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Trial record 7 of 33 for:    Cough | Recruiting, Not yet recruiting, Available Studies | NIH, U.S. Fed

Using Biomarkers to Predict TB Treatment Duration

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ClinicalTrials.gov Identifier: NCT02821832
Recruitment Status : Recruiting
First Posted : July 4, 2016
Last Update Posted : May 9, 2018
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 65 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
Tuberculosis Procedure: blood draw Radiation: PET/CT Procedure: induced sputum 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.

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)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Basic Science
Official Title: Using Biomarkers to Predict TB Treatment Duration
Study Start Date : June 29, 2016
Estimated Primary Completion Date : December 30, 2022
Estimated Study Completion Date : December 30, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
A
Standard of Care DSTB treatment (2 months HRZE followed by 4 months HR)
Procedure: blood draw
blood draw

Radiation: PET/CT
Radiographic biomarkers using PET/CT as an early marker of treatment response and possibly as a marker for relapse at the end of treatment are being examined. The FDG-PET/CT scan will be performed at a facility local to the study site. The CT portion of the scan will be done without contrast and will be limited to the chest. Subjects will consent to receive a maximum of 4 FDG-PET/CT scans during the study baseline, 1 month, EOT, and at recurrence); however the vast majority of subjects will only receive 2-3 scans. The same scanner at each location will be used for subjects receiving subsequent scans as was used on their first scan. Subjects will be fully briefed with regard to what to expect and any precautions highlighted.

Procedure: induced sputum
Sputum induction, if necessary during the study, will take place in a designated area. Hypertonic saline will be administered via the mouthpiece of a nebulizer to induce expectoration.

Active Comparator: B
Standard of Care DSTB treatment(2 months HRZE followed by 4 months HR)
Procedure: blood draw
blood draw

Radiation: PET/CT
Radiographic biomarkers using PET/CT as an early marker of treatment response and possibly as a marker for relapse at the end of treatment are being examined. The FDG-PET/CT scan will be performed at a facility local to the study site. The CT portion of the scan will be done without contrast and will be limited to the chest. Subjects will consent to receive a maximum of 4 FDG-PET/CT scans during the study baseline, 1 month, EOT, and at recurrence); however the vast majority of subjects will only receive 2-3 scans. The same scanner at each location will be used for subjects receiving subsequent scans as was used on their first scan. Subjects will be fully briefed with regard to what to expect and any precautions highlighted.

Procedure: induced sputum
Sputum induction, if necessary during the study, will take place in a designated area. Hypertonic saline will be administered via the mouthpiece of a nebulizer to induce expectoration.

Experimental: C
2 months HRZE followed 2 months HR followed by 2months placebo
Procedure: blood draw
blood draw

Radiation: PET/CT
Radiographic biomarkers using PET/CT as an early marker of treatment response and possibly as a marker for relapse at the end of treatment are being examined. The FDG-PET/CT scan will be performed at a facility local to the study site. The CT portion of the scan will be done without contrast and will be limited to the chest. Subjects will consent to receive a maximum of 4 FDG-PET/CT scans during the study baseline, 1 month, EOT, and at recurrence); however the vast majority of subjects will only receive 2-3 scans. The same scanner at each location will be used for subjects receiving subsequent scans as was used on their first scan. Subjects will be fully briefed with regard to what to expect and any precautions highlighted.

Procedure: induced sputum
Sputum induction, if necessary during the study, will take place in a designated area. Hypertonic saline will be administered via the mouthpiece of a nebulizer to induce expectoration.




Primary Outcome Measures :
  1. The primary endpoint will be a comparison of the rate of treatment success at 18 months between Arms B and C. [ Time Frame: approximately 18 months ]

Secondary Outcome Measures :
  1. Endpoint relating to imaging include: PET total glycolytic activity volume in regions of interest [ Time Frame: baseline, 18 months ]
  2. Endpoint relating to imaging include: total volume of hard CT lesions (-100 to 200 Hu) [ Time Frame: baseline, 18 months ]
  3. Endpoint relating to imaging include: total volume of soft CT lesions (-500 to-100Hu) [ Time Frame: baseline, 18 months ]
  4. Endpoint relating to imaging include: cavity air (volume of air incavities) [ Time Frame: baseline, 18 months ]
  5. Endpoints relating to immunologic markers will be based on serumcytokine levels. [ Time Frame: baseline, 18 months ]


Information from the National Library of Medicine

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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. Willing to have samples, including DNA, stored
    11. 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. Extrapulmonary TB, including pleural TB
  2. Pregnant or desiring/trying to become pregnant in the next 6 months or breastfeeding.
  3. HIV infected
  4. Unable to take oral medications
  5. 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
  6. 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)
  7. Use of immunosuppressive medications, such as TNF-alpha inhibitors or systemic or inhaled corticosteroids, within the past 2 weeks
  8. Use of any investigational drug in the previous 3 months
  9. Substance or alcohol abuse that in the opinion of the investigator may interfere with the participant's adherence to study procedures.
  10. 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


Contacts
Contact: Laura E Via, Ph.D. (301) 451-9554 lvia@niaid.nih.gov

Locations
China
Xinmi City Center for Disease Control and Prevention Recruiting
Xinmi, Henan Province, China
Xinxiang Institute for the prevention and control of tuberculosis (XXCITPC) Recruiting
Xinxiang, Henan Province, China
Contact: Ruanqinq Zhang, DR.    8615690793288    532337216@qq.com   
Henan Provincial Chest Hospital Recruiting
Zhengzhou, Henan Province, China
Contact: Xin Liu    Not Listed    liuxin1962@hotmail.com   
Zhongmu County Station for Disease Control and Prevention Recruiting
Zhongmu, Henan Province, China
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)

Publications:
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     History of Changes
Other Study ID Numbers: 999916133
16-I-N133
First Posted: July 4, 2016    Key Record Dates
Last Update Posted: May 9, 2018
Last Verified: May 2, 2018

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):
Tuberculosis
PET/CT Scanning
Immunological Markers
4-Month Treatment Completion

Additional relevant MeSH terms:
Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections