Intraventricular Hemorrhage of Prematurity
Conditions
Keywords
Thyroxine, Intraventricular hemorrhage, MRI with DTI,, Neurodevelopmental outcome
Brief summary
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
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.
Interventions
DRUGThyroxine
8 µg/kg/day divided into two doses intravenous every 12 hours
DRUGPlacebo
Placebo
Sponsors
Westchester Medical Center
Morgan Stanley Children's Hospital
University of Pittsburgh
Children's Minnesota Hospital
University of Minnesota
St. Louis University
Arkansas Children's Hospital Research Institute
Brigham and Women's Hospital
University of North Carolina, Chapel Hill
Wake Forest University Health Sciences
Albert Einstein College of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded and randomized
Intervention model description
Double-blinded, placebo-controlled, and randomized controlled trial to compare outcomes between thyroxine and placebo treatment
Eligibility
Sex/Gender
ALL
Age
3 Days to 6 Days
Healthy volunteers
No
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.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Death or disability | 22-26 months of age | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| BSID-IV Cognitive subscale | 22-26 months of age | Bayley Scales of Infant and Toddler Development (BSID) IV score. |
| BSID-IV Language subscale | 22-26 months of age | Bayley Scales of Infant and Toddler Development (BSID) IV score. |
| Binary composite outcome of death or moderate/severe NDI | 22-26 months of age | 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) |
| Cerebral palsy incidence and severity | 22-26 months of age | We will perform neurological examination as in PENUT study and GMFCS scoring to determine cerebral palsy incidence and severity |
| BSID-IV Motor subscale | 22-26 months of age | Bayley Scales of Infant and Toddler Development (BSID) IV score. |
Other
| Measure | Time frame | Description |
|---|---|---|
| MRI studies: Kidokoro WM and global scores | 44+/-1 weeks of postmenstrual age | Kidokoro WM and global scores as in Kidokoro et al ( Am J Neuroradiol 34, 2208-2214:2013) |
| MRI studies: myelinated and unmyelinated WM brain volume | 44+/-1 weeks of postmenstrual age | 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) |
| MRI studies: dMRI measures (fractional anisotropy; radial, axial and mean diffusivity) in the corpus callosum and corticospinal tract | 44+/-1 weeks of postmenstrual age | dMRI analyses |
Countries
United States
Outcome results
None listed