Using Biomarkers to Predict TB Treatment Duration
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Other: Arm A Expected high risk of relapse |
Procedure: Saliva collection
For biomarker assessments
Procedure: Urine collection
For biomarker assessments
Procedure: Sputum collection
For primary endpoint assessments and other biomarker assessments
Procedure: Blood Collection
For biomarker and eligibility assessments
Radiation: PET/CT Scan
Imaging of the lungs to establish disease extent and severity
Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
Treatment-standard of care
|
| Active Comparator: Arm B Expected low risk of relapse |
Procedure: Saliva collection
For biomarker assessments
Procedure: Urine collection
For biomarker assessments
Procedure: Sputum collection
For primary endpoint assessments and other biomarker assessments
Procedure: Blood Collection
For biomarker and eligibility assessments
Radiation: PET/CT Scan
Imaging of the lungs to establish disease extent and severity
Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
Treatment-standard of care
|
| Experimental: Arm C Expected low risk of relapse |
Procedure: Saliva collection
For biomarker assessments
Procedure: Urine collection
For biomarker assessments
Procedure: Sputum collection
For primary endpoint assessments and other biomarker assessments
Procedure: Blood Collection
For biomarker and eligibility assessments
Radiation: PET/CT Scan
Imaging of the lungs to establish disease extent and severity
Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol
Treatment-standard of care
|
Outcome Measures
Primary Outcome Measures
- 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
- 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).
Eligibility Criteria
Criteria
- 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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Clinical Infectious Diseases Research Initiative (Khayelitsha site) | Cape Town | South Africa |
Sponsors and Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
- Principal Investigator: Clifton E Barry, Ph.D., National Institute of Allergy and Infectious Diseases (NIAID)
Study Documents (Full-Text)
None provided.More Information
Publications
- 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.
- 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.
- 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. Erratum in: N Engl J Med. 2015 Apr 23;372(17):1677.
- 999916133
- 16-I-N133