Clinical Trial of Phenylbutyrate and Vitamin D in Tuberculosis (TB)

Study Overview
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Brief Summary
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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
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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: Can improve response to standard short course TB therapy towards a rapid recovery (clinical, radiological, mycobacterial). Can induce expression of LL-37 in macrophages (immunological). 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

Official Title
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Clinical Trial of Oral Phenylbutyrate and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis in Bangladesh: a Pilot Study

Conditions
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Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: Active Sodium Phenylbutyrate and active cholecalciferol
* Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol
* Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol
* Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Sodium Phenylbutyrate and active cholecalciferol<br>500 mg sodium phenylbutyrate (4-phenylbutyric acid, sodium salt) in tablet form twice daily and 5000 IU of cholecalciferol once daily will be given orally for 2 months | Drug: Active Sodium Phenylbutyrate and active cholecalciferol<br>* Sodium Phenylbutyrate: 500 mg twice daily orally for 2 months Cholecalciferol: 5000 IU once daily orally for 2 months<br>* Other names: Vigantol oil;|
| Active Comparator: Placebo Sodium Phenylbutyrate plus active cholecalciferol<br>Drug: Cholecalciferol Placebo: Sodium Phenylbutyrate | Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol<br>* Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Cholecalciferol: 5000 IU once daily for 2 months<br>* Other names: Placebo Phenylbutyrate;|
| Active Comparator: Active Sodium Phenylbutyrate and placebo cholecalciferol<br>Drug: Sodium Phenylbutyrate Placebo: cholecalciferol | Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol<br>* Sodium phenylbutyrate: 500 mg twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months<br>* Other names: Placebo vigantol oil;|
| Placebo Comparator: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol<br>Placebo Sodium Phenylbutyrate Placebo cholecalciferol | Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol<br>* Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of pulmonary TB patients who are culture negative in sputum in 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. | week 4 | 
| Difference in improvement in clinical endpoints consisting of cough clearance, percentage chest x-ray clearance, fever remission and weight increase upto 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) | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sputum smear conversion time |  | weekly up to week 12; then at 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 | 
| 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 | 
| Hypercalcaemia (serum calcium > 2.6 mmol/L) |  | week 0, 2, 4, 8, 12 | 
| Gastrointestinal side effects |  | weekly to week 12 then at week 24 | 
| Immunological improvement (LL-37 in macrophages) |  | week 0, 4, 8, 12 | 
| Functional immunological improvement (killing by macrophages) |  | week 0, 4, 8, 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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tuberculosis, phenylbutyrate, vitamin D, cathelicidin, antimicrobial peptide, in adults