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

International Centre for Diarrhoeal Disease Research (icddr,b)

Status and phase: Completed; Phase 2

Conditions: Pulmonary Tuberculosis

Treatments: Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol; Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol; Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol; Drug: Active Sodium Phenylbutyrate and active cholecalciferol

Study type: Interventional

Funder types: Other

Identifiers

NCT01580007

PR-09068

Details and patient eligibility

About

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.

Full 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

Enrollment: 288 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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288 participants in 4 patient groups, including a placebo group

Active Sodium Phenylbutyrate and active cholecalciferol

Active Comparator group

Description:

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

Treatment:

Drug: Active Sodium Phenylbutyrate and active cholecalciferol

Placebo Sodium Phenylbutyrate plus active cholecalciferol

Active Comparator group

Description:

Drug: Cholecalciferol Placebo: Sodium Phenylbutyrate

Treatment:

Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol

Active Sodium Phenylbutyrate and placebo cholecalciferol

Active Comparator group

Description:

Drug: Sodium Phenylbutyrate Placebo: cholecalciferol

Treatment:

Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol

Placebo Sodium Phenylbutyrate plus placebo cholecalciferol

Placebo Comparator group

Description:

Placebo Sodium Phenylbutyrate Placebo cholecalciferol

Treatment:

Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol