Penicillamine Chelation for Children With Lead Poisoning

Condition(s) targeted: Lead Poisoning; Vitamin D Deficiency

Intervention: d-penicillamine (Device); placebo (Drug)

Phase: Phase 2/Phase 3

Status: Active, not recruiting

Sponsored by: FDA Office of Orphan Products Development

Official(s) and/or principal investigator(s):
Michael W Shannon, MD, Study Director, Affiliation: Children's Hospital Boston

Childhood Lead Poisoning is a widespread disease that has few effective treatments. The specific aims of this proposed clinical trial are threefold:

- To determine whether a six-week course of a newly formulated d-penicillamine suspension

will effectively reduce blood lead level in children aged 6 months to 16 years with blood lead levels of 15-25 μg/dL.

- To determine whether d-penicillamine chelation produces a sustained reduction in blood

lead level in comparison with succimer and other lead chelators which always produce a significant post-treatment "rebound".

- To determine whether chelation with d-penicillamine improves the physiologic

disturbances that can be measured in children with blood lead levels in this range.

Official title: A Phase 2/3 Trial of d-Penicillamine Chelation in Lead-Poisoned Children

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: • To determine whether a six-week course of a newly formulated d-penicillamine suspension will effectively reduce blood lead level in children aged 6 months to 16 years with blood lead levels of 15-25 μg/dL.

Secondary outcome: To determine whether d-penicillamine produces a sustained reduction in blood lead level and improves the physiologic disturbances that can be measured in children with blood lead levels in this range.

Detailed description: Approximately 300,000 children in the US have elevated blood lead 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 1-

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 and succimer. For children with blood lead 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. We propose to evaluate, in a Phase II/III randomized, placebo-controlled clinical trial, the effectiveness of d-penicillamine in 50 children aged 6 months to 16 years with blood lead 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 will also provide a basis for examining the drug's efficacy in improving neurodevelopment outcome in children exposed to harmful amounts of lead.

Minimum age: 6 Months. Maximum age: 16 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- Potential subjects will be children 6 months to 16 years of age with blood lead level

15-25 mcg/dL on two separate occasions separated by at least two weeks

Exclusion Criteria:

- allergic to d-penicillamine

- renal insufficiency

- taking immunosuppressive agents

- pre-existing idiopathic thrombocytopenia (platelet count < 100,000/mm3) or leukopenia

(WBC count < 5,000/mm3 or polymorphonuclear leukocyte count < 1000/mm3)

- blood lead level on the day of the initial clinic visit is below15 μg/dL or above 25

μg/dL

- blood lead level at the two-week follow up visit rises above 25 mcg/dL or falls below

15 mcg/dL

- currently undergoing chelation or have had chelation therapy in the previous two

months

Children's Hospital Boston, Boston, Massachusetts 02115, United States

Starting date: September 2007
Ending date: August 2010
Last updated: December 26, 2007