Study of Thyroid Hormones in Prematures (THOP2)

Phase III Study of Thyroid Hormones in Prematures

The investigators hypothesize that continuous infusion of 4 µg/Kg/day T4 with 30 µg/Kg/day oral potassium iodide (KI) for 42 days from birth will reduce by 30% or more (from an estimated 30% to 21%) the proportion of extremely low gestational age subjects with a composite endpoint of "cerebral palsy (CP) or a Bayley III Composite Cognitive Score < 85" at 36 months corrected postnatal age (CA).

Study Overview

• Status: Withdrawn
• Conditions: Transient Hypothyroxinemia of Prematurity (THOP)
• Intervention / Treatment: Drug: thryoid hormone T4 + oral potassium iodide (KI) for 42 days; Drug: D5W - 5% dextrose water

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • Valhalla, New York, United States, 10595
      • Maria Fareri Childrens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 hour to 1 day (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: T4 + KI; Continuous infusion of 4 µg/Kg/day T4 with 30 µg/Kg/day oral potassium iodide (KI) for 42 days	Drug: thryoid hormone T4 + oral potassium iodide (KI) for 42 days; Continuous infusion of 4 µg/Kg/day T4 with 30 µg/Kg/day oral potassium iodide (KI) for 42 days; Other Names: levothyroxin; postassium iodide
Placebo Comparator: D5W - 5% dextrose water; Receive the same volume as study drug but as D5W placebo	Drug: D5W - 5% dextrose water; Equivalent volume of infusion as study drug; Other Names: Standard hospital pharmacy solution

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare incidence of a COMPOSITE endpoint of "cerebral palsy (CP) or a Bayley III Composite Cognitive Score < 85" at 36 months corrected postnatal age (CA).	Bayley III Cognitive Score and a standardize ELGAN-type neurological exam (Kuban) plus a Palisano assessment of function	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Compare measures of cognitive and executive function and attention.	As assessed by the following tests: The mean scores of the Bayley III Parent Interview for Adaptive Behavior and the BRIEF-P (Behavioral Rating Inventory of Executive Function-Preschool Version).; The frequency of screening positive on the Modified Checklist for Autism in Toddlers (M-CHAT).	36 months corrected age

Collaborators and Investigators

• Sponsor: New York Medical College
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Edmund F La Gamma, MD, New York Medical College

Publications and helpful links

General Publications

• La Gamma EF, van Wassenaer AG, Ares S, Golombek SG, Kok JH, Quero J, Hong T, Rahbar MH, de Escobar GM, Fisher DA, Paneth N. Phase 1 trial of 4 thyroid hormone regimens for transient hypothyroxinemia in neonates of <28 weeks' gestation. Pediatrics. 2009 Aug;124(2):e258-68. doi: 10.1542/peds.2008-2837. Epub 2009 Jul 5.

Study record dates

Study Major Dates

• Study Start (Anticipated): July 1, 2020
• Primary Completion (Anticipated): May 1, 2025
• Study Completion (Anticipated): May 1, 2026

Study Registration Dates

• First Submitted: May 2, 2013
• First Submitted That Met QC Criteria: April 3, 2014
• First Posted (Estimate): April 4, 2014

Study Record Updates

• Last Update Posted (Actual): April 24, 2019
• Last Update Submitted That Met QC Criteria: April 22, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: cerebral palsy; brain development; extremely low gestational age neonate; hypothyroxinemia of prematurity; cognitive dealy
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Trace Elements; Micronutrients; Iodine; Hormones
• Other Study ID Numbers: THOP2 - NYMC - CCC

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No