L-arginine and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis (TB)

Study Overview
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Brief Summary
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The purpose of this study is to determine whether adjunctive L-arginine and vitamin D can improve response to standard short course TB therapy in people with newly diagnosed pulmonary TB.

Detailed Description
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The two major pathways proposed to mediate macrophage mycobacterial killing in humans are the arginine-nitric oxide and Vitamin D-1,25 dihydroxyvitamin D pathways. Our aim is to determine if the key immunomodulatory agents L-arginine and vitamin D can improve the rapidity and magnitude of the microbiological and clinical response in pulmonary TB. We will test the following hypotheses in newly-diagnosed TB patients in Timika, Papua, Indonesia: Our specific aims are to: Determine whether supplementation with L-arginine and/or vitamin D is safe, and results in more rapid improvement in clinical, mycobacterial, immunological, radiological, physiological and functional measures of treatment outcome. We will randomise patients with pulmonary TB to receive, in addition to standard TB therapy, adjunctive arginine, vitamin D and / or placebo in a randomised, double-blind factorial 2x2 design. We will relate serial measurements of plasma concentrations of L-arginine and vitamin D, and immunological responses (pulmonary NO production, T cell function and phenotype) to measures of treatment outcome [mycobacterial (sputum smear clearance and culture conversion), physiological (spirometry), clinical (symptoms and weight), radiological (chest Xray) and functional (six-minute walk test, modified St George Respiratory Questionnaire)]. Determine whether pulmonary production of NO is inversely related to disease severity at presentation. Baseline and serial measures of NO production will be related to disease severity and the magnitude and rapidity of clinical response

Official Title
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Phase 3 Trial of Oral L-arginine and / or Vitamin D as Adjunctive Therapies in Pulmonary Tuberculosis in Papua Province, Indonesia.

Conditions
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Smear Positive Pulmonary Tuberculosis

Intervention / Treatment
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* Drug: L-arginine
* Drug: Vitamin D
* Drug: Placebo L-arginine
* Drug: Placebo Vitamin D


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adults >15 years with sputum smear positive pulmonary TB New cases only Agree to continue treatment in Timika for the full six month course of treatment -Not pregnant Consent to enroll in the study. Exclusion Criteria: hypercalcaemia (ionized calcium >1.32 mmol/L) identified at baseline taking arginine or vitamin D

Ages Eligible for Study
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Minimum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Active L-arginine plus active vitamin D | Drug: L-arginine<br>* L-arginine 6g orally daily<br>* Other names: Argimax;Drug: Vitamin D<br>* Cholecalciferol 50000 IU once monthly orally<br>* Other names: Calciferol Strong;|
| Active Comparator: 2<br>Placebo L-arginine plus active Vitamin D | Drug: Vitamin D<br>* Cholecalciferol 50000 IU once monthly orally<br>* Other names: Calciferol Strong;Drug: Placebo L-arginine<br>* placebo L-arginine once daily<br>|
| Active Comparator: 3<br>Active L-arginine plus placebo vitamin D | Drug: L-arginine<br>* L-arginine 6g orally daily<br>* Other names: Argimax;Drug: Placebo Vitamin D<br>* placebo vitamin D orally once monthly<br>|
| Placebo Comparator: 4<br>placebo L-arginine plus placebo vitamin D | Drug: Placebo L-arginine<br>* placebo L-arginine once daily<br>Drug: Placebo Vitamin D<br>* placebo vitamin D orally once monthly<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of pulmonary TB patients who are culture negative at 1 month |  | 1 month | 
| Difference in improvement in composite clinical endpoint comprising weight, cough clearance and FEV1 at 2 months. |  | 2 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in plasma L-arginine concentration |  | week 0, 2, 4, 8, 24 | 
| Change in plasma 25(OH)D3 concentration |  | week 0, 2, 4, 8, 24 | 
| Death, clinical failure and default independently, and 'death or clinical failure or default'. |  | week 24 | 
| Hypercalcaemia |  | week 0, 2, 4, 8, 24 | 
| Gastrointestinal side effects |  | weekly to week 8 then at week 24 | 
| Sputum smear conversion time |  | weekly to week 8 then at week 24 | 
| Radiological improvement (percentage lung involvement on CXR at 2 months). |  | week 0, 2, 4, 8, 24 | 
| Cough clearance |  | weekly to week 8 then at week 24 | 
| Difference in improvement in percent predicted FEV1 at 2 and 6 months. |  | weeks 0, 4, 8, 24 | 
| Weight gain |  | weekly to week 8 then at week 24 | 
| Immunological improvement (exhaled NO) |  | week 0, 2, 4, 8, 24 | 
| Immunological improvement (T cell CD3ζ expression and T cell function) |  | week 0, 2, 4, 24 | 
| Functional improvement measured using six minute walk test |  | week 0, 4, 8, 24 | 
| Quality of life assessment using modified St George Respiratory Questionnaire. |  | weeks 0, 4, 8, 24 | 
| Primary end points stratified by HIV status. |  | weekly to week 8 then at week 24 | 
| Primary end points stratified by baseline vitamin D and L-arginine status. |  | weekly to week 8 then week 24 | 
| Primary end points stratified by ethnicity (Papuan and non-Papuan patients). |  | weekly to week 8 then week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tuberculosis, Adjunctive therapy, L-arginine, Nitric oxide, Vitamin D