Vitamin A Supplementation for Modulation of Mycobacterium Tuberculosis Immune Responses in Latent Tuberculosis

Sponsor

Medical Research Council Unit, The Gambia (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00558480

Collaborator

European and Developing Countries Clinical Trials Partnership (EDCTP) (Other), Department of State for Health and Social Welfare, The Gambia (Other)

Enrollment

Arms

Duration (Months)

Study Details

Study Description

Brief Summary

In populations with high prevalence of latent tuberculosis infection (LTBI), malnutrition (PEM) may influence incident rates of TB. PEM and specific micronutrient deficiencies compromise cell mediated immunity (CMI) and increase susceptibility to, or severity of infections. Vitamin A supplementation significantly reduces all-cause child mortality. The mechanism of the benefits of supplementation on clinical outcomes is largely unknown, but is likely to be related to an influence on the immune system. Vitamin A supplementation promotes lymphogenesis and induces a higher proportion of CD4 naïve T-cells in children. Most cases of LTBI that progress to active disease are vitamin A deficient. Vitamin A deficiency is common in most TB endemic countries. At the MRC, 32% of TBCC contacts were vitamin A deficient.

Hypothesis:

The investigators plan to test the hypotheses: that supplementation with vitamin A will affect the magnitude and quality of immune responses to mycobacterial antigens and progression to clinical disease.

Condition or Disease	Intervention/Treatment	Phase
Latent Tuberculosis Infection	Drug: Vitamin A Drug: Vitamin A placebo	N/A

Detailed Description

Tuberculosis (TB) remains a significant global health problem. Approximately a third of the world's populations are infected with Mycobacterium tuberculosis and 95% of cases occur in developing countries. This enormous pool of latently infected individuals is expected to pose a major obstacle for TB control in highly endemic countries and globally. In high income, low TB burden countries, targeted testing of TB case contacts and treatment for latent TB infection (LTBI) is practised as a component of TB control strategies. However, this is not practised in high burden, low-income countries. New evidence from mathematical modelling suggests that, to meet millennium development goals, interventions against M. tuberculosis infection will be required.

Children are at increased risk of rapid progression to active disease (usually within a year for infants). , Malnutrition has been identified as a major risk factor for progression to TB because of its profound effect on cellular immune function- the key host defence against TB. There are 2 types of risk associated with malnutrition: acquisition of infection and risk of infection progressing to disease. Therefore, in populations with high prevalence of latent TB infection, co-prevalent malnutrition may influence TB incidence rates.

Vitamin A supplementation has been clearly shown to reduce all-cause child mortality in developing countries. Vitamin A given at recommended doses has a profound effect on improving outcomes in measles and overall childhood mortality and morbidity. The mechanism for this has been attributed to its modulation of immune responses in addition to correcting underlying deficiency.

In TB patients, it is nearly impossible to determine nutritional status before disease and thus determine whether malnutrition led to TB or TB led to malnutrition. However, some studies have established a link between vitamin A deficiency and susceptibility to respiratory infections and progression from latent to active TB disease. Preschool children with symptomatic vitamin A deficiency have been found to have respiratory disease at twice the rate in non-deficient children, irrespective of anthropometric status. Getz et al found 81% of persons in a cohort with LTBI that had low levels of vitamin A developed disease compared to 30% of those with normal levels. We had previously observed a 32% prevalence of vitamin A deficiency in a subset of Tuberculosis case contact study contacts with latent TB (unpublished data). The mechanism of the benefits of vitamin A on clinical outcomes especially as related to measles is largely unknown and on tuberculosis is yet to be proven. However, it is likely to be related to an influence on the immune system.In experimental and animal models, vitamin A promotes differentiation and cytokine secretion by macrophages and may down regulate the secretion of pro-inflammatory cytokines e.g. TNF-alpha and IL-6. in children. Vitamin A supplementation has been reported to promote lymphogenesis and induce a higher proportion of CD4 naïve T-cells (CD4+ CD45RA). In addition, the quality of T-cell function may also be affected by Vitamin A.There are data indicating that IFN-gamma production is decreased in vitamin A deficient children while optimal in normal children. Immune responses of PBMCs from non-deficient children stimulated with specific antigens were biased towards more of IFN-gamma, and less of IL-10 and IL-4. This cytokine profile is reminiscent of decreased Treg differentiation and/or Th1-type immune response induced by vitamin A, which is required for protection against an intracellular pathogen such as M.tb. Indeed, data from our previous studies suggest that initial decrease in Treg induction in contacts of TB cases was associated with protection against progression to TB disease

To the best of our knowledge we are unaware of any trial of vitamin A for modulation of immune responses associated with progression to active disease in children with latent TB. We will conduct a parallel group comparison of a dose of 200,000 IU Vitamin A supplementation or placebo in latently infected children aged 5-14 years to evaluate qualitative and quantitative modulation of T-cell responses and clinical disease progression.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Official Title:

A Double Blind, Placebo Controlled Randomized Trial of Vitamin A Supplementation for Modulation of Mycobacterium Tuberculosis Immune Responses in Children Aged 5-14 Years With Latent Tuberculosis.

Study Start Date :

Jul 1, 2009

Anticipated Primary Completion Date :

Jul 1, 2011

Anticipated Study Completion Date :

Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Vitamin A	Drug: Vitamin A Vitamin A capsules, as retinol palmitate 200,000 IU at enrollment, 3 and 6 months Other Names: Retinol Palmitate
Placebo Comparator: 2 Vitamin A placebo	Drug: Vitamin A placebo Vitamin A placebo at enrollment, 3 and 6 months

Arm

Intervention/Treatment

Active Comparator: 1

Vitamin A

Drug: Vitamin A

Vitamin A capsules, as retinol palmitate 200,000 IU at enrollment, 3 and 6 months

Other Names:

Retinol Palmitate

Placebo Comparator: 2

Vitamin A placebo

Drug: Vitamin A placebo

Vitamin A placebo at enrollment, 3 and 6 months

Outcome Measures

Primary Outcome Measures

Measurement of cytokine (IFN-gamma, IL-10, TNF-alpha, TGF-beta) levels produced in response to M. tb. [2 years]

Secondary Outcome Measures

FoxP3 gene expression with RT-PCR on mRNA from PBMCs. [2 years]
Incidence of probable/confirmed TB; change in weight (mean weight gain) [2 years]
Qualitative (positive/negative) and quantitative (mean change in counts) reversion of the T-cell assay [2 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years to 14 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

Otherwise healthy children aged 5-14 years
Resident in the Greater Banjul area
Normal chest X-ray
Mantoux result ≥ 10mm in the widest diameter
Positive T-SPOT-TB
Negative HIV antibody test
Negative pregnancy test for 12-14 year-old females

Exclusion Criteria:

History of previous TB or treatment for TB
Clinical case TB
Current participation in another clinical trial (except SCC 1041, 1034)
Clinically significant history or evidence of skin disorders, allergy, immunodeficiency, organ-specific disorders causing immunodeficiency.
Likelihood of travel away from the study area during or for the duration of the study.
Chronic use (≥14 days) of any oral or systemic steroid or use of other immunosuppressive/ immunomodulating agents.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

Medical Research Council Unit, The Gambia
European and Developing Countries Clinical Trials Partnership (EDCTP)
Department of State for Health and Social Welfare, The Gambia

Investigators

Principal Investigator: Ifedayo MO Adetifa, MD FWACP, MRC (UK) Laboratories, The Gambia
Principal Investigator: Martin OC Ota, MD FWACP PhD, MRC (UK) Laboratories, The Gambia