Immune Reconstitution in Tuberculosis Disease

Study Overview
=================
Brief Summary
-----------------
The aim with study is to provide adjunctive therapy with vitamin D and phenylbutyrate together with standard anti-tuberculosis treatment to significantly improve clinical recovery among patients with untreated, active pulmonary tuberculosis.

Official Title
-----------------
Immune Reconstitution in Tuberculosis Disease Using Antimicrobial Treatment With Vitamin D and Phenylbutyrate

Conditions
-----------------
Pulmonary Tuberculosis (TB)

Intervention / Treatment
-----------------
* Drug: vitamin D (cholecalciferol) and PBA (sodium phenylbutyrate)
* Drug: Placebo tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: HIV negative patients, adult patients >18 years who has not started anti-TB therapy. Newly diagnosed pulmonary TB confirmed by microscopy or culture but also sputum-negative clinical TB cases (defined according to the WHO 2006 criteria for sputum smear-negative TB ie. clinical symptoms of TB, chest X-ray findings and response to standard treatment). Exclusion Criteria: Patients who have already started treatment with anti-TB drugs for more that 5 days. HIV-positive patients. History of anti-TB treatment in the past 2 years. Local extra-pulmonary TB in the absence of lung manifestations. Hypercalcaemia (serum calcium > 3 mmol/L) identified at baseline. Pregnant and breast feeding women. Any known liver or kidney function abnormality, malignancy or patients treated with cardiac glycosides.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: vitamin D (cholecalciferol) and PBA (sodium phenylbutyrate)<br>Dose of interventions: 5,000 IU of vitamin D (cholecalciferol tablets) once daily and 500 mg PBA (sodium phenylbutyrate tablets) twice daily for 16 weeks. | Drug: vitamin D (cholecalciferol) and PBA (sodium phenylbutyrate)<br>* Dose of interventions: 5,000 IU of vitamin D (cholecalciferol tablets) once daily and 500 mg PBA (sodium phenylbutyrate tablets) twice daily for 16 weeks.<br>|
| Placebo Comparator: Placebo tablets<br>Placebo tablets for vitamin D once daily and placebo tablets for PBA (phenylbutyrate) twice daily for 16 weeks. | Drug: Placebo tablets<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite clinical TB score | A previously described composite clinical TB score will be used to monitor the efficacy of vitamin D and phenylbutyrate treatment among TB patients on standard chemotherapy. The numerical TB score will include self-reported clinical symptoms (cough, night sweats and chest pain) as well as different parameters determined upon clinical examination anemia, haemoptysis, dyspnoea, tachycardia, positive finding at lung auscultation, fever, low body mass index (BMI) and low mid upper arm circumference (MUAC). The TB score will be determined at the time of diagnosis (time point 0) and at 4, 8, 16 and 24 weeks after initiation of antimicrobial treatment with vitamin D and phenylbutyrate. The primary endpoint will be assessed at time point 8 weeks compared to baseline (time point 0). | 0 (baseline) compared to 8 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical secondary endpoints | Clinical composite TB score (0, 4, 16, 24 weeks). Modified clinical composite TB score (0, 4, 8, 16, 24 weeks). Chest X-ray (0, 4, 8, 16, 24 weeks). Time to sputum- and/or TB culture conversion (0, 1, 2, 3, 4, 8 weeks). | 0-4, 8, 16 and 24 weeks | 
| Laboratory secondary endpoints | Peripheral CD4/CD8 T cell counts. Antibodies in lymphocytes secertions (ALS) (S Ashenafi, Thorax, 2012). Quantiferon-in-tube TB-gold (QFT). Plasma levels of vitamin D, LL-37 and also cytokine/chemokine profiles. Functional studies of immune cells (PBMCs). | 0, 4, 8, 16, 24 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pulmonary TB, cholecalciferol, sodium phenylbutyrate, antimicrobial peptides, immune response