Using Biomarkers to Predict TB Treatment Duration
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 nontheless 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-oftreatment 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.

 The NIAID Data Safety Monitoring Board conducted its 7th interim review of unblinded data on
 September 11, 2020. Following this review, the DSMB recommended halting randomization to Arms
 B and C. This recommendation is based on the result of the interim analysis, when 1/3 of
 randomized participants have been followed for 72 weeks from study entry. The protocol
 stopping guideline for inferiority of the treatment shortening arm was met. The DSMB was also
 presented with conditional power calculations relating to the futility interim analysis;
 although the protocol-specified time for this analysis had not been reached, the results of
 the analysis were consistent with a decision to terminate randomization into Arms B and C,
 but to continue enrollment into Arms A and B at the discretion of the investigators.
 Pre-emptive retreatment of participants who have completed the course of treatment in Arm C
 is not recommended and should be left to the discretion of the treating clinician.

 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.
-  INCLUSION CRITERIA:

 1. Age 18 to 75 years with body weight from 35 kg to 90 kg

 2. Has not been treated for active TB within the past 3 years

 3. Not yet on TB treatment

 4. Xpert positive for M.tb

 5. Rifampin-sensitive pulmonary tuberculosis as indicated by Xpert

 6. Laboratory parameters within previous 14 days before enrollment:

 1. Serum AST and ALT <3x upper limit of normal (ULN)

 2. Creatinine <2x ULN

 3. Hemoglobin >7.0 g/dL

 4. Platelet count >50 x10(9) cells/L

 7. Able and willing to return for follow-up visits

 8. Able and willing to provide informed consent to participate in the study

 9. Willing to undergo an HIV test

 10. 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

 11. Willing to have samples, including DNA, stored

 12. 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:

 1. Clinical suspicion of or confirmed extrapulmonary TB, including pleural TB

 2. Pregnant or desiring/trying to become pregnant in the next 6 months or breastfeeding.

 3. HIV infected

 4. Currently COVID-19 infected

 5. Unable to take oral medications

 6. 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

 7. 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)

 8. Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or
 inhaled corticosteroids, within the past 2 weeks

 9. Use of any investigational drug in the previous 3 months

 10. Substance or alcohol abuse that in the opinion of the investigator may interfere with
 the participant's adherence to study procedures.

 11. Any person for whom the physician feels this study is not appropriate