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

Pulmonary Tuberculosis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01580007
• Other study ID #: PR-09068
• Status: Completed
• Phase: Phase 2
• First received: April 17, 2012
• Last updated: February 12, 2015
• Start date: December 2010
• Est. completion date: December 2014

Study information

• Verified date: January 2014
• Source: International Centre for Diarrhoeal Disease Research, Bangladesh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 288
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• Active Sodium Phenylbutyrate and active cholecalciferol
Sodium Phenylbutyrate: 500 mg twice daily orally for 2 months Cholecalciferol: 5000 IU once daily orally for 2 months
• Placebo Sodium Phenylbutyrate plus active cholecalciferol
Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Cholecalciferol: 5000 IU once daily for 2 months
• Active Sodium Phenylbutyrate and placebo cholecalciferol
Sodium phenylbutyrate: 500 mg twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months
• Placebo Sodium Phenylbutyrate plus placebo cholecalciferol
Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months

Locations

Country	Name	City	State
Bangladesh	National Institute of Diseases of Chest and Hospital (NIDCH)	Dhaka

Sponsors (4)

Lead Sponsor	Collaborator
International Centre for Diarrhoeal Disease Research, Bangladesh	Karolinska Institutet, National Tuberculosis Reference Laboratory, National Institute of Diseases of Chest and Hospital (NIDCH), Dhaka, Bangladesh, University of Iceland

Country where clinical trial is conducted

Bangladesh, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Sputum smear conversion time		weekly up to week 12; then at week 24
Secondary	Radiological improvement (percent lung involvement on CXR)		week 0, 8, 12 and 24
Secondary	Cough clearance		weekly up to week 12; then at week 24
Secondary	Weight gain		weekly up to week 12, then at week 24
Secondary	Change in plasma PBA concentrations		week 0, 4, 8, 12
Secondary	Change in plasma 25(OH)D3 concentration		week 0, 4, 8, 12, 24
Secondary	Clinical failure and default independently and 'death or clinical failure or default'		week 24
Secondary	Hypercalcaemia (serum calcium > 2.6 mmol/L)		week 0, 2, 4, 8, 12
Secondary	Gastrointestinal side effects		weekly to week 12 then at week 24
Secondary	Immunological improvement (LL-37 in macrophages)		week 0, 4, 8, 12
Secondary	Functional immunological improvement (killing by macrophages)		week 0, 4, 8, 12