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Clinical Evaluation of tNGS for Diagnosis of DR-TB (Seq&Treat)

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04239326
Recruitment Status : Not yet recruiting
First Posted : January 27, 2020
Last Update Posted : July 22, 2020
Sponsor:
Information provided by (Responsible Party):
Foundation for Innovative New Diagnostics, Switzerland

Brief Summary:

Current rapid molecular assays for detection of drug-resistant TB from direct clinical samples have important limitations. They are not suited for high-throughput settings; can only be used to detect a limited number of target gene regions and are not ideal for detection of phenotypic resistance conferred by mutations across large gene regions (e.g. pyrazinamide).

Culture-free, end-to-end targeted NGS (tNGS) Solutions for Diagnosis of Drug Resistant TB can offer higher throughput and greater accuracy across more TB drugs than current WHO endorsed molecular assays, and a significantly faster time to result than phenotypic drug susceptibility testing (DST).

Evidence regarding the clinical diagnostic accuracy and operational characteristics of tNGS solutions is needed to comprehensively evaluate tNGS for diagnosis of drug-resistant TB among patients who have been diagnosed with TB, and will be critical to inform global and national policy.


Condition or disease Intervention/treatment
Tuberculosis, Multidrug-Resistant Diagnostic Test: targeted Next Generation Sequencing (tNGS)

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Study Type : Observational
Estimated Enrollment : 750 participants
Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: Multicentre Clinical Trial to Assess the Performance of Culture-free, End-to-end Targeted NGS (tNGS) Solutions for Diagnosis of Drug Resistant TB (DR-TB)
Estimated Study Start Date : October 2020
Estimated Primary Completion Date : October 2021
Estimated Study Completion Date : December 2021

Intervention Details:
  • Diagnostic Test: targeted Next Generation Sequencing (tNGS)
    The index tests used in this trial will include up to three end-to-end, targeted next generation sequencing (tNGS) solutions for diagnosis of DR-TB. Each solution will include all of the equipment, reagents, and software necessary for handling the entire sequencing workflow, including DNA extraction from processed sputum samples (i.e. sediment), library preparation, sequencing, and data analysis/interpretation for clinical result reporting.


Primary Outcome Measures :
  1. Point estimates, with 95% confidence intervals, of sensitivity and specificity for RIF resistance detection for each of up to 3 tNGS solutions [ Time Frame: January 2021 - March 2021 ]
    Outcomes 1.1 to 1.5 will be evaluated on the PP population. Point estimates (with 95% CI) of sensitivity and specificity will be derived based on pooled data for all sites. In order to assess whether there is an association between the results and the clinical site from where the samples were collected, the estimates of sensitivity and specificity for each site will be compared with each other by use of a Pearson's chi-squared test, at a significance level of 5%, adjusted by Bonferroni correction for the total number of tests performed. A random effect model will be used if it is believed that a high site-effect is present: this will be assessed by the evaluation of heterogeneity using Cochran's Q (with a significance level set at 0.1) and the I2 statistics (with a value >0.5).

  2. Point estimates, with 95% confidence intervals, of sensitivity and specificity for INH resistance detection for each of up to 3 tNGS solutions [ Time Frame: January 2021 - March 2021 ]
    Outcomes 1.1 to 1.5 will be evaluated on the PP population. Point estimates (with 95% CI) of sensitivity and specificity will be derived based on pooled data for all sites. In order to assess whether there is an association between the results and the clinical site from where the samples were collected, the estimates of sensitivity and specificity for each site will be compared with each other by use of a Pearson's chi-squared test, at a significance level of 5%, adjusted by Bonferroni correction for the total number of tests performed. A random effect model will be used if it is believed that a high site-effect is present: this will be assessed by the evaluation of heterogeneity using Cochran's Q (with a significance level set at 0.1) and the I2 statistics (with a value >0.5).

