Thyroxine Treatment in Premature Infants With Intraventricular Hemorrhage (IVHT4)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Intraventricular Hemorrhage of Prematurity
• Intervention / Treatment: Drug: Placebo; Drug: Thyroxine

Detailed Description

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.

• Study Type: Interventional
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • Bronx, New York, United States, 10461
      • Praveen Ballabh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 3 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRI studies: dMRI measures (fractional anisotropy; radial, axial and mean diffusivity) in the corpus callosum and corticospinal tract	dMRI analyses	44+/-1 weeks of postmenstrual age
MRI studies: myelinated and unmyelinated WM brain volume	After visual quality control, initial total brain segmentation for tissue types will be done using T2 weighted images with MANTIS, an in-house method of automated Morphologically Adaptive Neonatal Tissue Segmentation (Alexander, et al. 2017)	44+/-1 weeks of postmenstrual age
MRI studies: Kidokoro WM and global scores	Kidokoro WM and global scores as in Kidokoro et al ( Am J Neuroradiol 34, 2208-2214:2013)	44+/-1 weeks of postmenstrual age

Collaborators and Investigators

• Sponsor: Albert Einstein College of Medicine
• Collaborators: University of Pittsburgh; Brigham and Women's Hospital; Wake Forest University Health Sciences; University of Minnesota; University of North Carolina, Chapel Hill; Morgan Stanley Children's Hospital; Arkansas Children's Hospital Research Institute; St. Louis University; Westchester Medical Center; Children's Minnesota Hospital
• Investigators: Principal Investigator: PRAVEEN BALLABH, MD, Albert Einstein College of Medicine

Study record dates

Study Major Dates

• Study Start (Anticipated): January 18, 2022
• Primary Completion (Anticipated): December 18, 2025
• Study Completion (Anticipated): January 18, 2027

Study Registration Dates

• First Submitted: December 21, 2017
• First Submitted That Met QC Criteria: December 28, 2017
• First Posted (Actual): January 4, 2018

Study Record Updates

• Last Update Posted (Actual): July 8, 2022
• Last Update Submitted That Met QC Criteria: July 5, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Keywords: Intraventricular hemorrhage; Thyroxine; Neurodevelopmental outcome; MRI with DTI,
• Additional Relevant MeSH Terms: Pathologic Processes; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Intracranial Hemorrhages; Hemorrhage; Cerebral Hemorrhage
• Other Study ID Numbers: 2017-8707

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No