Efficacy of Newborn Vitamin A Supplementation in Improving Immune Function

Vitamin A Deficiency Clinical Trial

Official title:

Efficacy of Newborn Vitamin A Supplementation in Improving Immune Function

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01583972
• Other study ID #: N3-TSA-003
• Secondary ID: PR-10012
• Status: Completed
• Phase: N/A
• First received: April 14, 2012
• Last updated: August 22, 2014
• Start date: January 2012
• Est. completion date: August 2014

Study information

• Verified date: August 2014
• Source: USDA, Western Human Nutrition Research Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Switzerland: Federal Office of Public HealthUnited States: Federal Government
• Study type: Interventional

Clinical Trial Summary

Vitamin A supplementation at birth may increase survival of infants through one year of age by reducing mortality from infectious diseases, though current studies are not conclusive on this point. The goal of our study is to determine if supplementation of newborn infants with 50,000 IU of vitamin A improves aspects of immune function that may be impaired by vitamin A deficiency. Our underlying assumption is that supplementation may thus decrease risk of death by improving immune function and the ability to survive infections. This project will be limited to the examination of the impact of vitamin A on immune function and will not aim to determine the impact on morbidity or mortality, which would require larger sample sizes. The hypotheses addressed by this study are as follows: Provision of vitamin A supplements to newborns at risk of vitamin A deficiency will (1) improve functioning of the thymus (the source of T lymphocytes, cells of the immune system that are important in response to infection and immunization); (2) enhance T lymphocyte-mediated responses to standard vaccines given at birth and early in infancy; and (3) improve gut barrier function (i.e., ability to prevent bacterial infection across the epithelial barrier), relative to provision of a placebo.

Description:

This project will examine the effect of vitamin A supplementation (50,000 IU) or placebo given with BCG and oral polio virus (OPV) immunization within 48 h of birth on immune function in 300 Bangladeshi infants (150 in each group) at risk of vitamin A deficiency recruited in a poor community of Dhaka, Bangladesh. Infants will be followed from birth through 15 wk of age. Current evidence from community-based mortality trials is not conclusive but suggests that such supplementation will decrease infant mortality from infectious disease through 6 m of age. The biological mechanism underlying this potential benefit is unclear but is presumed to include improving immune function. The investigators hypothesize that vitamin A supplementation at birth prevents vitamin A deficiency during a critical window of a few days to weeks when the immune system is first exposed to both normal, non-pathogenic organisms (e.g., commensal gut flora) and to potential pathogens. During this period the investigators propose that vitamin A supplementation will improve three aspects of immune function that will have sustained benefits throughout infancy: (1) normal thymus maturation and function; (2) development and mucosal targeting of adaptive immune responses, including regulatory T-cells (Treg), T-helper type 2 (Th2) cells, and IgA-secreting plasma cells and memory B-cells; and (3) mucosal barrier function. The three specific objectives of our project are: (1) Determine if vitamin A supplementation improves thymus maturation and function as indicated by ultrasonic analysis of thymus size and by analysis of thymic output of naïve T-cells using flow cytometric analysis of peripheral blood T-cells and by quantification of T-cell-receptor excision circles (TRECs) in peripheral blood. (2) Determine if vitamin A supplementation at birth alters (2.1) the T-cell response to BCG and OPV immunization assessed at 6 and 15 wk of age; (2.2) the T- and B-cell response to OPV immunization, assessed at 15 wk of age, and the secretory IgA response to OPV assessed at 6, 11 and 15 wk of age; and (2.3) the B-cell response to tetanus toxoid (TT) immunization, assessed at 15 wk of age. (3) Determine if vitamin A supplementation at birth will decrease bacterial lipopolysaccharide (LPS) concentrations in capillary blood, a marker of bacterial translocation.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 300
• Est. completion date: August 2014
• Est. primary completion date: July 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: N/A to 48 Hours

Eligibility

Inclusion Criteria:

• Infant receiving OPV and BCG within 48 hr of birth

Exclusion Criteria:

