Vitamin D Supplementation for Extremely Preterm Infants

Early Vitamin D Supplementation for Prevention of Respiratory Morbidity in Extremely Preterm Infants: A Randomized Clinical Trial

The study hypothesis states that giving early enteral Vitamin D supplementation to preterm infants will decrease respiratory morbidity in extremely preterm infants.

Study Overview

• Status: Completed
• Conditions: Vitamin D Deficiency; Preterm Infants; Bronchopulmonary Dysplasia
• Intervention / Treatment: Dietary supplement: Cholecalciferol; Dietary supplement: Cholecalciferol; Dietary supplement: Placebo

Detailed Description

After informed consent obtained, infants will be randomized using computer-generated stratified randomization codes by the pharmacy. Clinicians, researcher, and primary caregivers will be masked. Subjects will be randomly assigned to one of the treatment arms or to a placebo concurrent control.

Early vitamin D supplementation/placebo will be initiated within the first 7 days after birth. Premature infants will be randomized to receive one of the 3 fixed doses of vitamin D: either placebo (zero dose), 200 IU/day, or 800 IU/day. The supplementation will be started within 72 hours of enteral feeds being initiated and will continue until postnatal day 28. After this period of supplementation, routine supplementation will be conducted in all groups.

Remnant cord blood samples will be analyzed for vitamin D levels (serum hydroxyvitamin D [25(OH)D]. Two circulating vitamin D concentrations (25(OH)D concentrations) will be measured on postnatal days 14 and 28. Urine samples will be collected weekly, to determine calcium excretion if high serum calcium concentrations are found.

Supplementation will be discontinued and infant will exit the study if surgical necrotizing enterocolitis/bowel perforation is diagnosed, if 25 (OH)D concentrations >60ng/mL (>150nmol/L; potentially toxic) are detected or, if infant NPO for greater than 24 hours. If infant made briefly NPO (<24h) for feeding intolerance, suspected sepsis, hypotension,hemodynamically significant PDA, or respiratory difficulties, enteral vitamin D will not be discontinued.

All infants will be followed to discharge for primary, secondary outcomes as well as adverse events.

• Study Type: Interventional
• Enrollment (Actual): 100
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 minute to 1 week (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Infants admitted to the Regional Newborn ICU of the University of Alabama with gestational age between 23-27 completed weeks

Exclusion Criteria:

• Major congenital/chromosomal anomalies
• Moribund infant with low likelihood of survival, in opinion of the clinical team

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Oral Vitamin D--200 IU/day; Cholecalciferol 200 IU given orally once per day	Dietary supplement: Cholecalciferol; 200 IU/day given orally once per day as one of 4 doses of 0.5ml each given every 6 hours. Other 3 doses will be placebo (sterile water). Duration of 28 postnatal days; Other Names: Vitamin D; Dietary supplement: Cholecalciferol; 800 IU/day given orally per day as 4 doses of 200 IU/0.5ml each every 6 hours. Duration of 28 postnatal days; Other Names: Vitamin D
Placebo Comparator: Placebo; Identical-appearing treatment that does not contain the test drug given orally four times per day.	Dietary supplement: Placebo; Sterile water 0.5ml given orally every 6 hours. Duration of 28 postnatal days
Active Comparator: Oral Vitamin D--800 IU/day; Cholecalciferol 800 IU given orally once per day	Dietary supplement: Cholecalciferol; 200 IU/day given orally once per day as one of 4 doses of 0.5ml each given every 6 hours. Other 3 doses will be placebo (sterile water). Duration of 28 postnatal days; Other Names: Vitamin D; Dietary supplement: Cholecalciferol; 800 IU/day given orally per day as 4 doses of 200 IU/0.5ml each every 6 hours. Duration of 28 postnatal days; Other Names: Vitamin D

