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

Primary Purpose

Smear Positive Pulmonary Tuberculosis

Status
Completed
Phase
Phase 3
Locations
Indonesia
Study Type
Interventional
Intervention
L-arginine
Vitamin D
Placebo L-arginine
Placebo Vitamin D
Sponsored by
Menzies School of Health Research
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Smear Positive Pulmonary Tuberculosis focused on measuring Tuberculosis, Adjunctive therapy, L-arginine, Nitric oxide, Vitamin D

Eligibility Criteria

15 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Timika Tuberculosis Clinic and Community Hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Active Comparator

Active Comparator

Placebo Comparator

Arm Label

1

2

3

4

Arm Description

Active L-arginine plus active vitamin D

Placebo L-arginine plus active Vitamin D

Active L-arginine plus placebo vitamin D

placebo L-arginine plus placebo vitamin D

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
May 12, 2008
Last Updated
January 17, 2012
Sponsor
Menzies School of Health Research
Collaborators
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia, Australian National University
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1. Study Identification

Unique Protocol Identification Number
NCT00677339
Brief Title
L-arginine and Vitamin D Adjunctive Therapy in Pulmonary Tuberculosis (TB)
Acronym
AVDAPT
Official Title
Phase 3 Trial of Oral L-arginine and / or Vitamin D as Adjunctive Therapies in Pulmonary Tuberculosis in Papua Province, Indonesia.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2012
Overall Recruitment Status
Completed
Study Start Date
June 2008 (undefined)
Primary Completion Date
February 2010 (Actual)
Study Completion Date
May 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Menzies School of Health Research
Collaborators
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia, Australian National University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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: 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Smear Positive Pulmonary Tuberculosis
Keywords
Tuberculosis, Adjunctive therapy, L-arginine, Nitric oxide, Vitamin D

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Factorial Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
200 (Actual)

8. Arms, Groups, and Interventions

Arm Title
1
Arm Type
Active Comparator
Arm Description
Active L-arginine plus active vitamin D
Arm Title
2
Arm Type
Active Comparator
Arm Description
Placebo L-arginine plus active Vitamin D
Arm Title
3
Arm Type
Active Comparator
Arm Description
Active L-arginine plus placebo vitamin D
Arm Title
4
Arm Type
Placebo Comparator
Arm Description
placebo L-arginine plus placebo vitamin D
Intervention Type
Drug
Intervention Name(s)
L-arginine
Other Intervention Name(s)
Argimax
Intervention Description
L-arginine 6g orally daily
Intervention Type
Drug
Intervention Name(s)
Vitamin D
Other Intervention Name(s)
Calciferol Strong
Intervention Description
Cholecalciferol 50000 IU once monthly orally
Intervention Type
Drug
Intervention Name(s)
Placebo L-arginine
Intervention Description
placebo L-arginine once daily
Intervention Type
Drug
Intervention Name(s)
Placebo Vitamin D
Intervention Description
placebo vitamin D orally once monthly
Primary Outcome Measure Information:
Title
Proportion of pulmonary TB patients who are culture negative at 1 month
Time Frame
1 month
Title
Difference in improvement in composite clinical endpoint comprising weight, cough clearance and FEV1 at 2 months.
Time Frame
2 months
Secondary Outcome Measure Information:
Title
Change in plasma L-arginine concentration
Time Frame
week 0, 2, 4, 8, 24
Title
Change in plasma 25(OH)D3 concentration
Time Frame
week 0, 2, 4, 8, 24
Title
Death, clinical failure and default independently, and 'death or clinical failure or default'.
Time Frame
week 24
Title
Hypercalcaemia
Time Frame
week 0, 2, 4, 8, 24
Title
Gastrointestinal side effects
Time Frame
weekly to week 8 then at week 24
Title
Sputum smear conversion time
Time Frame
weekly to week 8 then at week 24
Title
Radiological improvement (percentage lung involvement on CXR at 2 months).
Time Frame
week 0, 2, 4, 8, 24
Title
Cough clearance
Time Frame
weekly to week 8 then at week 24
Title
Difference in improvement in percent predicted FEV1 at 2 and 6 months.
Time Frame
weeks 0, 4, 8, 24
Title
Weight gain
Time Frame
weekly to week 8 then at week 24
Title
Immunological improvement (exhaled NO)
Time Frame
week 0, 2, 4, 8, 24
Title
Immunological improvement (T cell CD3ζ expression and T cell function)
Time Frame
week 0, 2, 4, 24
Title
Functional improvement measured using six minute walk test
Time Frame
week 0, 4, 8, 24
Title
Quality of life assessment using modified St George Respiratory Questionnaire.
Time Frame
weeks 0, 4, 8, 24
Title
Primary end points stratified by HIV status.
Time Frame
weekly to week 8 then at week 24
Title
Primary end points stratified by baseline vitamin D and L-arginine status.
Time Frame
weekly to week 8 then week 24
Title
Primary end points stratified by ethnicity (Papuan and non-Papuan patients).
Time Frame
weekly to week 8 then week 24

10. Eligibility

Sex
All
Minimum Age & Unit of Time
15 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nicholas M Anstey, MBBS
Organizational Affiliation
Menzies School of Helath Research
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Anna P Ralph, MBBS
Organizational Affiliation
Australian National University, Canberra, Australia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Franciscus Thio, MPPM
Organizational Affiliation
District Ministry of Health, Timika
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Peter Morris, MBBS
Organizational Affiliation
Menzies School of Health Research, Northern Territory, Australia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Enny Kenangalem, MD
Organizational Affiliation
Papuan Community Health and Development Foundation
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jeanne R Poespoprodjo, MD
Organizational Affiliation
Mimika District Health Authority
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Richard N Price, MD
Organizational Affiliation
Menzies School of Health Research
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Tonia Woodberry, PhD
Organizational Affiliation
Menzies School of Health Research
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Paul M Kelly, MBBS
Organizational Affiliation
Australian Capital Territory Department of Health
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Emiliana Tjitra, MD, PhD
Organizational Affiliation
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sandjaja Sandjaja, PhD
Organizational Affiliation
National Institute of Health Research and Development, Ministry of Health Republic of Indonesia
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dina B Lolong, MD
Organizational Affiliation
National Institute of Health Research and Development
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mark Chatfield, PhD
Organizational Affiliation
National Health and Medical Research Council (Australia) Clinical Trials Centre
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ivan Bastian, MBBS
Organizational Affiliation
Institute of Medical and Veterinary Pathology, South Australia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Timika Tuberculosis Clinic and Community Hospital
City
Timika
State/Province
Papua Province
Country
Indonesia

12. IPD Sharing Statement

Citations:
PubMed Identifier
23967066
Citation
Ralph AP, Waramori G, Pontororing GJ, Kenangalem E, Wiguna A, Tjitra E, Sandjaja, Lolong DB, Yeo TW, Chatfield MD, Soemanto RK, Bastian I, Lumb R, Maguire GP, Eisman J, Price RN, Morris PS, Kelly PM, Anstey NM. L-arginine and vitamin D adjunctive therapies in pulmonary tuberculosis: a randomised, double-blind, placebo-controlled trial. PLoS One. 2013 Aug 14;8(8):e70032. doi: 10.1371/journal.pone.0070032. eCollection 2013.
Results Reference
derived

Learn more about this trial

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

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