Biomarker and Safety Study of Clozapine in Benign Ethnic Neutropenia

氯氮平治疗良性种族中性粒细胞减少症的生物标志物及安全性研究

• 批准号: 9179487
• 负责人: DEANNA L KELLY
• 金额: $ 4.66万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9179487
• 关键词: African; African American; Agranulocytosis; Alleles; American; Antigen Receptors; Antipsychotic Agents; Attention; Benign; Biological Assay; Biological Markers; Caucasians; Cells; Clozapine; Complex; Confidence Intervals; Data; Drops; European; Evaluation; Frequencies; Functional disorder; Genes; Genetic Markers; Genetic Polymorphism; Genotype; Guidelines; HLA Antigens; Homozygote; Improve Access; Individual; Infection; Leukocytes; Literature; Measurement; Measures; Monitor; Mutation; Neutropenia; Nigerian; Participant; Patients; Pattern; Persons; Pilot Projects; Population; Prevalence; Publishing; Refractory; Reporting; Research; Resistance; Risk; Risk Estimate; Safety; Sampling; Schizophrenia; Time; Variant; White Blood Cell Count procedure; Work; chemokine; genotyped patients; high risk; meetings; neutrophil; potential biomarker; safety study; safety testing

 DESCRIPTION (provided by applicant): Clozapine is the most effective antipsychotic for the treatment of schizophrenia however it is underused particularly in the African American population. Low Absolute Neutrophil Counts (ANC), either baseline or during treatment (a drop in ANC below the threshold of 1500 mm3 currently mandates clozapine discontinuation) is a significant barrier to clozapine use in AA patients. Our pilot work finds that discontinuation of clozapine (particularly for neutropenia) in AA patients is over twice that in Caucasians. Recently the phenomenon of Benign Ethnic Neutropenia (BEN) in AAs has gained attention. BEN is frequent in AA with low ANCs, but is NOT associated with an increased risk for agranulocytosis or infection. Normative ranges for white blood cell (WBC) and ANC counts were established with Caucasian samples and clozapine guidelines in the US do not permit lower fluctuations of ANC. Unfortunately, lower fluctuations are often seen in persons with BEN, requiring clozapine discontinuation. Our pilot work has shown that AA BEN patients may be successfully treated with clozapine despite low ANC (outside current guidelines) with no greater risk of agranulocytosis. Our work to date, if supported by a larger study, suggests that clozapine could be safely used in people with BEN, improving access to clozapine treatment for AA patients with schizophrenia as well as evaluation for the first time the Duffy Antigen Receptor Chemokine (DARC) gene in relation to BEN and ANC levels. We aim to safely use clozapine in 250 black patients (100-120 in US and 130-150 in a SubSaharan Nigerian population) to examine the safety of use and the risk of agranulocytosis. Our study will evaluate ANC twice weekly for 3 months prior and weekly 6 months after clozapine initiation. We also plan to evaluate the fluctuating patterns of WBC and ANC (mean levels, within subject s.d., frequency and duration of mild, moderate or severe neutropenia, and requirement for initiation of extra monitoring for very low ANC) in psychotic patients with BEN.

 描述（由申请人提供）：氯氮平是治疗精神分裂症最有效的抗精神病药物，但其使用不足，特别是在非裔美国人群体中，无论是基线还是治疗期间（ANC 下降到阈值以下）。 1500 mm3 目前要求停止使用氯氮平）是 AA 患者使用氯氮平的一个重大障碍。我们的试点工作发现，停止使用氯氮平。 AA 患者（尤其是中性粒细胞减少症）是白种人的两倍以上。最近，AA 中的良性种族中性粒细胞减少症 (BEN) 现象在 ANC 较低的 AA 中很常见，但与粒细胞缺乏症风险增加无关。白细胞 (WBC) 和 ANC 计数的正常范围是根据白种人样本确定的，美国的氯氮平指南不允许较低的波动。不幸的是，BEN 患者的波动较低，因此需要停用氯氮平，我们的试点工作表明，尽管 ANC 较低（超出现行指南），但 AA BEN 患者仍可成功治疗，且粒细胞缺乏症的风险不会增加。迄今为止，如果得到更大规模研究的支持，表明氯氮平可以安全地用于 BEN 患者，从而改善 AA 精神分裂症患者接受氯氮平治疗的机会，并评估我们首次研究了达菲抗原受体趋化因子 (DARC) 基因与 BEN 和 ANC 水平的关系，我们的目标是在 250 名黑人患者（美国 100-120 名，撒哈拉以南尼日利亚人口 130-150 名）中安全使用氯氮平，以检查其安全性。我们的研究将在开始氯氮平治疗前 3 个月每周两次评估 ANC，并在开始治疗后 6 个月每周评估一次 ANC。评估 BEN 精神病患者的 WBC 和 ANC 波动模式（受试者标准差内的平均水平、轻度、中度或重度中性粒细胞减少症的频率和持续时间，以及对极低 ANC 进行额外监测的要求）。