Clinical trial NCT00507000: Pulmonary Tuberculosis and Vitamin D
Official title: Role of Oral Vitamin D as an Adjunct Therapy in Category I Pulmonary Tuberculosis Along With Assessment of Immunological Parameters. (Double-blind, Randomized, Placebo-Controlled, Clinical Trial)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Tuberculosis
Lead sponsor: Indian Council of Medical Research
Sponsor class: OTHER_GOV
Collaborators: name: Ministry of Science and Technology, India
First posted: 2007-07-25
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Tuberculosis and vitamin D deficiency are important public health problems in India. Before the advent of effective antitubercular therapy, patients with tuberculosis were advised treatment and rest at sanatorium where sunshine was available in plenty. There have been reports associating vitamin D deficiency with tuberculosis in terms of incidence and beneficial response following addition of vitamin D to antitubercular therapy. Sputum AFB conversion rate is higher in patients with tuberculosis supplemented with vitamin D. The present study would systematically assess role of adjunct vitamin D therapy (cholecalciferol) in patients with pulmonary tuberculosis.

Detailed description: Tuberculosis and vitamin D deficiency are important public health problems in India. In recently published studies from our center, up to 90% of the apparently healthy subjects in Delhi were classified either as as vitamin D insufficient or deficient by using serum 25(OH)D cut off levels of 20 ng/ml and 32 ng/ml respectively. Before the advent of effective antitubercular therapy, patients with tuberculosis were advised treatment and rest at sanatorium where sunshine was available in plenty. In the western literature, there have been reports associating vitamin D deficiency with tuberculosis in terms of incidence and beneficial response following addition of vitamin D to antitubercular therapy. A few pilot studies have shown that sputum conversion rate is higher in patients with tuberculosis supplemented with vitamin D.

In the above context the mechanisms linking vitamin D deficiency and its effect on tuberculosis are currently under investigation. In order to understand the link two types of studies have been conducted (a) clinical studies associating vitamin D deficiency and tuberculosis and (b) in-vitro assessment of molecular immune changes related to vitamin D exposure. With the currently available knowledge, the linkage between the two disorders is being explained by the broad role of vitamin D deficiency in modulation of cell-mediated immunity.

Patients with military tuberculosis are characterized by decreased levels of Th1 cytokines and increased levels of IL-10 compared with the healthy infected and noninfected controls. Current literature suggests that long-term control of M. tuberculosis infection is associated with elevated Th1 responses and concomitant inhibition of the Th2 response

Peripheral blood mononuclear cells have been shown to express vitamin D receptors. Incubation of macro¬phages with physio¬logical concentration of 1,25 (OH)D \[10-9M\] results in inhibition of intracellular growth of Mycobacterium tuberculosis. 1,25-dihydroxycholecalciferol, has significant immunomodulatory effects leading to (a) shift in cytokine profile of T-helper (Th1 to Th2) and (b) reduced antigen presentation, reduced production of Th1-promoting cytokines, reduced expression of co-stimulatory molecules in the antigen-presenting cell. In addition, it was demonstrated that the addition of vitamin D3 derivatives inhibits the differentiation of IFN-gamma-producing Th1 cells while it augments the differentiation of IL-4- or IL-10-producing Th2 cells.

There are no systematic data from our country assessing association between vitamin D deficiency and tuberculosis and the possible role of vitamin D related modulation in the tuberculosis specific cellular immune response. The present study has been planned with the following hypothesis

Hypothesis: Patients with pulmonary tuberculosis and vitamin D deficiency when treated with vitamin and antitubercular therapy are likely to show early sputum conversion and immune response favoring resolution of tuberculosis

Eligibility criteria: Inclusion Criteria:

1. All patients of either sex with Newly diagnosed sputum positive pulmonary TB cases
2. Aged between 18 to 60 yrs

Exclusion Criteria:

1. Category II pulmonary TB and multi-drug resistant TB (MDR-TB) patients
2. Presence of secondary immunodeficiency states : HIV, organ transplantation, diabetes mellitus, malignancy, treatment with corticosteroids
3. Hepatitis B and C positivity
4. Patients with extrapulmonary TB and/or patients requiring surgical intervention
5. Currently receiving cytotoxic therapy, or have received it within the last 3 months
6. Pregnancy and lactation
7. Patients with a known seizure disorder
8. Patients with known symptomatic cardiac disease, such as arrhythmias or coronary artery disease
9. Patients with abnormal renal functions (serum creatinine more than 2 mg/dl; more than 2+ proteinuria)
10. Patients with abnormal hepatic functions (bilirubin = 1.5 mg/dl; AST, ALT, SAP \> 1.5 times above upper limit
11. Patients with hematological abnormalities (WBC lesser than or equal to 3000/mm3; platelet count less than or equal to 100,000/mm3)
12. Seriously ill and moribund patients with complications : tachypnoea, chronic cor pulmonale, congestive cardiac failure, BMI\<15, severe hypoalbuminemia
13. Patients unable to comply with the treatment regimen
14. Patients with history of alcohol or drug abuse

Primary outcomes:
measure: Time to convert from sputum positivity to negativity
timeFrame: Two months after the last recruitment
Secondary outcomes:
measure: 1 To study the relapse rate and safety assessment 2 To study the effect of Vitamin D supplementation on the pattern of effector immune function in patients suffering from pulmonary Tuberculosis.
timeFrame: Three years
Other outcomes:
Locations:
city: Delhi
country: India
facility: Depratment of Endocrinology;Medicine, All India Institute of Medical sciences, and DBT
state: New Delhi
Study officials:
affiliation: Associate Professor, Depratment of Endocrinology and Metabolism, All India Institute of Medical Sciences, New delhi 110029
name: Ravinder Goswami, MD, DM
role: PRINCIPAL_INVESTIGATOR
affiliation: Head, Depratment of Medicine, All India Institute of Medical Sciences, New Delhi 110029
name: SK Sharma, MD, PHD
role: PRINCIPAL_INVESTIGATOR
affiliation: Associate professor, Department of Transplant immunology and immunogenetics, All India Institute of Medicasl Sciences, New delhi 110029, India
name: DK Mitra, MBBS, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistant Professor, Deprtament of Microbiology, All India Institute of Medical Sciences, new delhi 110029
name: Urvashi B Singh, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Additional Porfessor, Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi 110029, India
name: Nandita Gupta, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Adviser, Department of Biotechnology, Lodhi Road, New Delhi-110003, India
name: Bindu Dey, PhD.
role: STUDY_DIRECTOR
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