Pulmonary Tuberculosis
Conditions
Keywords
tuberculosis, phenylbutyrate, vitamin D, cathelicidin, antimicrobial peptide, in adults
Brief summary
Vitamin D exerts its effects via the Vitamin D Receptor (VDR) present in activated macrophages and induces expression and release of the cathelicidin, LL-37, a human antimicrobial peptide involved in killing of MTB. We aimed to investigate whether treatment of newly diagnosed pulmonary TB patients for 2 months with adjunctive PBA and vitamin D (Cholecalciferol) in combination with standard DOTS therapy (i) can improve response to standard short course TB therapy towards a rapid recovery; (ii) can induce expression of LL-37 in macrophages; (iii) can enhance killing capacity of macrophages isolated from TB patients infected in vitro with MTB; and (iv) does not evoke any adverse effects.
Detailed description
This is a double-blind, randomized, placebo controlled clinical trial on clinical efficacy of phenylbutyrate and vitamin D3 therapy daily for 2 months in newly diagnosed sputum smear positive pulmonary TB patients. The clinical trial will take place in the National Institute of the Diseases of the Chest and Hospital (NIDCH) in Dhaka, Bangladesh. Our specific aims are: Objective 1: To determine the optimal oral dose of PBA required for induction of antimicrobial peptide in macrophages from healthy adults. Objective 2 The second aim of this study is to determine whether adjunctive sodium phenylbutyrate and vitamin D treatment (for 2 months) of newly diagnosed pulmonary TB patients: 1. Can improve response to standard short course TB therapy towards a rapid recovery (clinical, radiological, mycobacterial). 2. Can induce expression of LL-37 in macrophages (immunological). 3. Can enhance killing capacity of macrophages from TB patients infected in vitro with MTB (functional measures of treatment outcome). Study Design: The study will be a randomized, double blind (Subject, Caregiver, Investigator, Outcomes Assessor), placebo control trial for 2 months. It will also be a safety and efficacy phase III study. The study will have a 4x4 factorial design with 4-cell interventions. Enrolled patients will be randomized into the following four treatment arms in a 1:1:1:1 ratio: Group 1: PBA Group 2: Vitamin D3 (Cholecalciferol) Group 3: PBA plus vitamin D3 Group 4: Placebo
Interventions
DRUGActive Sodium Phenylbutyrate and placebo cholecalciferol
Sodium phenylbutyrate: 500 mg twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months
DRUGActive Sodium Phenylbutyrate and active cholecalciferol
Sodium Phenylbutyrate: 500 mg twice daily orally for 2 months Cholecalciferol: 5000 IU once daily orally for 2 months
DRUGPlacebo Sodium Phenylbutyrate plus active cholecalciferol
Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Cholecalciferol: 5000 IU once daily for 2 months
DRUGPlacebo Sodium Phenylbutyrate plus placebo cholecalciferol
Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months
Sponsors
Karolinska Institutet
National Institute of Diseases of the Chest and Hospital, Bangladesh
University of Iceland
International Centre for Diarrhoeal Disease Research, Bangladesh
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Adults, 18-60 years with sputum smear positive pulmonary TB * New cases only * Gender, both * Consent to enroll in the study
Exclusion criteria
* Hypercalcaemia (serum calcium \> 2.6 mmol/L) identified at baseline * Taking vitamin D * Pregnant and lactating * Any known liver or kidney function abnormality, malignancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of pulmonary TB patients who are culture negative in sputum in week 4 | week 4 | To determine the proportion of sputum culture positive patients becoming culture negative at 1 and 2 months after adjunctive sodium phenylbutyrate and vitamin D treatment of patients for 2 months. |
| Difference in improvement in clinical endpoints consisting of cough clearance, percentage chest x-ray clearance, fever remission and weight increase upto 8 weeks. | 8 weeks | Difference in improvement in clinical endpoints consisting of: cough clearance (weekly to week-8 then at week 24) chest x-ray impovement (percentage lung involvement on CXR at week 8) fever remission (weekly to week-8 then at week 24) weight increase (weekly to week-8 then at week 24) |
Secondary
| Measure | Time frame |
|---|---|
| Gastrointestinal side effects | weekly to week 12 then at week 24 |
| Immunological improvement (LL-37 in macrophages) | week 0, 4, 8, 12 |
| Change in plasma PBA concentrations | week 0, 4, 8, 12 |
| Change in plasma 25(OH)D3 concentration | week 0, 4, 8, 12, 24 |
| Clinical failure and default independently and 'death or clinical failure or default' | week 24 |
| Radiological improvement (percent lung involvement on CXR) | week 0, 8, 12 and 24 |
| Cough clearance | weekly up to week 12; then at week 24 |
| Weight gain | weekly up to week 12, then at week 24 |
| Functional immunological improvement (killing by macrophages) | week 0, 4, 8, 12 |
| Sputum smear conversion time | weekly up to week 12; then at week 24 |
| Hypercalcaemia (serum calcium > 2.6 mmol/L) | week 0, 2, 4, 8, 12 |
Countries
Bangladesh
Outcome results
None listed