Ignite Creation Date:
2024-05-05 @ 6:50 PM
Last Modification Date:
2024-10-26 @ 9:37 AM
Study NCT ID:
NCT00558480
Status:
WITHDRAWN
Last Update Posted:
2015-04-09
First Post:
2007-11-14
Brief Title:
Vitamin A Supplementation for Modulation of Mycobacterium Tuberculosis Immune Responses in Latent Tuberculosis
Sponsor:
Medical Research Council Unit The Gambia
Organization:
Medical Research Council Unit The Gambia
Study Overview
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
Status:
WITHDRAWN
Status Verified Date:
2015-04
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
Detailed Description:
Tuberculosis TB remains a significant global health problem Approximately a third of the worlds 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 systemIn experimental and animal models vitamin A promotes differentiation and cytokine secretion by macrophages and may down regulate the secretion of pro-inflammatory cytokines eg 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 AThere 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 andor Th1-type immune response induced by vitamin A which is required for protection against an intracellular pathogen such as Mtb 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 200000 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
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 systemIn experimental and animal models vitamin A promotes differentiation and cytokine secretion by macrophages and may down regulate the secretion of pro-inflammatory cytokines eg 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 AThere 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 andor Th1-type immune response induced by vitamin A which is required for protection against an intracellular pathogen such as Mtb 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 200000 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None