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

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

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Tuberculosis
• Intervention / Treatment: 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

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

• Study Type: Interventional
• Enrollment (Actual): 288
• Phase: Phase 2

Contacts and Locations

Study Locations

• Bangladesh
  • Dhaka, Bangladesh, 1212
    • National Institute of Diseases of Chest and Hospital (NIDCH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: QUADRUPLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Sodium Phenylbutyrate and active cholecalciferol; 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; Sodium Phenylbutyrate: 500 mg twice daily orally for 2 months Cholecalciferol: 5000 IU once daily orally for 2 months; Other Names: triButyrate®; Vigantol oil
Active Comparator: Placebo Sodium Phenylbutyrate plus active cholecalciferol; Drug: Cholecalciferol Placebo: Sodium Phenylbutyrate	Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol; Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Cholecalciferol: 5000 IU once daily for 2 months; Other Names: Vigantol oil; Placebo Phenylbutyrate
Active Comparator: Active Sodium Phenylbutyrate and placebo cholecalciferol; Drug: Sodium Phenylbutyrate Placebo: cholecalciferol	Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol; Sodium phenylbutyrate: 500 mg twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months; Other Names: triButyrate®; Placebo vigantol oil
Placebo Comparator: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol; Placebo Sodium Phenylbutyrate Placebo cholecalciferol	Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol; Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months

What is the study measuring?

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	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

Collaborators and Investigators

• Sponsor: International Centre for Diarrhoeal Disease Research, Bangladesh
• Collaborators: Karolinska Institutet; University of Iceland; National Institute of Diseases of the Chest and Hospital

Publications and helpful links

General Publications

• Rekha RS, Mily A, Sultana T, Haq A, Ahmed S, Mostafa Kamal SM, van Schadewijk A, Hiemstra PS, Gudmundsson GH, Agerberth B, Raqib R. Immune responses in the treatment of drug-sensitive pulmonary tuberculosis with phenylbutyrate and vitamin D3 as host directed therapy. BMC Infect Dis. 2018 Jul 4;18(1):303. doi: 10.1186/s12879-018-3203-9.
• Mily A, Rekha RS, Kamal SM, Arifuzzaman AS, Rahim Z, Khan L, Haq MA, Zaman K, Bergman P, Brighenti S, Gudmundsson GH, Agerberth B, Raqib R. Significant Effects of Oral Phenylbutyrate and Vitamin D3 Adjunctive Therapy in Pulmonary Tuberculosis: A Randomized Controlled Trial. PLoS One. 2015 Sep 22;10(9):e0138340. doi: 10.1371/journal.pone.0138340. eCollection 2015.
• Mily A, Rekha RS, Kamal SM, Akhtar E, Sarker P, Rahim Z, Gudmundsson GH, Agerberth B, Raqib R. Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis. BMC Pulm Med. 2013 Apr 16;13:23. doi: 10.1186/1471-2466-13-23.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): December 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: April 17, 2012
• First Submitted That Met QC Criteria: April 17, 2012
• First Posted (Estimate): April 18, 2012

Study Record Updates

• Last Update Posted (Estimate): February 13, 2015
• Last Update Submitted That Met QC Criteria: February 12, 2015
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: vitamin D; tuberculosis; phenylbutyrate; cathelicidin; antimicrobial peptide; in adults
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Physiological Effects of Drugs; Antineoplastic Agents; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol; 4-phenylbutyric acid
• Other Study ID Numbers: PR-09068