d-Penicillamine Chelation in lead-poisoned Children - A Phase ll/lll Trial

d-青霉胺螯合剂治疗铅中毒儿童 - II/III 期试验

• 批准号: 7371744
• 负责人: MICHAEL W SHANNON
• 金额: $ 17.83万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2009-06-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371744
• 关键词: Penicillamine; Chelation; lead; poisoned; Children

DESCRIPTION (provided by applicant): Approximately 300,000 children in the US have elevated blood levels (10 mcg/dl or greater). Lead poisoning in children is unequivocally harmful, producing the neurodevelopmental consequences of cognitive losses, attentional difficulties and behavioral disturbances, including antisocial or delinquent tendencies. Non-neurodevelopmental consequences of lead poisoning include impairment of heme synthesis, reduction in I-hydroxylation of 25(OH)-cholecalciferol (the Vitamin D precursor) and renal injury that results in microproteniuria, an increased risk of hypertension and a greater likelihood of renal failure in adulthood. Despite these well-defined toxicities, treatments for childhood lead poisoning have been inadequate. Currently chelation therapy is uniformly recommended only for children with severe lead poisoning (blood lead > 45 mcg/dl). Approved chelating agents for severe plumbism are CaNa2EDTA (edetate disodium calcium) and succimer. For children with blood levels less than 45 mcg/dl treatment is fraught with difficulties including inconsistent recommendations by clinical experts, lack of proven benefit of chelation and the absence of a chelating agent approved for use in this range. d-Penicillamine is a lead chelator that has been used off-label for almost 4 decades. Several studies have suggested that d-Penicillamine is both safe and effective in the treatment of low-level lead poisoning. The investigators propose to evaluate in a Phase 2/3 randomized, placebo-controlled clinical trial, the effectiveness of d-Penicillamine in 50 children, aged 6 months to 16 years, with blood levels 15 - 25 mcg/dl. The d-Penicillamine product will be a newly developed, IND-approved liquid formulation. The study will be performed in the Pediatric Environmental Health Center of Children's Hospital Boston. The primary outcome measure will be the ability of a 6-week course of d-Penicillamine to produce sustained reductions in blood lead level. Secondary outcome measures will be normalization of non-neurodevelopmental physiologic aberrations known to occur with lead poisoning, specifically abnormalities in heme and Vitamin D synthesis. If this clinical trial demonstrates safety and efficacy, d-Penicillamine will potentially provide another option among the limited treatment choices for lead-poisoned children. This trial may also provide a basis for examining the drug's efficacy in improving neurodevelopment outcome in children exposed to harmful amounts of lead.

描述（由申请人提供）： 在美国，大约有30万儿童血液中的浓度升高（10 mcg/dl或更高）。 儿童铅中毒无疑是有害的，会造成认知丧失、注意力困难和行为障碍等神经发育后果，包括反社会或犯罪倾向。 铅中毒的非神经发育后果包括血红素合成受损、25（OH）-胆钙化醇（维生素D前体）的I-羟基化减少和导致微蛋白尿的肾损伤、高血压风险增加和成年后肾衰竭的可能性增加。 尽管有这些明确的毒性，但对儿童铅中毒的治疗一直不足。目前，螯合疗法仅被统一推荐用于严重铅中毒（血铅> 45 mcg/dl）的儿童。 批准用于治疗严重铅中毒的螯合剂是CaNa 2 EDTA（依地酸二钠钙）和琥珀酰亚胺。 对于血液水平低于45 mcg/dl的儿童，治疗充满了困难，包括临床专家的建议不一致，缺乏螯合作用的证明益处，以及缺乏批准用于该范围的螯合剂。 d-青霉胺是一种主要螯合剂，已被用于标签外近40年。 几项研究表明，d-青霉胺在治疗低水平铅中毒方面既安全又有效。 研究人员建议在2/3期随机，安慰剂对照临床试验中评估d-青霉胺在50名6个月至16岁儿童中的有效性，血液浓度为15 - 25 mcg/dl。d-青霉胺产品将是一种新开发的IND批准的液体制剂。该研究将在波士顿儿童医院的儿科环境健康中心进行。主要的结局指标是d-青霉胺6周疗程持续降低血铅水平的能力。次要结局指标将是已知铅中毒发生的非神经发育生理异常的正常化，特别是血红素和维生素D合成的异常。 如果这项临床试验证明了安全性和有效性，d-青霉胺将可能为铅中毒儿童提供另一种有限的治疗选择。这项试验也可能为检查药物在改善暴露于有害量铅的儿童神经发育结果方面的疗效提供基础。