Vitamin D Supplementation for Extremely Preterm Infants

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

Detailed Description
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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.

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

Conditions
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Vitamin D Deficiency, Preterm Infants, Bronchopulmonary Dysplasia

Intervention / Treatment
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* Dietary Supplement: Cholecalciferol
* Dietary Supplement: Cholecalciferol
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Minute
Maximum Age: 7 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oral Vitamin D--200 IU/day<br>Cholecalciferol 200 IU given orally once per day | Dietary Supplement: Cholecalciferol<br>* 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<br>* Other names: Vitamin D;|
| Placebo Comparator: Placebo<br>Identical-appearing treatment that does not contain the test drug given orally four times per day. | Dietary Supplement: Placebo<br>* Sterile water 0.5ml given orally every 6 hours. Duration of 28 postnatal days<br>|
| Active Comparator: Oral Vitamin D--800 IU/day<br>Cholecalciferol 800 IU given orally once per day | Dietary Supplement: Cholecalciferol<br>* 800 IU/day given orally per day as 4 doses of 200 IU/0.5ml each every 6 hours. Duration of 28 postnatal days<br>* Other names: Vitamin D;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin D, Newborn, Preterm, Supplementation, Respiratory