Randomized Trial of Enteral Vitamin D Supplementation in Infants < 28 Weeks Gestational Age or <1000 Grams Birth Weight

Overview

The objective of the study is to compare supplementation with vitamin D at 800 IU/day to usual care for the first 28 days after birth with respect to 25 (OH) vitamin D levels and indicators of likely or plausible effects of vitamin D supplementation on the function or structure of the lung, bones, immune system, and brain in extremely premature (EP) infants who are <28 weeks gestational age (GA) or <1000 grams of birth weight (BW). The study results will be analyzed as intention to treat Bayesian analyses (Frequentist analyses will also be performed).

Study Type

• Study Type: Interventional
• Study Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Primary Purpose: Other
  • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Study Primary Completion Date: January 1, 2025

Interventions

• Dietary Supplement: Placebo
  • Placebo is normal saline, given in the first 28 days after birth, prepared to have the same volume and appearance as vitamin D, which is a clear odorless solution.
• Dietary Supplement: 800 IU/day vitamin D supplementation with feedings in the first 28 days after birth
  • 800 IU/day Vitamin D supplementation until 400 IU/ day are provided as part of usual care. At that point the intervention becomes a supplement of 400 IU/day above that given with usual care. In this way all infants in the intervention group receive 800 IU/day of vitamin D total supplementation in the first 28 days after birth with feedings.
• Other: Usual Care
  • Co-interventions will be unaffected and provided based on the judgment of the attending neonatal faculty and NICU policies and routine practices

Arms, Groups and Cohorts

• Active Comparator: Usual care plus placebo
  • Infants will receive placebo (normal saline) in the first 28 days after birth. Co-interventions will be unaffected and provided based on the judgment of the attending neonatal faculty and NICU policies and routine practices.
• Experimental: Usual care plus vitamin D supplementation
  • Infants will receive cholecalciferol 800 IU/day in the first 28 days after birth, given enterally four times per day (0.5mL per dose = 200 IU) until the infant is provided 400 IU/day. At that point the study cholecalciferol will be reduced to 400 IU/day for a total supplementation of 800 IU/day.

