Treatment of Lead-exposed Children The TLC Clinical Trial The Study

Prevention of Lead-induced Developmental Delay with Oral Chelation:
the Treatment of Lead-exposed Children (TLC) trial

1. Background
   Prospective, observational studies have shown that lead produces a dose- (or blood level-) related reduction in developmental test scores (Needleman and Gatsonis, 1990; Pocock et al., 1994) . The clearest relationship is between peak blood lead, which occurs at 20 to 30+ months of age, and test scores beginning at age 48-57 months and thereafter. There is no demonstrated threshold for this effect; it occurs at levels achieved by one million or more children in the US (Pirkle et al., 1994), and at levels that produce no symptoms or laboratory abnormalities. Although childhood lead exposure may also affect growth, hearing, behavior, and blood pressure, the best quantified effect at low levels is on developmental test scores; an increase in blood lead of 10 µg/dl is associated with a decrease in IQ of 2-3 points. If lead causes developmental delay, that effect can be prevented by preventing lead exposure. However, since the mechanism of the effect is unknown, it is unclear whether it can be reversed or attenuated once exposure has occurred. It is this question of reversibility which underlies the TLC project.
   
   
2. Research problem
   In 1991, the Centers for Disease Control recommended universal screening of children for elevated blood lead (Centers for Disease Control, 1991). They recommended medical therapy, i.e., chelation, for children with blood leads greater than 45 µg/dl. They recommended against medical therapy for children whose blood leads were less than 20 µg/dl, and left the option of therapy, no therapy, or participation in trials of therapy for children between 20 and 45 µg/dl. Until 1991, chelation of lead-poisoned children had been done in specialized centers, which admitted children and treated them parenterally (usually intravenously). However, also in 1991, the orally active chelating drug Chemet® (succimer, McNeil) was licensed (as an Orphan Drug) for treatment of young children with blood levels of 45 µg/dl.
   
   NIEHS and its advisors, especially the American Academy of Pediatrics Committee on Environmental Health, believed that many children would be treated with this drug at blood leads below the labelled level, despite the fact that there was relatively little evidence of safety and no evidence of efficacy for prevention of the latent effects of lead, including developmental delay. Lowering of blood lead per se at these levels is without known clinical benefit.
   
   NIEHS believed that a formal trial of succimer for the prevention of developmental delay in children was warranted. Drug therapy is costly (Chemet® costs about $300/course, most children need multiple courses over months), potentially hazardous, and would be given to asymptomatic children. Effective, simple intervention to regain lost IQ points, however, would be useful in these children and be very cost-effective in the long run. Primary prevention, i.e., prevention of exposure, is perhaps another generation away for millions of children. Good data on which to base therapy were necessary. McNeil (the pharmaceuticals company) was interested only in further studies showing that Chemet reduced blood lead, and had no plans to test the ability of the drug to prevent developmental delay.
   
   
3. Methods
   • Hypothesis
     The Treatment of Lead-exposed Children (TLC) trial is the NIEHS-sponsored, four-center, placebo-controlled randomized trial of succimer for the prevention of lead-induced alterations in growth, behavior, and development. For all participants, TLC provides vitamin and mineral supplementation, and either cleans the families' homes or helps move them in order to reduce lead dust exposure. The TLC protocol was developed collaboratively, and is summarized here.
     
     
   • First Stage Eligibility
     Most children in TLC have been referred to TLC Clinical Centers for management of their elevated blood lead. Children must be between 12 and 33 months at the time of randomization, have a referral blood lead between 20 and 45 µg/dl, and be testable in English (or Spanish, in Newark).
     
     At the first clinic visit, parents or guardians of referred eligible children are asked to sign a Phase I consent, which covers the eligibility parts of the study (up to randomization). The families are also given an explanation of the whole study and the Phase II consent form for treatment to take home with them. The children have a physical exam and blood drawn for blood lead and ferritin levels done at CDC, and some screening clinical lab work.
     
     Families are given a month's supply of TLC vitamins and minerals and a vitamin diary. Appointments are made for TLC home inspection and clean-up, and for a second pre-treatment clinic visit about one month later. For most visits, the centers pay for transportation, give TLC logo items, like hats, T-shirts, and magnets, and offer other small emoluments (e.g. disposable diapers, apple sauce, grocery coupons) for participation.
     
     
   • Reduction of Exposure to Lead Dust
     The environmental visits -- inspection, clean-up and dust wipes -- are scheduled in the month between the two pre-treatment clinic visits. Children whose blood lead level from CDC is still between 20 and 44 µg/dl then have their homes inspected. The purpose of the home inspection is to determine whether the cleaning and minor repair work that TLC does can be expected to suppress leaded dust for a period of six months (the maximum time a child will be on drug in TLC). We try to have the clean-up completed before the child goes on drug; although there is no evidence that succimer enhances lead absorption and some evidence that it does not, we do not want a child on drug to have access to heavily leaded dust. Inspectors often re-check and sometimes re-clean a house at 3 months.
     
     We have paid special attention to the safety of the TLC cleaning and inspection crews, but very few houses have been disqualified because our staff felt unsafe. We have also tried to be sensitive to the families' fears, and try to have male-female cleaning crews working in the houses of the single female parents. TLC environmental staff work in pairs, never go into homes alone, and most environmental visits are done in the morning and early afternoon hours.
     
