Study of Thyroid Hormones in Prematures

This study is a Phase III multicenter, masked, placebo controlled randomized clinical trial
(RCT) of thyroid hormone supplementation in premature infants. Survival for extremely low
gestational age neonates (ELGAN; 24 - 28 weeks) has risen to >80% over the past 40 years yet
cognitive delays or cerebral palsy (CP) still affect 30% of survivors. Since more than
25,000 ELGANs are born each year in the United States, a major priority in newborn medicine
must be to translate the gains in survival into gains in healthy survival without the
current high frequency of impairments. Transient hypothyroxinemia of prematurity (THOP)
occurs in 50% of ELGANs and is strongly associated as an independent risk factor with lower
IQ scores, behavioral abnormalities and CP in ELGANs. Prior evidence suggested a benefit
from replacement therapy but studies were underpowered to prove this. The current project
extends the findings of our Phase 1 trial (THOP1; R01-NS45109) where four thyroid hormone
regimens were tested. We showed that continuous infusion of 4 µg/Kg/day thyroxine x 42d
could safely correct transient hypothyroxinemia without markedly lowering TSH - creating a
"biochemical euthyroid" state. THOP2 is designed to test the primary hypothesis that
compared to placebo, thyroid hormone supplementation from birth will reduce from 30% to 21%
the proportion of subjects with a composite endpoint of "CP or a Bayley III Cognitive Score
< 85." A Secondary hypothesis is that hormone treatment will improve other measures of
cognitive and executive function or attention as assessed by: i) Bayley III Parent Interview
for Adaptive Behavior and the BRIEF-P (Behavioral Rating Inventory of Executive
Function-Preschool Version) and ii) the frequency of screening positive on the Modified
Checklist for Autism in Toddlers (M-CHAT). We plan to enroll 1,224 subjects over a 19.8
month period at 14 centers to obtain 388 surviving toddlers at 36 months corrected age in
each of two arms. The current application describes the scientific basis of the proposed
overall clinical trial; it is linked to a cluster application creating a Data Monitoring and
Analysis Coordinating Center (DCC) at Michigan State University (MSU). The additional
societal cost from CP in an affected person's lifetime is estimated at $1 million; the costs
of mental retardation are even higher. If this trial shows that an inexpensive intervention
can reduce the risks of CP and mental retardation by 30% in ELGANs, we estimate the overall
savings from preventing more than 2,000 such cases (9% of 25,000) at about $2 billion per
year.

Inclusion Criteria:

1. Neonates 24 0/7 to 27 6/7 weeks gestational age

2. inborn or transferred; < 24 hours old

Exclusion Criteria:

1. Maternal or congenital thyroid disease or

2. Maternal substance abuse by history at the time of birth (heroin or cocaine)

3. Major congenital or surgical malformations of neonate

4. Known chromosomal anomalies detected by antepartum testing or direct physical
examination

5. Absence of parental consent or treating physician assent

6. A concurrent clinical trial with another randomized drug

7. Death expected < 48h vi) Another concern by the treating physician that either
mandates or prohibits study treatment such as known adverse drug interaction

8. mother < 18 years old at delivery