A Placebo-Controlled Trial of Org 24448 (Ampakine) Added to Atypical Antipsychotics in Patients With Schizophrenia
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 8
- 主要终点
- MCCB: MATRICS Consensus Cognitive Battery
研究概览
简要总结
The TURNS is a National Institute of Mental Health (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.). Despite advances in the safety, tolerability, and effectiveness of antipsychotic medications for the treatment of schizophrenia, many patients continue to be plagued by impairments in social and work functioning. Persons with schizophrenia commonly show deficits in a number of areas of cognition that include impairments in attention, memory, and executive functioning (the ability and organize one's behavior). Importantly, a large body of literature now shows a link between cognition and community functioning in schizophrenia. It is believed that treatments that improve cognitive deficits may lead to improvements in work and social functioning.
A promising approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness. One type of pharmacological compound that has shown promise at improving cognition is a group of drugs called ampakines. These drugs are believed to improve the activity of a neurotransmitter system in the brain called the glutamate system. Increased activity of this system has been linked to improvements in cognitive functioning. The current study is an eight-week trial comparing two doses of the ampakine drug, Org 24448, that will be added to patients' current atypical antipsychotic medication. One hundred thirty-five patients with schizophrenia, drawn from seven sites, will participate in the study. Cognition will be measured using a variety of paper-and-pencil and computerized measures from the consensus-derived NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) cognitive battery. Psychiatric symptoms and the ability to perform community-based tasks of daily living will also be measured. Because previous trials with this drug and other similar drugs have detected lasting cognitive benefits, this trial will also repeat clinical assessments four weeks after completion of the study medication.
详细描述
This study is an eight-week, randomized, placebo-controlled, parallel group, fixed dose trial comparing two doses of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor positive modulator, Org 24448, added to a stable dose of atypical antipsychotic medication in 135 patients with schizophrenia studied at seven sites. The primary endpoint for this trial is a composite score derived from the MATRICS cognitive battery. Measures of psychiatric symptoms and functioning are secondary endpoints. Because previous trials in animals and humans with this and other AMPA modulators detected persistence of cognitive benefits, this trial will also repeat clinical assessments at follow-up, four weeks after completion of the study medication.
Primary Objective:
- Compare the effects of an eight-week trial of Org 24448 250 mg BID, 500 mg BID and placebo upon cognitive function as assessed by the MATRICS cognitive battery.
Secondary Objectives: 2. Compare the effects of an eight-week trial of Org 24448 250 mg BID, 500 mg BID and placebo upon level of functioning as measured by the SCoRS and UPSA. 3. Compare effects of Org 24448 250 mg BID, 500 mg BID and placebo on overall symptoms measured by the BPRS total, psychotic symptoms measured by the BPRS positive symptom items, and negative symptoms measured by the SANS total. 4. Evaluate tolerability of Org 24448 250 mg BID and 500 mg BID compared to placebo measured by the Side Effect Checklist, AIMS, SAS, study completion rates, and frequency of abnormal laboratory values.
Tertiary Objective: 5. Evaluate persistence of effects on clinical ratings 4 weeks after completion of the 8-week trial.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis: schizophrenia, any subtype (DSM-IV/DSM-IV-TR)
- •Age: 18-55 years
- •Gender: male or female
- •Capable of providing informed consent
- •Antipsychotic: aripiprazole, olanzapine, quetiapine, risperidone or ziprasidone.
- •Subjects must have been maintained on current psychotropic medications for 8 weeks and on current doses for 4 weeks.
- •Subjects must be clinically stable and in the residual (non-acute) phase of their illness for at least 12 weeks.
- •Symptom Ratings:
- •No more than a "moderate" severity rating on hallucinations and delusions (i.e., Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior or Unusual Thought Content item score 4)
- •No more than a "moderate" severity rating on positive formal thought disorder (i.e., BPRS Conceptual Disorganization item score 4)
- •No more than "moderate" severity rating on negative symptoms (i.e., all Scale for the Assessment of Negative Symptoms global items 3)
- •A minimal level of extrapyramidal symptoms (i.e., Simpson-Angus Scale total score 6)
- •A minimal level of depressive symptoms (i.e., Calgary Depression Scale total score 10).
- •Cognitive Status:
- •Performance less than the maximum cutoff (in parentheses) for ONE of the following MCCB tests:
- •Letter-number span (.20)
- •Hopkins Verbal Learning Test (HVLT) total (.31) and
- •Continuous Performance Test- Identical Pairs (CPT) d-prime (.3.47)
- •Able to complete the baseline MCCB validly as assessed by Chief Neuropsychologist or neuropsychology tester
- •Raw score of 6 or greater on the WTAR
排除标准
- •Concomitant medications are allowed except for:
- •Conventional antipsychotics and clozapine
- •Antipsychotic polypharmacy
- •Anticholinergic agents (including anticholinergic antidepressants)
- •Carbamazepine, phenytoin and lamotrigine
- •DSM-IV/DSM-IV-TR diagnosis of alcohol or substance abuse (other than nicotine) within the last 3 months or a DSM-IV/DSM-IV-TR diagnosis of alcohol or substance dependence (other than nicotine) within the last 6 months
- •A history of significant head injury/trauma, as defined by:
- •Loss of consciousness (LOC) for more than 1 hour
- •Recurring seizures resulting from the head injury
- •Clear cognitive sequelae of the injury
- •Cognitive rehabilitation following the injury
- •History of seizures or abnormal EEG
- •Epileptogenic abnormalities on screening EEG
- •A baseline white blood count (WBC) less than 3500/mm3 or absolute neutrophil count (ANC) less than 2000/mm3
- •Serious medical or neurological illness (unstable cardiac disease, AIDS, malignancy, liver or renal impairment) or treatment for a medical disorder that could interfere with study participation.
- •History of transient ischemic attack (TIA) or cerebral vascular accident (CVA)
- •History of neutropenia or medication-induced blood dyscrasia
- •Clinically-significant abnormalities on screening laboratory or EKG.
- •Untreated hyper- or hypothyroidism
- •Pregnancy, nursing, or if female and fertile, unwilling to use appropriate birth control measures during study participation
- •Unable to complete neuropsychological tests
- •Serious suicidal or homicidal risk within the past six months
- •Participation in a trial of another investigational agent within 2 months
- •Treatment with Electroconvulsive therapy (ECT) within 2 months
研究组 & 干预措施
Org 24448 250 mg
Two capsules (one Org 24448 250 mg capsule and one placebo capsule that is identical to the active treatment) will be ingested orally daily for eight weeks.
干预措施: Org 24448 (Drug)
Og 244448 500 mg
Two capsules (two Org 24448 250 mg capsules) will be ingested orally daily for eight weeks.
干预措施: Org 24448 (Drug)
Inactive Capsule
Two capsules (two placebo capsules that are identical to the active treatment) will be ingested orally daily for eight weeks.
干预措施: Placebo (Other)
结局指标
主要结局
MCCB: MATRICS Consensus Cognitive Battery
时间窗: Baseline, Week 4 and Week 8
The MATRICS Consensus Cognitive Battery assesses cognitive function in the following domains: speed of processing, attention/vigilance, verbal learning, visual learning, reasoning and problem solving, and social cognition.
次要结局
- UPSA: UCSD Performance-Based Skills Assessment(Baseline, Week 4 and Week 8)
- SCoRS: Schizophrenia Cognition Rating Scale(Baseline, Week 4 and Week 8)
研究者
Stephen R. Marder
Principal Investigator
University of California, Los Angeles