Study of Thyroid Hormones in Prematures (THOP2)

• ClinicalTrials.gov Identifier: NCT02103998
• Recruitment Status: Withdrawn
• First Posted: April 4, 2014
• Last Update Posted: April 24, 2019
• Sponsor: New York Medical College
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Edmund F LaGamma, MD, New York Medical College

Study Description

Brief Summary:

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).

Condition or disease	Intervention/treatment	Phase
Transient Hypothyroxinemia of Prematurity (THOP)	Drug: thryoid hormone T4 + oral potassium iodide (KI) for 42 days; Drug: D5W - 5% dextrose water	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase III Study of Thyroid Hormones in Prematures
• Estimated Study Start Date: July 1, 2020
• Estimated Primary Completion Date: May 2025
• Estimated Study Completion Date: May 2026

Arms and Interventions

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 Name: Standard hospital pharmacy solution

Outcome Measures

Primary Outcome Measures :

1. 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). [ Time Frame: 36 months ]
   Bayley III Cognitive Score and a standardize ELGAN-type neurological exam (Kuban) plus a Palisano assessment of function

Secondary Outcome Measures :

1. Compare measures of cognitive and executive function and attention. [ Time Frame: 36 months corrected age ]

   As assessed by the following tests:

   1. The mean scores of the Bayley III Parent Interview for Adaptive Behavior and the BRIEF-P (Behavioral Rating Inventory of Executive Function-Preschool Version).
   2. The frequency of screening positive on the Modified Checklist for Autism in Toddlers (M-CHAT).

Eligibility Criteria

• Ages Eligible for Study: up to 24 Hours (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

United States, New York

Maria Fareri Childrens Hospital

Valhalla, New York, United States, 10595

Sponsors and Collaborators

New York Medical College

National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Edmund F La Gamma, MD; New York Medical College

More Information

Publications of Results:

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.

• Responsible Party: Edmund F LaGamma, MD, Professor of Pediatrics, New York Medical College
• ClinicalTrials.gov Identifier: NCT02103998
• Other Study ID Numbers: THOP2 - NYMC - CCC
• First Posted: April 4, 2014
• Last Update Posted: April 24, 2019
• Last Verified: April 2019

• 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

Keywords provided by Edmund F LaGamma, MD, New York Medical College:

extremely low gestational age neonate; hypothyroxinemia of prematurity; brain development; cerebral palsy; cognitive dealy

Additional relevant MeSH terms:

Premature Birth; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Iodine; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Trace Elements; Micronutrients; Nutrients; Growth Substances