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

Smear Positive Pulmonary Tuberculosis Clinical Trial

— AVDAPT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00677339
• Other study ID #: AVDAPT 1
• Status: Completed
• Phase: Phase 3
• First received: May 12, 2008
• Last updated: January 17, 2012
• Start date: June 2008
• Est. completion date: May 2010

Study information

• Verified date: January 2012
• Source: Menzies School of Health Research
• Contact: n/a
• Is FDA regulated: No
• Health authority: Indonesia: Ministry of Health
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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:

1. 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)].

2. 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: May 2010
• Est. primary completion date: February 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 15 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Smear Positive Pulmonary Tuberculosis
• Tuberculosis
• Tuberculosis, Pulmonary

Intervention

Drug:
• L-arginine
L-arginine 6g orally daily
• Vitamin D
Cholecalciferol 50000 IU once monthly orally
• Placebo L-arginine
placebo L-arginine once daily
• Placebo Vitamin D
placebo vitamin D orally once monthly

Locations

Country	Name	City	State
Indonesia	Timika Tuberculosis Clinic and Community Hospital	Timika	Papua Province

Sponsors (3)

Lead Sponsor	Collaborator
Menzies School of Health Research	Australian National University, National Institute of Health Research and Development (NIHRD), Indonesia

Country where clinical trial is conducted

Indonesia, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of pulmonary TB patients who are culture negative at 1 month		1 month	No
Primary	Difference in improvement in composite clinical endpoint comprising weight, cough clearance and FEV1 at 2 months.		2 months	No
Secondary	Change in plasma L-arginine concentration		week 0, 2, 4, 8, 24	Yes
Secondary	Change in plasma 25(OH)D3 concentration		week 0, 2, 4, 8, 24	Yes
Secondary	Death, clinical failure and default independently, and 'death or clinical failure or default'.		week 24	Yes
Secondary	Hypercalcaemia		week 0, 2, 4, 8, 24	Yes
Secondary	Gastrointestinal side effects		weekly to week 8 then at week 24	Yes
Secondary	Sputum smear conversion time		weekly to week 8 then at week 24	No
Secondary	Radiological improvement (percentage lung involvement on CXR at 2 months).		week 0, 2, 4, 8, 24	No
Secondary	Cough clearance		weekly to week 8 then at week 24	No
Secondary	Difference in improvement in percent predicted FEV1 at 2 and 6 months.		weeks 0, 4, 8, 24	No
Secondary	Weight gain		weekly to week 8 then at week 24	No
Secondary	Immunological improvement (exhaled NO)		week 0, 2, 4, 8, 24	No
Secondary	Immunological improvement (T cell CD3? expression and T cell function)		week 0, 2, 4, 24	No
Secondary	Functional improvement measured using six minute walk test		week 0, 4, 8, 24	No
Secondary	Quality of life assessment using modified St George Respiratory Questionnaire.		weeks 0, 4, 8, 24	No
Secondary	Primary end points stratified by HIV status.		weekly to week 8 then at week 24	No
Secondary	Primary end points stratified by baseline vitamin D and L-arginine status.		weekly to week 8 then week 24	No
Secondary	Primary end points stratified by ethnicity (Papuan and non-Papuan patients).		weekly to week 8 then week 24	No