Using Biomarkers to Predict TB Treatment Duration
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| ClinicalTrials.gov Identifier: NCT02821832 |
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Recruitment Status :
Active, not recruiting
First Posted : July 4, 2016
Results First Posted : December 20, 2022
Last Update Posted : April 10, 2023
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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 |
|---|---|---|
| Pulmonary Tuberculosis | Procedure: Saliva collection Procedure: Urine collection Procedure: Sputum collection Procedure: Blood Collection Radiation: PET/CT Scan Drug: Isoniazid, Rifampicin, Pyrazinamide and Ethambutol | Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Actual Enrollment : | 946 participants |
| Allocation: | Randomized |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Using Biomarkers to Predict TB Treatment Duration |
| Actual Study Start Date : | June 21, 2017 |
| Actual Primary Completion Date : | October 9, 2021 |
| Estimated Study Completion Date : | September 30, 2023 |
| Arm | Intervention/treatment |
|---|---|
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Arm A - Expected high risk of relapse, standard of care TB treatment
Expected high risk of relapse, standard of care TB treatment
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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 |
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Active Comparator: Arm B - Expected low risk of relapse, standard of care TB treatment
Expected low risk of relapse, standard of care TB treatment
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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 |
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Experimental: Arm C - Expected low risk of relapse, shortened TB treatment
Expected low risk of relapse, shortened TB treatment
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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 |
- Comparison of the Rate of Treatment Success at 18 Months (After Treatment Initiation) Between Arms B and C [ Time Frame: 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.
- Radiologic, Immunologic and Microbiologic Measures [ Time Frame: 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).
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| Ages Eligible for Study: | 18 Years to 75 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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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
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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
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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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02821832
| South Africa | |
| Clinical Infectious Diseases Research Initiative (Khayelitsha site) | |
| Cape Town, South Africa | |
| Principal Investigator: | Clifton E Barry, Ph.D. | National Institute of Allergy and Infectious Diseases (NIAID) |
Documents provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Institute of Allergy and Infectious Diseases (NIAID) |
| ClinicalTrials.gov Identifier: | NCT02821832 |
| Other Study ID Numbers: |
999916133 16-I-N133 |
| First Posted: | July 4, 2016 Key Record Dates |
| Results First Posted: | December 20, 2022 |
| Last Update Posted: | April 10, 2023 |
| Last Verified: | March 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Undecided |
| Plan Description: | .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. |
| Studies a U.S. FDA-regulated Drug Product: | No |
| Studies a U.S. FDA-regulated Device Product: | No |
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Drug-Resistance Heteroresistance Relapse-markers Medical Imaging Treatment-shortening |
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Tuberculosis Tuberculosis, Pulmonary Mycobacterium Infections Actinomycetales Infections Gram-Positive Bacterial Infections Bacterial Infections Bacterial Infections and Mycoses Infections Respiratory Tract Infections Lung Diseases Respiratory Tract Diseases Rifampin Isoniazid Pyrazinamide Ethambutol |
Antibiotics, Antitubercular Antitubercular Agents Anti-Bacterial Agents Anti-Infective Agents Leprostatic Agents Nucleic Acid Synthesis Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Cytochrome P-450 CYP2B6 Inducers Cytochrome P-450 Enzyme Inducers Cytochrome P-450 CYP2C8 Inducers Cytochrome P-450 CYP2C19 Inducers Cytochrome P-450 CYP2C9 Inducers Cytochrome P-450 CYP3A Inducers Fatty Acid Synthesis Inhibitors |