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Pulmonary TuberculosisPhase 2NCT02821832

Using Biomarkers to Predict TB Treatment Duration

A Phase 2 study testing Saliva collection, Urine collection and Sputum collection in people with Pulmonary Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in South Africa.

Completed

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

Official record
Search all trials

Trial summary

Background: Tuberculosis (TB) is a bacterial lung infection. Typical treatment using anti-TB drugs lasts about 6 months. Some people with less severe TB might not need to take the drugs that long. Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Pulmonary Tuberculosis
What is being tested?
Saliva collection, Urine collection and Sputum collection
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
946 participants
Where
1 siteSouth Africa
Study dates
21 Jun 2017to 28 Feb 2022
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

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 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Age 18 to 75 years with body weight from 35 kg to 90 kg
  • Has not been treated for active TB within the past 3 years
  • Not yet on TB treatment
  • Xpert positive for M.tb
  • Rifampin-sensitive pulmonary tuberculosis as indicated by Xpert
  • Laboratory parameters within previous 14 days before enrollment:
Show all 17Show fewer
  • Serum AST and ALT <3x upper limit of normal (ULN)
  • Creatinine <2x ULN
  • Hemoglobin >7.0 g/dL
  • Platelet count >50 x10(9) cells/L
  • Able and willing to return for follow-up visits
  • Able and willing to provide informed consent to participate in the study
  • Willing to undergo an HIV test
  • At sites with sufficient SARS-CoV-2 testing capacity and personal protective equipment for study staff, willing to undergo COVID-19 testing:
  • viral RNA PCR testing for SARS-CoV-2 to determine active infection and antibody testing for SARS-CoV-2 to determine prior infection
  • Willing to have samples, including DNA, stored
  • Willing to consistently practice a highly reliable, non-hormonal method of pregnancy prevention (e.g., condoms) during treatment if participant is a premenopausal female unless she has had a hysterectomy or bilateral tubal ligation or her male partner has had a vasectomy. If hormonal contraception is used an additional method of pregnancy prevention (as above) should be used.

Who cannot join

  • Clinical suspicion of or confirmed extrapulmonary TB, including pleural TB
  • Pregnant or desiring/trying to become pregnant in the next 6 months or breastfeeding.
  • HIV infected
  • Currently COVID-19 infected
  • Unable to take oral medications
  • Diabetes as defined by point of care HbA1c greater than 6.5%, random glucose greater than 200 mg/dL (or 11.1 mmol/L), fasting plasma glucose greater than or equal to 126 mg/dL (or 7.0 mmol/L), or the presence of any antidiabetic agent (including traditional medicines) as a concomitant medicine
Show all 11Show fewer
  • Disease complications or concomitant illnesses that may compromise safety or interpretation of trial endpoints, such as known diagnosis of chronic inflammatory condition (e.g. sarcoidosis, rheumatoid arthritis, connective tissue disorder)
  • Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within the past 2 weeks
  • Use of any investigational drug in the previous 3 months
  • Substance or alcohol abuse that in the opinion of the investigator may interfere with the participant's adherence to study procedures.
  • Any person for whom the physician feels this study is not appropriate

Trial locations and contacts

1 site in 1 country.

South Africa1 site

  • Clinical Infectious Diseases Research Initiative (Khayelitsha site)

    Cape Town

Other trials in South Africa

About this study

Background:

Tuberculosis (TB) is a bacterial lung infection. Typical treatment using anti-TB drugs lasts about 6 months. Some people with less severe TB might not need to take the drugs that long. Researchers think a PET/CT lung scan along with estimating how much TB is in the lungs might show who will be cured after only 4 months of treatment.

Read more

Objective:

To demonstrate that 4 months of treatment is not inferior to 6 months of treatment for people with less severe TB.

Eligibility:

People 18-75 years old who have TB treatable with standard TB drugs

Design:

Participants will be screened with:

Medical history

Physical exam

Blood and urine tests

HIV test

Sputum sample: Participants will be asked to cough sputum into a cup.

Chest x-ray

Participants will start TB drugs. They will have visits at weeks 1, 2, 4, 8, 12, and about 6 more times during the 18-month study. Visits include:

Sputum samples

Physical exam

Blood tests

PET/CT scans at 2-3 visits: Participants fast for about 6 hours before the scan. Participants get FDG, a type of sugar that gives off a small amount of radiation, through an arm vein. They lie on a table in a machine that takes pictures of the body.

Chest x-rays at 1-2 visits

Participants who we believe are likely to be cured at 4 months will be randomly assigned to get either 6 months of treatment or 4 months of treatment.

