Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy (D-Wheeze)

• ClinicalTrials.gov Identifier: NCT01601847
• Recruitment Status: Completed
• First Posted: May 18, 2012
• Results First Posted: June 8, 2018
• Last Update Posted: June 8, 2018
• Sponsor: Case Western Reserve University
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Office of Dietary Supplements (ODS)
• Information provided by (Responsible Party): Anna Maria Hibbs, Case Western Reserve University

Study Description

Brief Summary:

The goal of this study is to identify a vitamin D supplementation strategy that best promotes the lung, immune, and overall health of black infants born preterm (28-36 weeks gestational age). This is a high risk population that seems to have unique vitamin D needs, and inappropriate supplementation may promote wheezing or allergy. The results of this study will help form nutritional recommendations for the approximately 100,000 black infants born at 30-36 weeks gestational age in the U.S. every year.

Condition or disease	Intervention/treatment	Phase
Wheezing; Allergy	Dietary Supplement: Cholecalciferol; Drug: Cholecalciferol	Phase 4

Detailed Description:

Black infants face the highest rates of prematurity in the U.S. (18%), have high rates of prematurity-associated wheezing illnesses, and tend to have lower vitamin D levels. The goal of this [comparative effectiveness] study is to identify a vit. D supplementation strategy that minimizes recurrent wheezing in infancy. Long recognized as important for bone health, a growing body of evidence suggests that vit. D may play a role in the regulation and development of many organ systems. The D pathway regulates lung inflammation and impacts morphogenesis, structure, and cell growth and survival in bronchial smooth muscle. Vit. D exposure has the potential to skew cytokine expression from a Th1 (less allergic) to a Th2 (more allergic) phenotype. Due to their developmental immaturity, preterm infants may be particularly vulnerable to any positive or negative effects of vit. D supplementation on the lung, airway, and immune system. Our preliminary data, supported by the literature, suggests that overly aggressive vit. D supplementation may inadvertently increase wheezing in infancy in black, but not white, preterm infants; however, vit. D deficiency could theoretically also increase wheezing via vulnerability to respiratory pathogens. The proposed study is a randomized clinical trial comparing the effect of two different enteral vitamin D supplementation strategies on recurrent wheezing in infancy in 300 black infants born preterm at 28 0/7-36 6/7 wks gestational age, a population for whom neither vit. D requirements nor optimal vit. D serum levels have been established. The investigators will test two strategies: (I) sustained supplementation until 6 mo. of age adjusted for prematurity, and (II) cessation of supplementation when a minimum dietary intake of 200 IU/day is reached. The specific aims are to characterize the effect of each strategy on (aim 1) recurrent wheezing and (aim 2) allergic sensitization and atopy. The investigators will (aim 3) explore the relationship between vit. D serum levels and recurrent wheezing. The investigators hypothesize that strategy II will be more effective in promoting pulmonary health by minimizing recurrent wheezing, allergic sensitization, and overall healthcare utilization, and will be sufficient to prevent clinical vit. D deficiency. The investigators also hypothesize that optimal vit. D serum levels will be lower than the norms for other populations.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 300 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Wheezing in Black Preterm Infants: Impact of Vitamin D Supplementation Strategy
• Study Start Date: January 2013
• Actual Primary Completion Date: March 12, 2017
• Actual Study Completion Date: March 12, 2017

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Sustained; Infants will remain on 400 IU/day of cholecalciferol until 6 months of age adjusted for prematurity, regardless of dietary intake	Drug: Cholecalciferol; Infants will receive cholecalciferol 400 IU/day PO until they are 6 months of age adjusted for prematurity; Other Names: D-Vi-Sol; Vitamin D
Placebo Comparator: Diet-Limited; Infants will receive placebo once their dietary intake of vitamin D has exceeded 200 IU/day	Dietary Supplement: Cholecalciferol; Once the dietary intake of vitamin D has exceeded 200 IU/Day, the infants will receive placebo until they are 6 months of age adjusted for prematurity

Outcome Measures

Primary Outcome Measures :

1. Number of Infants With Recurrent Wheezing [ Time Frame: up to 12 months adjusted age ]
   Recurrent wheezing was defined as more than 1 episode of wheezing reported during the study period. Separate episodes were defined as occurring at least 2 weeks apart.

