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

This study is currently recruiting participants.
Verified April 2012 by International Centre for Diarrhoeal Disease Research, Bangladesh
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
International Centre for Diarrhoeal Disease Research, Bangladesh
ClinicalTrials.gov Identifier:
NCT01580007
First received: April 17, 2012
Last updated: January 1, 2013
Last verified: April 2012
History of Changes
  Purpose

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.


Condition Intervention Phase
Pulmonary Tuberculosis
 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
 Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Factorial Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Clinical Trial of Oral Phenylbutyrate and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis in Bangladesh: a Pilot Study

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by International Centre for Diarrhoeal Disease Research, Bangladesh:

Primary Outcome Measures:
  • 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)



Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 288
Study Start Date: December 2010
Estimated Study Completion Date: December 2013
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01580007

Locations
Bangladesh
National Institute of Diseases of Chest and Hospital (NIDCH) Recruiting
Dhaka, Bangladesh, 1212
Contact: Rubhana Raqib, PhD     8802-9885795     rubhana@icddrb.org    
Sub-Investigator: SM Mostafa Kamal, MD, MPhil            
Sponsors and Collaborators
International Centre for Diarrhoeal Disease Research, Bangladesh
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
  More Information

No publications provided

Responsible Party: International Centre for Diarrhoeal Disease Research, Bangladesh
ClinicalTrials.gov Identifier: NCT01580007     History of Changes
Other Study ID Numbers: PR-09068
Study First Received: April 17, 2012
Last Updated: January 1, 2013
Health Authority: Bangladesh: Ethical Review Committee

Keywords provided by International Centre for Diarrhoeal Disease Research, Bangladesh:
tuberculosis
phenylbutyrate
vitamin D
 cathelicidin
antimicrobial peptide
in adults

Additional relevant MeSH terms:
Tuberculosis
Tuberculosis, Pulmonary
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Cholecalciferol
Vitamin D
 Ergocalciferols
Vitamins
4-phenylbutyric acid
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Bone Density Conservation Agents
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 22, 2013