• Mother is less than 18 years of age

• Infant is part of a multiple birth

• Infant will likely not remain in the study area for the next 4 months

• Infant has a condition precluding vaccination

• Infant is unable to breastfeed or drink other fluids

• Birth weight is less than 1.5 kg

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Night Blindness
• Vitamin A Deficiency

Intervention

Dietary Supplement:
• retinyl palmitate
50,000 IU vitamin A in oil given within 48 h of birth from single-dose capsule
• Placebo
edible oil used as diluent for vitamin A given within 48 h of birth from single-dose capsule identical in appearance to vitamin A capsule

Locations

Country	Name	City	State
Bangladesh	International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b)	Dhaka

Sponsors (3)

Lead Sponsor	Collaborator
USDA, Western Human Nutrition Research Center	International Centre for Diarrhoeal Disease Research, Bangladesh, World Health Organization

Country where clinical trial is conducted

Bangladesh, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Thymus size measured by ultrasound	Thymus size will be assessed sonographically using a validated method in which the transverse diameter of the thymus and the sagittal area of its largest lobe are multiplied to give a volume-related thymic index (TI). This index has been shown to correlate with thymus weight and has been used to show that the human thymus is sensitive to environmental influences during infancy.	through 15 wk of age	No
Primary	peripheral blood naive T-helper lymphocyte concentration	Naive and memory CD4 T lymphocytes will be measured by flow cytometric analysis using the CD45RA and CD45RO markers to identify naive and memory CD4+ T-cells, respectively. Naive T cells develop in the thymus and their level in peripheral blood is an index of thymic function.	through 15 wk of age	No
Primary	T-cell receptor excision circle (TREC) level in peripheral blood mononuclear cells (PBMC)	Thymic T-cell production can be assessed by measuring signal-joint T cell receptor excision circles (TRECs) as a traceable molecular marker in newly produced naive T-cells. Thus, the content of TRECs in peripheral blood is an indicator of thymopoiesis or newly synthesized and exported naive T-cells. TREC assessment will be conducted in the stored peripheral blood mononuclear cells (PBMC) isolated from infant's blood by standard Ficoll density gradient methods.	through 15 wk of age	No
Primary	T-cell response to BCG (Bacillus Calmette-Guérin; to protect against tuberculosis) and oral polio virus (OPV) immunization	The Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA) will be used on peripheral blood mononuclear cells to determine the percentage of CD4+ T cells that that are responsive to the BCG and OPV vaccines given at birth (OPV is given again at 6, 10 and 14 wk of age). The BCG response will be elicited using purified protein derivative of M. tuberculosis and the OPV response using formalin-inactivated polio virus antigen (types 1, 2 and 3).	through 15 wk of age	No
Primary	Antibody response to oral polio virus (OPV) immunization	The antibody in lymphocyte supernatant (ALS) assay will be used to assess the production of polio-specific antibody by peripheral blood mononuclear cells (PBMC) at 15 wk of age and the secretory IgA response to OPV will be assessed at 6, 11 and 15 wk of age by measuring antibody in stool	through 15 wk of age	No
Primary	T-cell and antibody response to tetanus toxoid (TT) and hepatitis B virus (HBV) vaccinations given at 6, 10 and 14 wk of age	The Flow-cytometric Assay of Specific Cell-mediated Immune response in Activated whole blood (FASCIA) will be used to measure the T-cell response to TT and HBV immunization using these vaccine antigens to stimulate a response at 6 and 15 wk of age. The antibody in lymphocyte supernatant assay (ALS) will be used to measure the antibody responses to these vaccines at 15 wk of age.	through 15 wk of age	No
Primary	bacterial translocation to blood	Bacterial lipopolysaccharide (LPS) concentrations will be measured in plasma as a marker of bacterial translocation.	through 15 wk of age	No
Secondary	vitamin A status by modified, relative dose-response (MRDR) test	vitamin A status will be measured using the MRDR in a subset of 30 subjects in each study arm.	through 15 wk of age	No
Secondary	bulging fontanelle	The crainial fontanelle will be examined by study personnel to identify "bulging" as in indication of increased intracranial volume.	48 h after vitamin A dosing	Yes