     
   • Second Stage Eligibility
     At the second pre-treatment clinic visit, a second blood lead is drawn, and the vitamin diary is reviewed with the family. Clinic staff explains the treatment and follow-up parts of the study, and the families are asked to sign the Phase II consent form. Children whose second blood lead remains in the 20-44 µg/dl range are then randomized by the Data Coordinating Center. Drug administration must begin within two weeks of this blood lead, so the first treatment visit is scheduled accordingly. Turnaround times on blood leads done at CDC are crucial to the success of TLC. Average time from receipt of samples to data reporting at CDC is 1.2 days. Results are transmitted electronically from the Central Laboratory to the Data Coordinating Center.
     
     
   • Treatment
     The drug as dispensed is not suitable for administration to children this age, and so at the first treatment visit, staff instructs the parents how to open the capsule and sprinkle the coated beads onto apple sauce. Families are given a medication diary, information about overdose or ingestions, and a number where they can reach study staff. Patients do not know whether they have active drug or placebo. The bottles have a scratch off site that identifies them as placebo or control in the event that it is medically necessary to know off hours. Families are told that we will do pill counts.
     
     At the Ohio site, we are using bottles with a computer chip in the cap that records when the bottle is opened. It also beeps to remind parents of the ideal time to administer drug. We do baseline, age-appropriate psychometric testing (Bayley Scales of Infant Development II) at this first treatment visit, weigh the child using TLC scales, measure the child using a stadiometer, and measure blood pressure. All of these are primary or secondary outcome measures, and some degree of quality control and standardization has gone in to all of the measurements. No blood leads are done at this visit.
     
     
   • Patient monitoring
     Blood lead levels and laboratory tests done after study drug is begun are masked from the treating physician. There is a designated physician at each site who gets the results of the laboratory tests and checks whether the child has violated pre-determined boundaries for white cell count, platelets, or serum enzymes.
     
     Children return for clinic visits at 7, 28, and 42 days after the beginning of therapy. At each of these treatment visits, a blood lead is done. The Data Coordinating Center reviews treatment period blood leads, which they receive electronically from the Central Laboratory at CDC. If a child's blood lead exceeds pre-determined boundaries, the Coordinating Center notifies the Clinical Center to either to do an immediate repeat blood lead, or, if appropriate, to interrupt treatment and treat the child according to the Clinical Center's local standards of care. If a child's end-of-treatment blood lead is not below 15 µg/dl, they are retreated for a maximum of 3 courses of treatment.
     
     TLC has an aggressive drug dosing regimen, which uses body surface area calculations to determine daily dose, and treats for 7 days longer than the 19 days on the label. Pre-treatment blood leads average in the low 20s; nevertheless, 85% of children are requiring a second course of drug, and 85% of them a third. TLC has an explicit, formal, documented procedure for reporting of adverse drug events, as well as yearly re-training for all clinicians.
     
     
   • Follow-up
     In follow-up, children are seen at about three month intervals clinically and for blood lead measurement during the first two years, and at about four month intervals in the last (third) follow-up year. Follow-up visits follow the 1991 CDC guidelines for frequency of visits at these blood lead levels. Post-treatment blood leads are managed openly, but the blind is not explicitly broken, and a given child cannot be identified as having been on drug or placebo from their blood lead.
     
     At the one year follow-up visit, we test maternal IQ using the Wechsler Adult Intelligence Scale -- Revised, Short Form (WAISR-SF). Psychometric follow-up of children is at 6 months, 18 months and 36 months post randomization. TLC uses the Bayley Scales (BSID2) up to age 42 months; after that, we use the Wechsler Primary and Pre-school Scales of Intelligence, Revised (WPPSI-R); therefore, all children are old enough to be tested using the WPPSI at the 36 month post randomization visit. At this, the last follow-up visit, we also assess the child's behavior, and do some tests of cognition, including the recently published Developmental Assessment of Neuropsychological Functions (NEPSY).
     
     
4. Progress to date
   TLC began randomizing patients in Fall, 1994. Enrollment was completed in January 1997, with 780 total children.
   
   In all, TLC clinical centers screened about 2,000 children, performed more than 1,200 home environmental assessments, and randomized 780 children. All children have completed their treatment course, and are in various stages of TLC follow up. TLC's first 36-month follow up visits, which include the final IQ asssessment and NEPSY administration, are scheduled for late in 1997.
   
   Publication of the description of the baseline data from TLC will appear in the journal Paediatric and Perinatal Epidemiology sometime in Spring 1998. (See "Publications")
   
   TLC has a Data and Safety Monitoring Committee which has provided on-going peer review. Its primary functions were to approve the protocol and to review risks and benefits of therapy, but it has also worked with recruitment, and has provided evaluations of study plans and tactics. Individual members have attended some of the site visits.
   
   
5. Significance
   It will be at least another 20 years before all US children live in homes that do not expose them to lead. Millions of children will experience lead exposure during those years that will delay their intellectual development, slow their growth, interfere with hearing and balance, etc. A small number of IQ points in a given child is not even clinically detectable and is within the test re-test variability of the instruments. However, with a pervasive exposure, the entire distribution of IQ is shifted in some groups of children. A small change in the population mean increases the number of children who are below 80 and need special services, and decreases the number above 120, from whom we expect much. A relatively simple oral regimen would be extremely useful in these children, very cost effective in the long run, and the right thing to do. On the other hand, if drug therapy does not prevent this delay, it has very little to recommend it, children can be spared exposure to side effects, and agencies the cost of the drug. The only way to make the decision rationally is to have data from formal trials.