Secondary Outcome Measures :

1. Number With Infants With Allergic Sensitization as Measured by the PhadiaTop Infant Assay [ Time Frame: Measured at the 12 month adjusted age visit ]
   Measured using the Phadiatop Infant IgE panel
2. Bone Density [ Time Frame: Measured at the 12 month adjusted age visit ]
   Measured by bone speed of sound (ultrasound)

Eligibility Criteria

• Ages Eligible for Study: up to 1 Year (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

1. 28 0/7-36 6/7 weeks gestational age (GA) at birth;
2. family identifies the child as black or African American;
3. < 28 days of supplemental oxygen (subsequent oxygen therapy for < 72 hrs for a brief subsequent illness or surgery will be allowed);
4. admitted to a participating site NICU, special care nursery, transitional care nursery, or well-baby nursery as a neonate; and
5. < 40 weeks corrected GA at enrollment.

Exclusion criteria:

1. BPD (> 28 days of supplemental oxygen);
2. pre-existing diagnosis of moderate to severe osteopenia of prematurity and/or alkaline phosphatase > 700;
3. history of fracture;
4. gastrointestinal surgery, including for NEC;
5. known gastrointestinal malabsorption;
6. major congenital anomaly;
7. congenital pulmonary or airway disorder (e.g., cystic fibrosis, tracheomalacia, swallowing disorder, bronchopulmonary sequestration);
8. documented wheezing or stridor prior to enrollment;
9. previous vit. D supplementation with > 400 IU/day;
10. family plans to move more than 60 miles from CWRU or other pre-defined radius at other sites;
11. baseline hypo- or hypercalcemia, hypo- or hyperphosphatemia; and
12. baseline 25(OH) D level < 10 ng/ml.

Contacts and Locations

Locations

United States, New York

Montefiore Medical Center

New York, New York, United States, 10467

United States, Ohio

Case Western Reserve University

Cleveland, Ohio, United States, 44023

University Hospitals

Cleveland, Ohio, United States, 44023

MetroHealth Medical Center

Cleveland, Ohio, United States, 44109

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

Sponsors and Collaborators

Case Western Reserve University

National Heart, Lung, and Blood Institute (NHLBI)

Office of Dietary Supplements (ODS)

Investigators

• Principal Investigator: Anna Maria Hibbs, MD, MSCE; Case Western Reserve University

  Study Documents (Full-Text)

Documents provided by Anna Maria Hibbs, Case Western Reserve University:

Study Protocol and Statistical Analysis Plan  [PDF] March 19, 2014

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Benson AC, Chen Z, Minich NM, Tatsuoka C, Furman L, Ross K, Hibbs AM. Human milk feeding and wheeze in Black infants born preterm. J Perinatol. 2022 Nov;42(11):1480-1484. doi: 10.1038/s41372-022-01471-w. Epub 2022 Aug 4.

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.

Ledingham L, Tatsuoka C, Minich N, Ross KR, Kerns LA, Wagner CL, Fuloria M, Groh-Wargo S, Zimmerman T, Hibbs AM. Burden of prematurity-associated recurrent wheezing: caregiver missed work in the D-Wheeze trial. J Perinatol. 2021 Jan;41(1):69-76. doi: 10.1038/s41372-020-0729-7. Epub 2020 Jul 21.

Hibbs AM, Ross K, Kerns LA, Wagner C, Fuloria M, Groh-Wargo S, Zimmerman T, Minich N, Tatsuoka C. Effect of Vitamin D Supplementation on Recurrent Wheezing in Black Infants Who Were Born Preterm: The D-Wheeze Randomized Clinical Trial. JAMA. 2018 May 22;319(20):2086-2094. doi: 10.1001/jama.2018.5729. Erratum In: JAMA. 2018 Aug 14;320(6):605.

• Responsible Party: Anna Maria Hibbs, Assistant Professor of Pediatrics, Case Western Reserve University
• ClinicalTrials.gov Identifier: NCT01601847
• Other Study ID Numbers: R01HL109293 ( U.S. NIH Grant/Contract ); R01HL109293 ( U.S. NIH Grant/Contract )
• First Posted: May 18, 2012
• Results First Posted: June 8, 2018
• Last Update Posted: June 8, 2018
• Last Verified: May 2018

Additional relevant MeSH terms:

Respiratory Sounds; Signs and Symptoms, Respiratory; Vitamin D; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents