Using Biomarkers to Predict TB Treatment Duration

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.

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.

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.

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).

INCLUSION CRITERIA: 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: 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. EXCLUSION CRITERIA: 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 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

.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.

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