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

• Proportion of pulmonary TB patients who are culture negative in sputum in week 4 [ Time Frame: week 4 ] [ Designated as safety issue: No ]
  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. [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]

  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)

• Sputum smear conversion time [ Time Frame: weekly up to week 12; then at week 24 ] [ Designated as safety issue: No ]
• Radiological improvement (percent lung involvement on CXR) [ Time Frame: week 0, 8, 12 and 24 ] [ Designated as safety issue: No ]
• Cough clearance [ Time Frame: weekly up to week 12; then at week 24 ] [ Designated as safety issue: No ]
• Weight gain [ Time Frame: weekly up to week 12, then at week 24 ] [ Designated as safety issue: No ]
• Change in plasma PBA concentrations [ Time Frame: week 0, 4, 8, 12 ] [ Designated as safety issue: No ]
• Change in plasma 25(OH)D3 concentration [ Time Frame: week 0, 4, 8, 12, 24 ] [ Designated as safety issue: Yes ]
• Clinical failure and default independently and 'death or clinical failure or default' [ Time Frame: week 24 ] [ Designated as safety issue: Yes ]
• Hypercalcaemia (serum calcium > 2.6 mmol/L) [ Time Frame: week 0, 2, 4, 8, 12 ] [ Designated as safety issue: Yes ]
• Gastrointestinal side effects [ Time Frame: weekly to week 12 then at week 24 ] [ Designated as safety issue: Yes ]
• Immunological improvement (LL-37 in macrophages) [ Time Frame: week 0, 4, 8, 12 ] [ Designated as safety issue: No ]
• Functional immunological improvement (killing by macrophages) [ Time Frame: week 0, 4, 8, 12 ] [ Designated as safety issue: No ]

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.

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

• 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
• 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
• 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
• Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol
  Placebo Sodium Phenylbutyrate: twice daily orally for 2 months Placebo cholecalciferol: once daily orally for 2 months

• 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
  Intervention: Drug: Active Sodium Phenylbutyrate and active cholecalciferol
• Active Comparator: Placebo Sodium Phenylbutyrate plus active cholecalciferol
  Drug: Cholecalciferol Placebo: Sodium Phenylbutyrate
  Intervention: Drug: Placebo Sodium Phenylbutyrate plus active cholecalciferol
• Active Comparator: Active Sodium Phenylbutyrate and placebo cholecalciferol
  Drug: Sodium Phenylbutyrate Placebo: cholecalciferol
  Intervention: Drug: Active Sodium Phenylbutyrate and placebo cholecalciferol
• Placebo Comparator: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol
  Placebo Sodium Phenylbutyrate Placebo cholecalciferol
  Intervention: Drug: Placebo Sodium Phenylbutyrate plus placebo cholecalciferol

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

• Dept. of medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
• National Tuberculosis Reference Laboratory, National Institute of Diseases of Chest and Hospital (NIDCH), Dhaka, Bangladesh
• University of Iceland