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total number of days alive and off respiratory support in the first 28 days	The total number of days alive and off respiratory support. Respiratory support is defined as need of supplemental oxygen and/or positive pressure ventilation to maintain normal target oxygen saturations (88-95%).	28 days
Serum vitamin D concentration	Serum vitamin D levels determined by enzyme immunoassay obtained from whole blood (remnant sample or obtained during clinical blood draw)	Day after birth 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of sepsis episodes treated with antibiotics for at least 5 days	Number of episodes of culture proven or clinically suspected sepsis episodes treated with antibiotics for at least 5 days	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Sepsis	Culture proven or culture negative clinically treated course consistent with sepsis	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Need for supplemental oxygen at 36 weeks of corrected age (Physiologic definition)	A physiologic oxygen challenge test will be administered to infants from 36.0 weeks gestation to 37.0 weeks gestation to determine a need for supplemental oxygen to keep saturation levels between 88-95%.	36 weeks gestational age corrected
Duration of mechanical ventilation after randomization	Counted as number of days on which an infant is on mechanical ventilation for any part of a calendar day	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Days alive and off mechanical ventilation in the first 28 days after birth	Counted as days alive without mechanical ventilation for any part of a day	28 days
Number of re-intubation events	Counted as number of reintubations for purposes of respiratory support	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Death	Cardiorespiratory failure	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Surgical necrotizing enterocolitis or intestinal perforation	Radiographic documentation of pneumatosis or intestinal perforation or treatment course for clinical necrotizing enterocolitis per Bell's stage greater than 1.	Participants will be followed for the duration of hospital stay, an expected average of 4 months
25(OH)D concentrations >60ng/ml (150 nmol/L)	Vitamin D measurement per blood obtained either centrally or by heel stick.	14 postnatal (+/- 2 days)
25(OH)D concentrations >60ng/ml (150 nmol/L)	Vitamin D measurement per blood obtained either centrally or by heel stick.	28 days postnatal age (+/- 3 days)
Serum calcium level	Serum calcium measurement per blood obtained either centrally or by heel stick, performed for clinical care. High serum calcium level is greater than 3 mmol/l of total calcium or total calcium of >12 mg/dL, or ionized calcium >2 mml/L.	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Urine calcium level	Calcium measurement per urine, random sampling. High level (>95%tile) urine calcium to creatinine ratio is >3.8 mmol/mmol.	Participants will be followed for the duration of hospital stay, an expected average of 4 months
Meningitis	Culture proven or culture negative clinically treated course consistent with meningitis	Participants will be followed for the duration of hospital stay, an expected average of 4 months

Other Outcome Measures

Outcome Measure	Time Frame
Death or Neurodevelopmental Impairment	Birth to 22-26 months of age

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Children's Health System, Alabama
• Investigators: Study Director: Ariel A. Salas, MD, University of Alabama at Birmingham

Publications and helpful links

General Publications

• Huey SL, Acharya N, Silver A, Sheni R, Yu EA, Pena-Rosas JP, Mehta S. Effects of oral vitamin D supplementation on linear growth and other health outcomes among children under five years of age. Cochrane Database Syst Rev. 2020 Dec 8;12(12):CD012875. doi: 10.1002/14651858.CD012875.pub2.
• Fort P, Salas AA, Nicola T, Craig CM, Carlo WA, Ambalavanan N. A Comparison of 3 Vitamin D Dosing Regimens in Extremely Preterm Infants: A Randomized Controlled Trial. J Pediatr. 2016 Jul;174:132-138.e1. doi: 10.1016/j.jpeds.2016.03.028. Epub 2016 Apr 11.

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: May 14, 2012
• First Submitted That Met QC Criteria: May 15, 2012
• First Posted (Estimate): May 17, 2012

Study Record Updates

• Last Update Posted (Actual): February 10, 2017
• Last Update Submitted That Met QC Criteria: February 8, 2017
• Last Verified: February 1, 2017

More Information

Terms related to this study

• Keywords: Vitamin D; Supplementation; Newborn; Respiratory; Preterm
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Lung Injury; Infant, Premature, Diseases; Ventilator-Induced Lung Injury; Vitamin D Deficiency; Premature Birth; Bronchopulmonary Dysplasia; Physiological Effects of Drugs; Micronutrients; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; Vitamins; Ergocalciferols
• Other Study ID Numbers: UAB Neo 006