Participants may be asked to join a substudy using their sputum samples or additional blood tests.

Read the detailed description

Shortening the duration of treatment for patients with drug sensitive tuberculosis from 6 to 4 months has been attempted many times in clinical trials but thus far all have failed. These failures reveal our incomplete understanding of factors driving the need for such extensive treatments. Consistently, trials have demonstrated that 80-85% of patients are successfully cured after 4 months of therapy, including the extensive set of studies from the British Medical Research Council (BMRC) in the 1970s and 1980, the Tuberculosis Research Unit (TBRU) treatment shortening study in non-cavitary patients who achieve early culture conversion, and the more recent treatment shortening trials using fluoroquinolones like REMoxTB. The current standard of care is to over-treat all patients for a total of 6-months to avoid relapse in a small subset of patients at higher risk for incompletely understood reasons.

For decades, clinical investigators have attempted to establish culture conversion as a predictor of treatment success. Despite the appealing logic, the real correlation of culture conversion as a surrogate endpoint has been consistently disappointing. In the REMoxTB trial, in particular, the intensive microbiological data collected revealed unambiguously that clearance of bacteria from the sputum did not sufficiently correlate with relapse risk to be a useful surrogate for durable cure. An important subset of patients, despite clearing their sputum of TB quickly and complying with all of their medications, still remained at high risk of relapsing with active disease after stopping treatment. Likewise there are patients who clear their sputum of bacteria slowly that nonetheless go on to achieve durable cure. Intuitively this makes sense: only those bacteria at the surface of a cavity are directly open to the airways to seed the sputum. Yet this is not the full story as there are also heterogeneous lesions within each individual patient which respond differently to treatment with chemotherapy.

This protocol builds upon the historical trials and several successful small studies that suggest that directly monitoring lung pathology using (18F)- FDG PET/CT correlates better with treatment outcome than culture status. We will prospectively identify patients at low risk based on their baseline radiographic extent of disease, and further refine this risk score by evaluating the rate of resolution of the lung pathology (CT) and inflammation (PET) at one month as well as checking an end-of-treatment GeneXpert test for the sustained presence of bacteria. Patients classified as low risk will be randomized to receive a shortened 4- month or a full 6-month course of therapy. If successful, this trial will both offer a badly needed alternative to culture status as a trial-level surrogate marker for outcome as well as provide critical information for preclinical and early clinical efforts to identify new agents and combinations with the potential to shorten therapy.

Hypothesis: A combination of radiographic characteristics at baseline, the rate of change of these features at one month, and markers of residual bacterial load at the end of treatment will identify patients with tuberculosis who are cured with 4 months (16 weeks) of standard treatment.

Being tested
Saliva collection, Urine collection, Sputum collection, Blood Collection, PET/CT Scan
Keywords
Drug-Resistance, Heteroresistance, Relapse-markers, Medical Imaging, Treatment-shortening
Medical subject headings
Tuberculosis, Pulmonary

What participants receive

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

  • Saliva collectionProcedure or surgery

    For biomarker assessments

  • Urine collectionProcedure or surgery

    For biomarker assessments

  • Sputum collectionProcedure or surgery

    For primary endpoint assessments and other biomarker assessments

  • Blood CollectionProcedure or surgery

    For biomarker and eligibility assessments

  • PET/CT ScanRadiation

    Imaging of the lungs to establish disease extent and severity

  • Isoniazid, Rifampicin, Pyrazinamide and EthambutolDrug

    Treatment-standard of care

Study groups in NCT02821832
Study groupRoleWhat they receive
Arm A - Expected high risk of relapse, standard of care TB treatmentOtherExpected high risk of relapse, standard of care TB treatment
Receives: Procedure: Saliva collection; Procedure: Urine collection; Procedure: Sputum collection; Procedure: Blood Collection; Radiation: PET/CT Scan; Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
Arm B - Expected low risk of relapse, standard of care TB treatmentActive comparatorExpected low risk of relapse, standard of care TB treatment
Receives: Procedure: Saliva collection; Procedure: Urine collection; Procedure: Sputum collection; Procedure: Blood Collection; Radiation: PET/CT Scan; Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
Arm C - Expected low risk of relapse, shortened TB treatmentExperimentalExpected low risk of relapse, shortened TB treatment
Receives: Procedure: Saliva collection; Procedure: Urine collection; Procedure: Sputum collection; Procedure: Blood Collection; Radiation: PET/CT Scan; Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol

What is being measured

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

  1. Comparison of the Rate of Treatment Success at 18 Months (After Treatment Initiation) Between Arms B and C

    Estimation of the lower bound of a one-sided 95% confidence interval of the difference in success rates between arms B and C. If the lower bound is greater than -7%, this will be evidence that the treatment-shortening arm is not inferior to the standard duration arm.

