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The New England Childrens Amalgam Trial (CAT)

• David C. Bellinger, Ph.D., M.Sc.
• Harvard Medical School
• Childrens Hospital Boston
• Funded by a cooperative agreement between the
  NIDCR and New England Research Institutes (Sonja
  M. McKinlay, Ph.D., Principal Investigator)

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Protocol Synopsis

• Objective Evaluate the potential adverse health
  effects of mercury exposure from dental amalgams
  in children by conducting a randomized clinical
  trial comparing silver dental amalgam versus
  alternative restorative materials (thus avoiding
  possible selection and confounding biases often
  present in a strictly observational study)
• Primary Outcomes Neuropsychological function
• Secondary Outcomes Renal function

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Protocol Synopsis

• Children were recruited from two geographic areas
  (1997-1999)
• Boston/Cambridge MA (5 community dental clinics)
• Farmington, ME (county dental health center)
• All dental care provided by CAT staff
• Baseline restorations
• Semi-annual visits for

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Protocol Synopsis

• Eligibility Criteria
• Age 6 to 10
• No prior amalgams
• 2 posterior teeth with caries such that
  restoration would involve an occlusal surface
• English-speaking
• No major health disorders that would be expected
  to affect performance on neuropsychological tests
  or affect renal function

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Recruitment

• Dental clinics in community-health centers
• In Boston/Cambridge area, also
• Mass mailings
• Newspaper advertisements
• Brochures in affiliated dental clinics
• Referrals from previously screened participants
  and non-CAT dental personnel
• Advertisements on local TV

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Subject Recruitment Flow Diagram
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Protocol Synopsis

• Two treatment arms (equal allocation of 500
  children 534 actually enrolled)
• Amalgam restoration (posterior teeth
  only--composite in front teeth, as per current
  standard clinical practice)
• Non-amalgam (composite) restoration
• Stratification
• 4 equally-sized cells, defined jointly by site
  (MA/ME) and number of caries at baseline (2-4/5)
• Mean number of caries (all surfaces) was 9.4
• In NHANES III, mean was 4.1 decayed surfaces in 5
  to 9 year olds

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Characteristic Arm A Arm B
Site
Boston/Cambridge 53.9 55.1
No. carious surfaces primary 8.0 (6.7) 7.4 (6.1)
No. carious surfaces permanent 1.8 (2.4) 1.8 (2.3)
Age 7.9 (1.3) 7.9 (1.4)
Male 50.9 41.6
Race/ethnicity
White 62.9 61.4
Black 22.5 19.1
Hispanic 7.1 11.6
Other/Unknown 7.5 7.9
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Characteristic Arm A Arm B
Total Income
lt10,000 11.9 10.4
10,001-20,000 17.4 22.7
20,001-30,000 25.7 22.7
30,001-40,000 19.0 19.2
40,001-50,000 13.8 11.5
gt50,000 12.3 13.5
WISC-III FSIQ 95.1 (14.5) 96.1 (12.1)
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Exposure Indices for Purposes of Analyses

• Treatment group assignment amalgam vs. composite
  (intent-to-treat)
• Cumulative surface-years of amalgam exposure
  (external dose)
• loss of filled primary dentition
• incident caries
• Urinary mercury (absorbed dose) baseline, 2 mos
  (A only), 6 mos (A only), 12 mos, 24 mos, 36 mos,
  48 mos, 60 mos

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Outcomes Neuropsychological Function

• Primary Full-Scale IQ (WISC-III)
• Secondary
• Achievement
• Wechsler Individual Achievement Test
• Psychosocial status
  baseline, 12, 24, 36, 48, 60 mos
• Behavior Assessment System for Children
• Memory and Learning
• Wide Range Assessment of Memory and Learning
• Visual Motor Ability
• Wide Range Assessment of Visual Motor Ability
• Executive Functions
• Wisconsin Card Sorting Test
• Trail-Making Test
• Stroop Color-Word Interference Test
• Attention
• Verbal cancellations
• Reaction time
• Language
• Verbal fluency

baseline, 36, 60 mos
Baseline, 12, 24, 48 mos
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Outcomes Renal Function

• Urinary markers (spot sample, Cr-adjusted)
• Gamma glutamyl transpeptidase (?-GT)
• Protein HC (a1-microglobulin)
• N-acetyl-ß-D-glucosaminidase (NAG)
• Microalbuminuria

proximal tubule damage
glomerular damage
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Biological Sample Collection Schedule
Baseline 2 mos 6 mos Yr 1 Yr 2 Yr 3 Yr 4 Yr 5
anthropometry X A A X X X X X
blood draw X X
urine sample
mercury X A A X X X X X
?-GT X A A X X X X X
protein HC X X
NAG X X
albumin X X
hair sample X X X X
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Immune Function Substudy

• N 61 randomly selected (CAT) children
• Blood samples collected pre-randomization, 5-7 d
  after baseline dental treatment, and at 6, 12,
  18, and 60 mos post-randomization
• Indices
• Total white cell count
• Lymphocyte distribution (CD3, CD4, CD8,
  monocytes, B cells)
• T-cell function (activation marker CD69, IL-2R)
• B-cell function (activation markers CD69 and CD23
• Immunoglobulin (IgG, IgM)

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Power and Sample Size

• Assumptions
• Target effect size is a 3 point difference
  between treatment arms on WISC-III Full-Scale IQ
  at 60 mos post-restoration
• a of 0.045 for final look, due to spending 0.005
  of an overall a of 0.05 on an interim look at
  36-mos. (safety analysis for DSMB)
• SD of IQ 15 and correlation between baseline
  and 60-month IQ score 0.75 thus SD for IQ
  change, adjusting for baseline value 9.92 pts
• Target power of 80 (ß of 0.2)
• Therefore, 179 children per treatment arm (a
  retention rate as low as 75) will provide 80
  power to detect the target effect size

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Actual Power/Sample Size Per Treatment Arm
Initial Assumption Based on 36-Month Data
SD of IQ 15.0 13.4
Correlation between baseline 60-mos IQ 0.75 0.82
needed per arm For 80 power For 85 power For 90 power 179 204 238 107 122 142
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Sample Size Summary

• Standard deviation of Full-Scale IQ slightly
  lower than initially assumed
• Correlation of baseline 36-month Full-Scale IQ
  slightly higher than initially assumed
• We anticipate at least 215 children per treatment
  arm will provide 60-month outcome data
• If these revised assumptions hold, power to
  detect a treatment group difference of 3 points
  in Full-Scale IQ will be 97

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Annual Outcome Timeline
(2003 DSMB Report)
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Outcome Cycle Disposition
Open cycles
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CAT Investigators

• Principal Investigator Sonja M. McKinlay, Ph.D.1
• Dental Mary Tavares, D.M.D.2
• Exposure Thomas W. Clarkson, Ph.D.3
• Neuropsychology David C. Bellinger, Ph.D.,4
  David Daniel, Ph.D.5
• Renal Lars Barregard, Ph.D.6
• Immune Bruce Shenker, Ph.D.7
• Biostatistics Felicia Trachtenberg, Ph.D.1
• NIDCR Norman S. Braveman, Ph.D.
• New England Research Institutes 5.
  University of Maine at Farmington
• Forysth Institute
  6. University of Goteberg
• University of Rochester 7.
  University of Pennsylvania Dental
• Harvard Medical School
  School