antipsychotic other than clozapine. Subjects must have been treated with the same antipsychotic for 2 months, with no change in dose for the previous month. Subjects who are receiving concurrent medications, other than benzodiazepines or GABAergic compounds, will be able to remain on those medications during the course of the study. If a subject is receiving other medications, they must be on the same dose for the previous month.

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: the four positive symptom items conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content will be used to measure positive psychotic symptoms.

ii) SANS: 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: the CDS total score will be used to measure depressive symptoms. iv) CGI: 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 judgement 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 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 MATRICS battery is designed to be completed in 90 minutes or less. The N-Back and CPT-AX are both computerized measures of prefrontal cortex dependent cognitive behavior. The N-Back is a working memory test, in which the working memory load can be varied. Three conditions will be used: 0-back condition; 1-back condition; and 2-back condition. In the 0-back condition, the subject is asked to respond to the presentation of a prespecified target letter (e.g. "X"). In the 1-back condition, the subject is asked to respond to the second of two consecutive, identical letters. In the 2-back condition, the subject is asked to respond if a letter is identical to a letter presented two trials previous to the current letter presentation. In the CPT-AX, the subject is required to respond to a target letter (e.g. "X") every time the "X" is preceded by an "A". They are not to respond to an "X" if it preceded by a letter other than "A". They are also not to respond to the letter following an "A" if it is not an "X".

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, 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.

Medication Titration Schedule: On week 1,day 1 - subjects randomized to MK-0777 GEM 3mg BID, will receive one 3 mg tablet and one placebo tablet in the morning and one 3 mg tablet and one placebo tablet in the evening.

On week 1, day 1 - subjects randomized to MK-0777 8 mg BID, will receive one 3 mg tablet and one placebo tablet in the morning and one 3 mg tablet and one placebo tablet in the evening. On week 1, day 3 - the dose will be increased to one 3 mg tablet and one placebo tablet in the morning and one 3 mg tablet and 5 mg tablet in the evening. On week 1, day 5 - the dose will be increased to one 3 mg tablet and one 5 mg tablet in the morning and one 3 mg tablet and 5 mg tablet in the evening.

Subjects who are randomized to placebo will get two placebo tablets in the morning and two in the evening.

Regardless of randomization assignment each subject will receive the same number of tablets per day (4). The MK-0777 3 mg, MK-0777 5 mg, and the placebo tablets will have the same identical appearance.

If subjects randomized to MK-0777 3mg BID are unable to tolerate the medication, then they will be instructed to skip the next scheduled dose of study medication. If the side effects dissipate, then they will be re-challenged with the original dose. If they are still unable to tolerate the original dose, then the non-blind pharmacist will reduce their dose to one 3 mg tablet and one placebo tablet. If subjects randomized to MK-0777 8 mg BID are unable to tolerate the medication, they will be instructed to skip the next scheduled dose of study medication. If their side effects subside, then they will be re-challenged on the higher dose. If still unable to tolerate the higher dose, then they will complete the study on the highest tolerated dose.

Each subject will receive their medications in four bottles: two in the morning and two in the evening, which will allow for specific dose reduction to occur and compliance checks to occur.

4 Day Follow-up Phase: After the end of week 4, subjects will be tapered off study medication according to the following schedule: in week 5, subjects who were randomized to MK-0777 GEM 3 mg BID, will take two placebo tablets in the morning and one 3 mg tablet and one placebo tablet at night for 4 days, then study meds will be discontinued; in week 5, subjects who were randomized to MK-0777 GEM 8 mg BID will take one 3 mg tablet and one placebo tablet in the morning and one 3 mg tablet and one 5 mg tablet in the evening for 1 day. Then they will take one 3 mg tablet and one placebo tablet in the morning and one 5 mg tablet and one placebo tablet in the evening for 1 day. Then they will take one 3 mg tablet and one placebo tablet in the morning and one 3 mg tablet and one placebo tablet in the evening for 1 day. Then they will take two tablets in the morning and one 3 mg tablet and one placebo tablet in the evening for 1 day. After week 5, day 4, study medication will be discontinued. Subjects who have been randomized to placebo will continue to receive two placebo tablets in the morning and two placebo tablets in the evening through week 5, day 4. At the end of the follow-up phase, subjects will have a neurological exam and laboratory tests of major organ functions (i.e., CBC, liver function tests, electrolytes, glucose, BUN/Creatinine, Urinalysis (UA), urine toxicology, and thyroid functions) -as well as a side effects checklist and evaluation of vital signs.

Maintenance of the Blind: Study medication will be dispensed on a weekly basis. Subjects will be given two extra days of medication in case of a missed appointment. The blind will be broken only if a medical emergency requires this information. If this occurs, the subject will be withdrawn from the study. All raters, investigators and other staff will be blind to treatment assignment except for the pharmacist. The pharmacist does not participate in assessing any of the primary symptom or side effect dependent variables and conveys no information about treatment assignment to subjects or staff except in a medical emergency.

Compliance: Subjects receiving 75% of their assigned medication will be considered compliant. The 75% criterion ensures that subjects will receive adequate treatment to evaluate the comparative efficacy of MK-0777 and placebo. Compliance will be monitored through bi-weekly pill counts and subject interviews. Study medications will be dispensed on a weekly basis and will only be dispensed after compliance is assessed and all assessments are completed. If a subject is observed to have a compliance problem, then this will be discussed with the subject and a plan formulated to bring the subject back within the compliance parameter. The plan may include contacting the subject's caretaker or scheduling increased clinic visits. These monitoring procedures have resulted in high levels of compliance. Compliance patterns will be carefully monitored in each treatment group and will be described as part of any presentation of study results.

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. Those who express initial interest will be provided with additional information about the study, including the purpose of the study, a description of the procedures, and the overall length of the study. The length of the evaluation phase; the length of the double blind study period; an explanation of double blind and how it is determined; a list of the risks and side effects; expectations of the study participant, including all study tests and assessments; how to withdraw from the study; and what to do in case of a potential side effect will also be explained to potential subjects.

Overdose Management: In managing overdose with test medication, basic life support and CPR will be provided. Gastric lavage should be considered. Activated charcoal may be administered every 4 to 6 hours during the first 24 to 48 hours after ingestion. The possibility of multiple drug involvement will be considered. An ECG should be taken and monitoring of cardiac function instituted if there is any evidence of abnormality. Supportive care with frequent monitoring of vital signs and careful observation will be provided. If hypotension is present, standard medical practice will be used to manage the condition, including vasopressor therapy if indicated. The value of dialysis is unclear for MK-0777. The efficacy of flumazenil, a benzodiazepine antagonist, to treat MK-0777 overdose is unknown. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physician's Desk Reference (PDR).