Smear Positive Pulmonary TuberculosisPhase 3AVDAPTNCT00677339

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

A Phase 3 study testing L-arginine and Vitamin D in people with Smear Positive Pulmonary Tuberculosis, run by Menzies School of Health Research at 1 site in Indonesia.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record

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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. Read more about this study

Who is it for?: Ages 15 years and older
Conditions the study is for: Smear Positive Pulmonary Tuberculosis
What is being tested?: L-arginine and Vitamin D
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 200 participants
Where: 1 siteIndonesia
Study dates: Jun 2008to May 2010
Phase: Phase 3
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 15 years and older
All sexes
No healthy volunteers
Child, Adult, Older adult

Who may be able to join

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.

Who cannot join

hypercalcaemia (ionized calcium >1.32 mmol/L) identified at baseline
taking arginine or vitamin D

Trial locations and contacts

1 site in 1 country.

Indonesia1 site

Timika Tuberculosis Clinic and Community Hospital
Timika, Papua Province

Other trials in Indonesia

About this study

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

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.

Read the 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

Conditions: Smear Positive Pulmonary Tuberculosis
Being tested: L-arginine, Vitamin D, Placebo L-arginine, Placebo Vitamin D
Keywords: Tuberculosis, Adjunctive therapy, L-arginine, Nitric oxide, Vitamin D
Medical subject headings: Tuberculosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

L-arginineDrug
Also called Argimax
L-arginine 6g orally daily
Vitamin DDrug
Also called Calciferol Strong
Cholecalciferol 50000 IU once monthly orally
Placebo L-arginineDrug
placebo L-arginine once daily
Placebo Vitamin DDrug
placebo vitamin D orally once monthly

Study groups in NCT00677339
Study group	Role	What they receive
1	Active comparator	Active L-arginine plus active vitamin D Receives: Drug: L-arginine; Drug: Vitamin D
2	Active comparator	Placebo L-arginine plus active Vitamin D Receives: Drug: Vitamin D; Drug: Placebo L-arginine
3	Active comparator	Active L-arginine plus placebo vitamin D Receives: Drug: L-arginine; Drug: Placebo Vitamin D
4	Placebo comparator	placebo L-arginine plus placebo vitamin D Receives: Drug: Placebo L-arginine; Drug: Placebo Vitamin D

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (17)

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jun 2008May 2010

First posted14 May 2008 (estimated)
Study startJun 2008
Primary completionFeb 2010
Study completionMay 2010

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (1)Papers the sponsor has linked to this study.
Other trials for Smear Positive Pulmonary TuberculosisStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Factorial
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 200 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT00677339
Sponsor's protocol ID: AVDAPT 1
Acronym: AVDAPT
Status last verified: Jan 2012
First submitted: 12 May 2008
Last updated: 18 Jan 2012
Results posted: No
Data monitoring committee: Yes

Publications

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.
PubMed 23967066

Study at a glance

From the registry record, last updated by the sponsor on 18 Jan 2012. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: Phase 3 Trial of Oral L-arginine and / or Vitamin D as Adjunctive Therapies in Pulmonary Tuberculosis in Papua Province, Indonesia.
ClinicalTrials.gov ID: NCT00677339
Acronym / sponsor ID: AVDAPT / AVDAPT 1
Conditions: Smear Positive Pulmonary Tuberculosis
Keywords: Tuberculosis, Adjunctive therapy, L-arginine, Nitric oxide, Vitamin D
Phase: Phase 3
Study type: Interventional
Recruitment status: Completed
Enrolment: 200 participants (actual)
Lead sponsor: Menzies School of Health ResearchUniversity, hospital or other
Collaborators: National Institute of Health Research and Development, Ministry of Health Republic of Indonesia, Australian National University
Study start: Jun 2008
Primary completion: Feb 2010 (actual)
Study completion: May 2010 (actual)
First posted: 14 May 2008 (estimated)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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

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

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Factorial
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
1	Active comparator	Drug: L-arginine, Drug: Vitamin DActive L-arginine plus active vitamin D
2	Active comparator	Drug: Vitamin D, Drug: Placebo L-argininePlacebo L-arginine plus active Vitamin D
3	Active comparator	Drug: L-arginine, Drug: Placebo Vitamin DActive L-arginine plus placebo vitamin D
4	Placebo comparator	Drug: Placebo L-arginine, Drug: Placebo Vitamin Dplacebo L-arginine plus placebo vitamin D

Who may qualify

Ages: 15 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Child, Adult, Older adult

Key inclusion criteria (4 listed)

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.

Key exclusion criteria (2 listed)

hypercalcaemia (ionized calcium >1.32 mmol/L) identified at baseline
taking arginine or vitamin D

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
L-arginineAlso: ArgimaxL-arginine 6g orally daily	Drug	1, 3
Vitamin DAlso: Calciferol StrongCholecalciferol 50000 IU once monthly orally	Drug	1, 2
Placebo L-arginineplacebo L-arginine once daily	Drug	2, 4
Placebo Vitamin Dplacebo vitamin D orally once monthly	Drug	3, 4

Primary outcome

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

17 secondary outcomes

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

Results and safety

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 18 Jan 2012.
Derived from this study: PubMed 23967066Ralph 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.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

Nicholas M Anstey, MBBS study director

Menzies School of Helath Research

Anna P Ralph, MBBS principal investigator

Australian National University, Canberra, Australia

Franciscus Thio, MPPM principal investigator

District Ministry of Health, Timika

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing L-arginine and Vitamin D in people with Smear Positive Pulmonary Tuberculosis, run by Menzies School of Health Research at 1 site in Indonesia.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Jan 2012. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Indonesia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Proportion of pulmonary TB patients who are culture negative at 1 month (time frame: 1 month). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00677339, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jan 2012.