Using Biomarkers to Predict TB Treatment Duration
- Conditions
- Pulmonary Tuberculosis
- Interventions
- Procedure: Saliva collectionProcedure: Urine collectionProcedure: Sputum collectionProcedure: Blood CollectionRadiation: PET/CT ScanDrug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
- Registration Number
- NCT02821832
- Brief 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. 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.
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 946
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Arm A - Expected high risk of relapse, standard of care TB treatment Saliva collection Expected high risk of relapse, standard of care TB treatment Arm A - Expected high risk of relapse, standard of care TB treatment Urine collection Expected high risk of relapse, standard of care TB treatment Arm A - Expected high risk of relapse, standard of care TB treatment Sputum collection Expected high risk of relapse, standard of care TB treatment Arm A - Expected high risk of relapse, standard of care TB treatment Blood Collection Expected high risk of relapse, standard of care TB treatment Arm A - Expected high risk of relapse, standard of care TB treatment PET/CT Scan Expected high risk of relapse, standard of care TB treatment Arm C - Expected low risk of relapse, shortened TB treatment Saliva collection Expected low risk of relapse, shortened TB treatment Arm C - Expected low risk of relapse, shortened TB treatment Urine collection Expected low risk of relapse, shortened TB treatment Arm C - Expected low risk of relapse, shortened TB treatment Sputum collection Expected low risk of relapse, shortened TB treatment Arm A - Expected high risk of relapse, standard of care TB treatment Isoniazid, Rifampicin, Pyrazinamide and Ethambutol Expected high risk of relapse, standard of care TB treatment Arm B - Expected low risk of relapse, standard of care TB treatment Saliva collection Expected low risk of relapse, standard of care TB treatment Arm B - Expected low risk of relapse, standard of care TB treatment Urine collection Expected low risk of relapse, standard of care TB treatment Arm B - Expected low risk of relapse, standard of care TB treatment Sputum collection Expected low risk of relapse, standard of care TB treatment Arm B - Expected low risk of relapse, standard of care TB treatment Blood Collection Expected low risk of relapse, standard of care TB treatment Arm B - Expected low risk of relapse, standard of care TB treatment PET/CT Scan Expected low risk of relapse, standard of care TB treatment Arm B - Expected low risk of relapse, standard of care TB treatment Isoniazid, Rifampicin, Pyrazinamide and Ethambutol Expected low risk of relapse, standard of care TB treatment Arm C - Expected low risk of relapse, shortened TB treatment Blood Collection Expected low risk of relapse, shortened TB treatment Arm C - Expected low risk of relapse, shortened TB treatment PET/CT Scan Expected low risk of relapse, shortened TB treatment Arm C - Expected low risk of relapse, shortened TB treatment Isoniazid, Rifampicin, Pyrazinamide and Ethambutol Expected low risk of relapse, shortened TB treatment
- Primary Outcome Measures
Name Time Method Comparison of the Rate of Treatment Success at 18 Months (After Treatment Initiation) Between Arms B and C 18 months 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.
- Secondary Outcome Measures
Name Time Method Radiologic, Immunologic and Microbiologic Measures 18 months 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).
Trial Locations
- Locations (1)
Clinical Infectious Diseases Research Initiative (Khayelitsha site)
🇿🇦Cape Town, South Africa