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

描述（由申请人提供）：

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.