    Measured: 18 months

Secondary outcomes (1)

  1. Radiologic, Immunologic and Microbiologic Measures

    The difference (and 95% confidence interval) in treatment success rates between a combined A+B Arm (with Arm A participants selected to represent a true 6-month standard of care population) and a combined Arm A+C (with the remaining Arm A participants selected to represent a treatment shortening strategy arm, and no overlap in Arm A participants assigned to B and C).

    Measured: 18 months

Timeline

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

  1. First posted4 Jul 2016 (estimated)
  2. Study start21 Jun 2017
  3. Primary completion9 Oct 2021
  4. Study completion28 Feb 2022

Resources

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 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
946 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02821832
Sponsor's protocol ID
999916133
Other IDs
16-I-N133
Status last verified
Apr 2024
First submitted
29 Jun 2016
Last updated
17 Apr 2024
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: .A data sharing committee will be formed to define when and how data will be shared. To protect study integrity, data will not generally be released externally as the study is ongoing, except under extraordinary circumstances. Prior to database lock, data releases will require approval from the data and safety monitoring board, in addition to the data sharing committee. Exceptions to these data release include limited data required for reporting to sponsors (e.g., enrollment updates). After the database has been locked, a formal process for data sharing will be implemented. The data sharing timelines will meet the requirements of the study funders.

Publications

  • Jindani A, Harrison TS, Nunn AJ, Phillips PP, Churchyard GJ, Charalambous S, Hatherill M, Geldenhuys H, McIlleron HM, Zvada SP, Mungofa S, Shah NA, Zizhou S, Magweta L, Shepherd J, Nyirenda S, van Dijk JH, Clouting HE, Coleman D, Bateson AL, McHugh TD, Butcher PD, Mitchison DA; RIFAQUIN Trial Team. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1599-608. doi: 10.1056/NEJMoa1314210.

    PubMed 25337749

  • Gillespie SH, Crook AM, McHugh TD, Mendel CM, Meredith SK, Murray SR, Pappas F, Phillips PP, Nunn AJ; REMoxTB Consortium. Four-month moxifloxacin-based regimens for drug-sensitive tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1577-87. doi: 10.1056/NEJMoa1407426. Epub 2014 Sep 7.

    PubMed 25196020

  • Merle CS, Fielding K, Sow OB, Gninafon M, Lo MB, Mthiyane T, Odhiambo J, Amukoye E, Bah B, Kassa F, N'Diaye A, Rustomjee R, de Jong BC, Horton J, Perronne C, Sismanidis C, Lapujade O, Olliaro PL, Lienhardt C; OFLOTUB/Gatifloxacin for Tuberculosis Project. A four-month gatifloxacin-containing regimen for treating tuberculosis. N Engl J Med. 2014 Oct 23;371(17):1588-98. doi: 10.1056/NEJMoa1315817.

    PubMed 25337748

  • Chen RY, Via LE, Dodd LE, Walzl G, Malherbe ST, Loxton AG, Dawson R, Wilkinson RJ, Thienemann F, Tameris M, Hatherill M, Diacon AH, Liu X, Xing J, Jin X, Ma Z, Pan S, Zhang G, Gao Q, Jiang Q, Zhu H, Liang L, Duan H, Song T, Alland D, Tartakovsky M, Rosenthal A, Whalen C, Duvenhage M, Cai Y, Goldfeder LC, Arora K, Smith B, Winter J, Barry Iii CE; Predict TB Study Group. Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial. Gates Open Res. 2017 Nov 6;1:9. doi: 10.12688/gatesopenres.12750.1.

    PubMed 29528048

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Saliva collection, Urine collection and Sputum collection in people with Pulmonary Tuberculosis, run by National Institute of Allergy and Infectious Diseases (NIAID) at 1 site in South Africa.

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 17 inclusion and 11 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 17 Apr 2024. 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 South Africa. 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. 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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

Are results available for this study?

Yes. Results are posted in the registry (first posted 20 Dec 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

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?

Comparison of the Rate of Treatment Success at 18 Months (After Treatment Initiation) Between Arms B and C (time frame: 18 months). 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 NCT02821832, which also lists 4 linked publications.

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 17 Apr 2024; AzTrials last refreshed its copy on 26 Oct 2026.

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