MK-0777 for the Treatment of Cognitive Impairments in Patients With Schizophrenia
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 8
- 主要终点
- Composite MATRICS Consensus Cognitive Battery Score
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
Placebo
Placebo tablet by mouth twice daily for 4 weeks
干预措施: placebo (Drug)
MK-0777 8 mg
MK-0777 8 mg tablet by mouth twice daily for 4 weeks
干预措施: MK-0777 (Drug)
MK-0777 3 mg
MK-0777 3 mg tablet by mouth twice daily for 4 weeks
干预措施: MK-0777 (Drug)
结局指标
主要结局
Composite MATRICS Consensus Cognitive Battery Score
时间窗: 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.
次要结局
- UPSA(UCSD Performance-Based Skills Assessment) Summary Score(Baseline and end of treatment, a total of four weeks.)
- Schizophrenia Cognition Rating Scale (SCoRS) Score(4 Weeks (Baseline to End of Treatment))
研究者
Stephen R. Marder
Principal Investigator
University of California, Los Angeles