Clinical Trial Outcome Measures

Primary Measures

• 25-hydroxyvitamin D (25[OH]D) level
  • Time Frame: about 28 days after birth

Secondary Measures

• 25-hydroxyvitamin D (25[OH]D) level
  • Time Frame: 36 weeks after birth
• Type of respiratory support required at 36 weeks postmenstrual age
  • Time Frame: 36 weeks postmenstrual age (or at the time of discharge home if earlier)
  • Data will be reported categorically as: Number of participants who survive without respiratory support Number of participants who survive with nasal cannula at ≤ 2 liters (L)/minute Number of participants who survive with nasal cannula >2 L/minute or noninvasive positive airway pressure Number of participants who survive with invasive mechanical ventilation Number of participants who die
• Length of Hospital stay
  • Time Frame: from time of birth to time of discharge (about 0 to 60 weeks after birth)
• Number of participants who are still on respiratory support
  • Time Frame: 22 to 26 months corrected age
  • Respiratory support includes supplemental oxygen and positive pressure ventilation.
• Number of days of supplemental oxygen
  • Time Frame: from time of birth to time of discharge (about 0 to 60 weeks after birth)
• Number of days of mechanical ventilation
  • Time Frame: from time of birth to time of discharge (about 0 to 60 weeks after birth)
• Number of days of positive pressure support
  • Time Frame: from time of birth to time of discharge (about 0 to 60 weeks after birth)
• Number of participants who receive steroid treatment to decrease respiratory support
  • Time Frame: from baseline to 36 weeks postmenstrual age
• Number of participants with pulmonary hypertension
  • Time Frame: 36 weeks postmenstrual age
• Number of participants with wheezing
  • Time Frame: 2 years
• Weight as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 28 days of life
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Weight as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 36 weeks postmenstrual age
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Weight as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 2 years
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Length as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 28 days of life
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Length as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 36 weeks postmenstrual age
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Length as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 2 years
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Head circumference as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 28 days of life
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Head circumference as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 36 weeks postmenstrual age
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Head circumference as assessed by sex-specific Z-score on the Fenton 2013 Growth Calculator
  • Time Frame: 2 years
  • Z-scores range from -4 standard deviations to +4 standard deviations. A higher Z-score indicates a better outcome.
• Number of participants with any fractures
  • Time Frame: from baseline to 36 weeks postmenstrual age
• Number of participants with hospital-acquired sepsis
  • Time Frame: from day 3 after birth to the time of discharge (which is 0 to 60 weeks after birth)
• Calcium level
  • Time Frame: 0 to 36 weeks postmenstrual age
• Phosphorus level
  • Time Frame: 0 to 36 weeks postmenstrual age
• Alkaline phosphatase level
  • Time Frame: 0 to 36 weeks postmenstrual age
• Neurodevelopment as assessed by the Bayley-IV Scale of Infant and Toddler Development (Cognitive composite score)
  • Time Frame: 2 years
  • Cognitive composite score ranges from 40 to 160, with a higher score indicating a better outcome.
• Neurodevelopment as assessed by the Bayley-IV Scale of Infant and Toddler Development (Language composite score)
  • Time Frame: 2 years
  • Language composite score ranges from 40 to 160, with a higher score indicating a better outcome.
• Neurodevelopment as assessed by the Bayley-IV Scale of Infant and Toddler Development (Motor composite score)
  • Time Frame: 2 years
  • Motor composite score ranges from 40 to 160, with a higher score indicating a better outcome.
• Number of participants with neurodevelopmental impairment (NDI)
  • Time Frame: 2 years
• Number of participants who die or have a morbidity
  • Time Frame: 36 weeks postmenstrual age
  • Morbidities include retinopathy of prematurity (ROP), intraventricular hemorrhage (IVH), bronchopulmonary dysplasia (BPD), neurodevelopmental impairment (NDI), necrotizing enterocolitis (NEC), and patent ductus arteriosus (PDA).
• Vitamin D status as indicated by serum concentration of 24,25(OH)2D3 as assessed by Liquid Chromatography with tandem mass spectrometry (LC-MS/MS)
  • Time Frame: about 28 days after birth
• Vitamin D status as indicated by serum concentration of 24,25(OH)2D3 as assessed by LC-MS/MS
  • Time Frame: 36 weeks postmenstrual age
• Vitamin D status as indicated by serum concentration of 3-epi-25(OH)D3 as assessed by LC-MS/MS
  • Time Frame: about 28 days after birth
• Vitamin D status as indicated by serum concentration of 3-epi-25(OH)D3 as assessed by LC-MS/MS
  • Time Frame: 36 weeks postmenstrual age
• Vitamin D status as indicated by serum concentration of 25(OH)D3 as assessed by LC-MS/MS
  • Time Frame: about 28 days after birth
• Vitamin D status as indicated by serum concentration of 25(OH)D3 as assessed by LC-MS/MS
  • Time Frame: 36 weeks postmenstrual age

Participating in This Clinical Trial

Inclusion Criteria

• Infants born at < 28 weeks gestational age (GA) or <1000 grams birth weight (BW) – Inborn – Informed written consent in an Institutional Review Board (IRB)-approved manner Exclusion Criteria:

• GA >32 weeks regardless of birth weight (BW) – Any major congenital anomaly – An known congenital nonbacterial infection – Prenatal diagnosis of disorders that affect vitamin D absorption (e.g, cystic fibrosis) – Such severe illness or immaturity that the attending neonatologist judges intensive care to be unjustified.

Gender Eligibility: All

Minimum Age: 24 Hours

Maximum Age: 96 Hours

Are Healthy Volunteers Accepted: No

Investigator Details

• Lead Sponsor
  • The University of Texas Health Science Center, Houston
• Provider of Information About this Clinical Study
  • Principal Investigator: Maria del Mar Romero López, Assistant Professor – The University of Texas Health Science Center, Houston
• Overall Official(s)
  • Sunil Jain, MD, Principal Investigator, The University of Texas Medical Branch
• Overall Contact(s)
  • Sunil Jain, MD, 409-772-2815, skjain@utmb.edu