Effect of Vitamin A Supplementation on Immune Responses in Human Neonates (NNVAS)

A Randomized Controlled Trial in Human Neonates to Determine the Effect of Vitamin A Supplementation on Immune Responses

Vitamin A supplementation (VAS) significantly reduces all-cause mortality when given after 6 months of age, but has a null or detrimental effect when given between 1-5 months. Studies of neonatal VAS (NNVAS) have produced conflicting findings. These age-pattern variations might result from immunological interactions between VAS and vaccines. The potential efficacy of NNVAS is being retested in 3 large new intervention trials with mortality as endpoint. Complementary mechanistic studies in animals and in human infants in The Gambia (this proposal) and Bangladesh have been commissioned to run in parallel.

The investigators will use a 2-arm double blind RCT to test whether NNVAS modulates the early ontogeny of human immune development. Neonates, recruited through a peri-urban clinic in The Gambia, will receive either 50,000 International Units (IU) VAS orally within 48 hours of birth (intervention group, n=100) or a placebo (control group, n=100). Male and female neonates will be randomized separately at enrolment for later analyses by sex. All infants will be followed up from birth to age 1 year. A broad panel of immunological outcomes will examine whether NNVAS: a). normalises thymic development (thymic index by ultrasound); b). skews mycobacterial and recall antigen responses towards a Th2 profile; c). diminishes Th1 and Th17 reactivity to mycobacterial and recall antigens; d). diminishes the tuberculin skin test (TST) response; e). causes increased innate immune reactivity; f). increases the frequency of circulating regulatory T cells (Tregs) expressing gut homing receptors; g). enhances B cell immune responses after routine vaccination (increase of B cell numbers and activation status); h). increases circulating IgA in mucosal immune compartment, especially oral polio vaccine (OPV) specific IgA post-vaccination; i). decreases bacterial translocation, by improving mucosal barrier function; and j). decreases markers of infection or inflammation. Growth and morbidity will also be assessed.

Study Overview

• Status: Unknown
• Conditions: Vitamin A Deficiency
• Intervention / Treatment: Dietary supplement: Vitamin A (retinyl palmitate).

• Study Type: Interventional
• Enrollment (Anticipated): 200
• Phase: Phase 2

Contacts and Locations

Study Locations

• Gambia
  • Fajara, Gambia
    • Medical Research Council, The Gambia Unit

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 hours to 2 days (CHILD)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• singleton birth,
• birth weight ≥1,500g,
• mother over 18 years willing to participate and residency within the study area.
• Birth vaccinations and vitamin A supplement must be administered within 48 hours of birth.

Exclusion Criteria:

• Infants having a congenital disease,
• a serious infection at birth
• an inability to feed (initially assessed by the lack of the suck reflex),
• mothers who are seriously ill at time of enrolment (defined as bed bound for more than 24 hours),
• mother participating in other studies,
• mothers who are HIV positive.

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Vitamin A; Capsule containing oil vehicle with Vitamin A (retinyl palmitate). Capsules are prepared by the manufacturer (Strides Arcolab Limited, India) and assigned blinded codes by World Health Organization officials.	Dietary supplement: Vitamin A (retinyl palmitate).; Active Comparator (Vitamin A): 1 capsule containing oil carrier and 50,000IU Vitamin A, within 48hs of birth Placebo Comparator: 1 capsule containing oil carrier and 0IU Vitamin A, within 48hs of birth
PLACEBO_COMPARATOR: Placebo; Capsule containing oil vehicle withOUT Vitamin A (retinyl palmitate). Capsules are prepared by the manufacturer (Strides Arcolab Limited, India) and assigned blinded codes by World Health Organization officials.	Dietary supplement: Vitamin A (retinyl palmitate).; Active Comparator (Vitamin A): 1 capsule containing oil carrier and 50,000IU Vitamin A, within 48hs of birth Placebo Comparator: 1 capsule containing oil carrier and 0IU Vitamin A, within 48hs of birth

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Frequency of circulating Tregs expressing gut homing receptors in infant participants.	17 week post-supplementation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Thymus size in infant participants	Assessed by ultrasonic analysis.	1, 6, 12 and 17 weeks
Difference in B cell immune responses after routine vaccination in infant participants	Assessed as an increase in B cell numbers and activation status.	6 and 17 weeks
Improved mucosal barrier function in infant participants	Assessed by quantifying bacterial translocation into the blood.	6 and 17 weeks

Collaborators and Investigators

• Sponsor: London School of Hygiene and Tropical Medicine
• Collaborators: World Health Organization
• Investigators: Principal Investigator: Suzanna LR McDonald, BSc (Hons) MSc PhD, London School of Hygiene and Tropical Medicine

Publications and helpful links

General Publications

• McDonald SL, Savy M, Fulford AJ, Kendall L, Flanagan KL, Prentice AM. A double blind randomized controlled trial in neonates to determine the effect of vitamin A supplementation on immune responses: The Gambia protocol. BMC Pediatr. 2014 Apr 4;14:92. doi: 10.1186/1471-2431-14-92.

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (ANTICIPATED): June 1, 2013

Study Registration Dates

• First Submitted: November 9, 2011
• First Submitted That Met QC Criteria: November 17, 2011
• First Posted (ESTIMATE): November 22, 2011

Study Record Updates

• Last Update Posted (ESTIMATE): November 14, 2012
• Last Update Submitted That Met QC Criteria: November 12, 2012
• Last Verified: November 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Eye Diseases; Nutrition Disorders; Avitaminosis; Deficiency Diseases; Malnutrition; Vision Disorders; Night Blindness; Vitamin A Deficiency; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Micronutrients; Vitamins; Antioxidants; Anticarcinogenic Agents; Vitamin A; Retinol palmitate
• Other Study ID Numbers: RPC389