Thyroxine Treatment in Premature Infants With Intraventricular Hemorrhage

Study Overview
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Brief Summary
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Brain bleed in premature infants damages the brain and survivors suffer from cerebral palsy (weakness in the extremities), cognitive deficits, and neurobehavioral disorders. In this clinical trial, investigators will test whether thyroxine (hormone from thyroid gland) treatment in premature infants with moderate-to-large brain bleeds show recovery in the brain structure on MRI evaluation at the time of discharge (44+/-1 weeks) and neurodevelopmental improvement at 2 years of age.

Detailed Description
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Intraventricular hemorrhage (IVH) remains a major complication of prematurely born infants. Survivors of IVH suffer from cerebral palsy, cognitive deficits and neurobehavioral disorders. In the proposed study We hypothesize that T4 treatment in preterm (230/7-276/7 weeks) infants with grade II-IV IVH will: a) improve MRI biomarkers, including total myelinated white matter volume, Kidokoro scoring, functional connectivity between motor brain regions, and fractional anisotropy in the corpus callosum of preterm infants with grade II-IV IVH at 36 weeks postmenstrual age, and b) better composite outcome of disability and death. The composite outcome will be derived by integrating scores for Bayley Scales of Infant and Toddler Development (BSID-IV) Motor subscale at 22-26 months in survivors and BSID IV value of 46 assigned to deceased infants. To test these hypotheses, we will perform a randomized double-blinded placebo-controlled trial to determine the effect of T4 treatment on preterm infants with grade II-IV IVH. Ten participating neonatal intensive care units will enroll 346 premature infants (230/7-276/7 weeks gestational age. 173 in each arm) with unilateral or bilateral grade II-IV IVH over a period of 3 years. The treatment will consist of T4 administration (8 µg/kg/day divided into two doses) up to 34 weeks of postmenstrual age, which will be initiated at 2-5 days of postnatal age in all cases. The infants will undergo MRI with DTI at 36 weeks and neurobehavioral evaluation at 22-26 months of corrected age. We have assumed a 7.5 point mean difference (SD=15) in BSID-IV motor subscale between T4 and placebo groups, an overall mortality rate of 25%, and 5% reduction in mortality for each SD change in outcome. Based on these, we expect an increase in the induced composite outcome by ≥5.6 points in T4 treated group compared to placebo controls. The study will conclusively determine whether the proposed clinical trial of T4 treatment enhances motor outcome and diminishes composite endpoint of death or disability in preterm infants with grade II-IV IVH.

Official Title
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Thyroxine Treatment in Premature Infants With Intraventricular Hemorrhage: Phase III Clinical Trial

Conditions
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Intraventricular Hemorrhage of Prematurity

Intervention / Treatment
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* Drug: Thyroxine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria NICU inpatients born between 23-0/7 and 27-6/7 weeks of gestation Postnatal age 3-6days (≥3 d ≤ 6 d) Unilateral or bilateral Grade 3 or 4 IVH Parental consent Exclusion criteria: Major malformations, including surgical, cardiac, cerebral, chromosomal, or genetic syndromes, identifiable at or before birth; Congenital bacterial infection proven by culture at birth or viral syndrome known prior to delivery (e.g. chicken pox, rubella, etc.)

Ages Eligible for Study
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Minimum Age: 3 Days
Maximum Age: 6 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blinded, placebo-controlled, and randomized controlled trial to compare outcomes between thyroxine and placebo treatment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Thyroxine treatment<br>Intravenous thyroxine in a dose of 8 µg/kg/day divided into two doses (every 12 hours) | Drug: Thyroxine<br>* 8 µg/kg/day divided into two doses intravenous every 12 hours<br>* Other names: Levothyroxine;|
| Placebo Comparator: Placebo treatment<br>Intravenous placebo treatment every 12 hours. | Drug: Placebo<br>* Placebo<br>* Other names: Inactive substance in a similarly looking solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Death or disability | The primary outcome will be a quantitative composite outcome using the BSID-IV Motor score measured at 22-26 months among survivors while incorporating death using a floor value of 46. | 22-26 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BSID-IV Motor subscale | Bayley Scales of Infant and Toddler Development (BSID) IV score. | 22-26 months of age | 
| BSID-IV Cognitive subscale | Bayley Scales of Infant and Toddler Development (BSID) IV score. | 22-26 months of age | 
| BSID-IV Language subscale | Bayley Scales of Infant and Toddler Development (BSID) IV score. | 22-26 months of age | 
| Binary composite outcome of death or moderate/severe NDI | NDI will be defined as the presence of any of the following: BSID-IV Cognitive < 85, BSID-IV Motor <85, GMFCS ≥ 2 (NICHD, Neonatal Res. Network 2018) | 22-26 months of age | 
| Cerebral palsy incidence and severity | We will perform neurological examination as in PENUT study and GMFCS scoring to determine cerebral palsy incidence and severity | 22-26 months of age | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thyroxine, Intraventricular hemorrhage, MRI with DTI,, Neurodevelopmental outcome