Vitamin D and Vascular Health in Children

Vitamin D and Vascular Function in Obese Children

In this study, we will test the central hypothesis that enhancement of vitamin D status in obese and overweight children will improve their vascular health and their cardiovascular disease (CVD) and metabolic syndrome risk profile.

Study Overview

• Status: Completed
• Conditions: Obesity; Vitamin D Deficiency
• Intervention / Treatment: Dietary supplement: Vitamin D3

Detailed Description

Our primary objective is to determine, in obese and overweight children aged 10 to 18 years with vitamin D deficiency (defined as serum 25-hydroxyvitamin D <20 ng/mL), the efficacy of enhanced vitamin D3 supplementation in improving vascular endothelial function, arterial stiffness, insulin sensitivity, and metabolic syndrome risk status; and to assess whether these effects are dose-dependent. As a secondary objective, we will examine the vitamin D supplementation-induced effect on adipokines and inflammatory markers relevant to CVD risk. In a double-masked, controlled trial, we will randomize 252 eligible children to receive either 600 IU (conventional supplementation), or 1000 IU or 2000 IU (enhanced supplementation) of vitamin D3 daily for 6 months.

In terms of reporting of results, the following pre-specified outcomes are included in the primary manuscript (PubMed PMID:31950134 -- see Reference section for citation details)

1. Waist Circumference
2. Serum High Density Lipoprotein (HDL) Cholesterol
3. Serum Triglycerides
4. Inflammatory markers (Plasma TNF-alpha, high-sensitivity C-reactive protein, and IL-6)
5. Adiopkines (Plasma Leptin and Adiponectin)

Plasma nitric oxide metabolites were not measured.

• Study Type: Interventional
• Enrollment (Actual): 225
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Primary Care Center, Children's Hospital of Pittsburgh of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 18 years (Child, Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eligible subjects will be 10 to 18 years of age;
• obese or overweight (BMI ≥85th %tile);
• otherwise healthy, and
• have a serum 25(OH)D concentration <20 ng/mL

Children taking multivitamins should be able to hold off their multivitamins during the course of the study.

Exclusion Criteria:

Children will be excluded if they

• (a) have hepatic or renal disease, metabolic rickets, malabsorptive disorders, primary hyperparathyroidism, hyperthyroidism, or other chronic disorders that could affect vitamin D metabolism;
• (b) are receiving treatment with anticonvulsants, systemic glucocorticoids, pharmacologic doses of vitamin D (≥1000 IU of vitamin D2 or D3 daily), antihypertensives, vasoactive drugs, antilipidemics, metformin, antipsychotics, or other oral insulin regulators;
• (c) have cholelithiasis or urolithiasis;
• (d) have type 1 or type 2 diabetes; or
• (e) have a condition or underlying abnormality that could compromise the safety of the subject.

Post-menarchial girls with a positive pregnancy test at randomization, or subjects found during the screening phase to have hypercalcemia (serum calcium >10.8 mg/dL) or significant fasting hyperglycemia (fasting blood glucose ≥ 125 mg/dL) will also be excluded.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vitamin D3 2000 IU; Vitamin D3 2000 IU tablet once daily by mouth for 6 months	Dietary supplement: Vitamin D3; Tablet form; Other Names: Cholecalciferol
Active Comparator: Vitamin D3 1000 IU; Vitamin D3 1000 IU tablet by mouth once daily for 6 months	Dietary supplement: Vitamin D3; Tablet form; Other Names: Cholecalciferol
Placebo Comparator: Vitamin D3 600 IU; Vitamin D3 600 IU tablet by mouth once daily for 6 months	Dietary supplement: Vitamin D3; Tablet form; Other Names: Cholecalciferol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Flow-mediated Dilation (FMD) Percentage	Brachial artery flow-mediated dilation percentage is a measure of endothelial function. FMD percentage calculation is based on baseline brachial artery diameter(brachialADbase) and change in brachial artery diameter (brachialADchange) during post-occlusive reactive hyperemia. FMD% was determined using the formula (brachialADchange/brachialADbase) x 100.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse-wave Velocity (PWV)	PWV is a measure of arterial stiffness. Higher values of PWV indicate greater degree of arterial stiffness.	6 months
Augmentation Index at Heart Rate of 75 Beats/Min (AIx-75)	AIx-75 is a measure of arterial stiffness. AIx was measured through radial arterial tonometry using SphygmoCor. Radial pulse waveform are analyzed through an automatic software function to determine aortic pulse waveform and aortic or central systolic (cSBP) and diastolic blood pressure (cDBP), and these measurements are further analyzed automatically to calculate AIx. AIx is a composite measure of the magnitude of wave reflection and arterial stiffness in all conduit arteries which affect the timing of the wave reflection. AIx = P2-P1/cSBP-cDBP, where P1 is the height of the incident pressure wave form during systole, P2 is the height of the reflected wave added to the incident wave, cSBP is the aortic systolic BP, and cDBP is the aortic diastolic BP. AIx adjusted to heart rate of 75 beats/min (AIx-75) is a validated index of arterial stiffness, with higher values indicating higher degree of arterial stiffness.	6 months
Central Systolic Blood Pressure	a measure of cardiometabolic health	6 months
Central Diastolic Blood Pressure	a measure of cardiometabolic health	6 months
Systemic Systolic Blood Pressure	a measure of cardiometabolic health	6 months
Systemic Diastolic Blood Pressure	a measure of cardiometabolic health	6 months
Fasting Blood Glucose	a measure of cardiometabolic health	6 months
1/Fasting Insulin Ratio	1/fasting insulin ratio is a measure of insulin sensitivity. Increases in 1/fasting insulin ratio indicate improvements in insulin sensitivity.	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body Mass Index (BMI)	a surrogate measure of adiposity	6 months

Collaborators and Investigators

• Sponsor: University of Pittsburgh
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Office of Dietary Supplements (ODS)
• Investigators: Principal Investigator: Kumaravel Rajakumar, MD, MS, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC

Publications and helpful links

General Publications

• Rajakumar K, Moore CG, Khalid AT, Vallejo AN, Virji MA, Holick MF, Greenspan SL, Arslanian S, Reis SE. Effect of vitamin D3 supplementation on vascular and metabolic health of vitamin D-deficient overweight and obese children: a randomized clinical trial. Am J Clin Nutr. 2020 Apr 1;111(4):757-768. doi: 10.1093/ajcn/nqz340.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2013
• Primary Completion (Actual): August 13, 2018
• Study Completion (Actual): August 13, 2018

Study Registration Dates

• First Submitted: February 20, 2013
• First Submitted That Met QC Criteria: February 20, 2013
• First Posted (Estimate): February 22, 2013

Study Record Updates

• Last Update Posted (Actual): June 24, 2020
• Last Update Submitted That Met QC Criteria: June 10, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Obesity; Insulin resistance; metabolic syndrome; Vascular Function; Vitamin D Deficiency
• Additional Relevant MeSH Terms: Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Vitamin D Deficiency; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: PRO12100034; R01HL112985 (U.S. NIH Grant/Contract); 5R01HL112985-05 (U.S. NIH Grant/Contract)