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Using Biomarkers to Predict TB Treatment Duration

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02821832
Recruitment Status : Active, not recruiting
First Posted : July 4, 2016
Last Update Posted : October 22, 2021
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

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
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

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 908 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
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
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




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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
Criteria
  • 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

Information from the National Library of Medicine

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


Locations
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South Africa
Clinical Infectious Diseases Research Initiative (Khayelitsha site)
Cape Town, South Africa
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Clifton E Barry, Ph.D. National Institute of Allergy and Infectious Diseases (NIAID)
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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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
Last Update Posted: October 22, 2021
Last Verified: April 7, 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Drug-Resistance
Heteroresistance
Relapse-markers
Medical Imaging
Treatment-shortening
Additional relevant MeSH terms:
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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