  3. Point estimates, with 95% confidence intervals, of sensitivity and specificity for fluoroquinolone (moxifloxacin, levofloxacin) resistance detection for each of up to 3 tNGS solutions [ Time Frame: January 2021 - March 2021 ]
    Outcomes 1.1 to 1.5 will be evaluated on the PP population. Point estimates (with 95% CI) of sensitivity and specificity will be derived based on pooled data for all sites. In order to assess whether there is an association between the results and the clinical site from where the samples were collected, the estimates of sensitivity and specificity for each site will be compared with each other by use of a Pearson's chi-squared test, at a significance level of 5%, adjusted by Bonferroni correction for the total number of tests performed. A random effect model will be used if it is believed that a high site-effect is present: this will be assessed by the evaluation of heterogeneity using Cochran's Q (with a significance level set at 0.1) and the I2 statistics (with a value >0.5).

  4. Point estimates, with 95% confidence intervals, of sensitivity and specificity for second-line injectable (amikacin, capreomycin, kanamycin) resistance detection for each of up to 3 tNGS solutions [ Time Frame: January 2021 - March 2021 ]
    Outcomes 1.1 to 1.5 will be evaluated on the PP population. Point estimates (with 95% CI) of sensitivity and specificity will be derived based on pooled data for all sites. In order to assess whether there is an association between the results and the clinical site from where the samples were collected, the estimates of sensitivity and specificity for each site will be compared with each other by use of a Pearson's chi-squared test, at a significance level of 5%, adjusted by Bonferroni correction for the total number of tests performed. A random effect model will be used if it is believed that a high site-effect is present: this will be assessed by the evaluation of heterogeneity using Cochran's Q (with a significance level set at 0.1) and the I2 statistics (with a value >0.5).

  5. Point estimates, with 95% confidence intervals, of sensitivity and specificity for pyrazinamide (PZA) resistance detection for each of up to 3 tNGS solutions [ Time Frame: January 2021 - March 2021 ]
    Outcomes 1.1 to 1.5 will be evaluated on the PP population. Point estimates (with 95% CI) of sensitivity and specificity will be derived based on pooled data for all sites. In order to assess whether there is an association between the results and the clinical site from where the samples were collected, the estimates of sensitivity and specificity for each site will be compared with each other by use of a Pearson's chi-squared test, at a significance level of 5%, adjusted by Bonferroni correction for the total number of tests performed. A random effect model will be used if it is believed that a high site-effect is present: this will be assessed by the evaluation of heterogeneity using Cochran's Q (with a significance level set at 0.1) and the I2 statistics (with a value >0.5).


Secondary Outcome Measures :
  1. Point estimates, with 95% confidence intervals, of sensitivity and specificity for additional second-line resistance detection (bedaquiline, linezolid, clofazimine, streptomycin) for up to 3 tNGS solutions. [ Time Frame: January 2021 - March 2021 ]
  2. Comparison of drug-specific point estimates of sensitivity and specificity (with 95% confidence intervals) for up to 3 tNGS solutions against Hain MTBDRplus/sl drug-specific results. [ Time Frame: January 2021 - March 2021 ]
  3. Comparison of overall test success rate (defined as the total number of full profiles i.e. calls across all drug targets) in up to 3 tNGS solutions against success rate in Xpert MTB/RIF and Hain MTBDRplus/sl. [ Time Frame: January 2021 - March 2021 ]
  4. Summary of technical performance characteristics in up to 3 tNGS solutions including invalid and indeterminate rates, ease of use metrics, and other operational characteristics [ Time Frame: January 2021 - March 2021 ]

Biospecimen Retention:   Samples With DNA
No patient genetic information will be collected, analyzed or recorded in this study. The proposed genetic sequencing and molecular analysis protocols are only intended to include TB pathogen-specific sequences and will be limited to analysis of MTB bacteria genomes.


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Adults with pulmonary TB, confirmed by Xpert MTB/RIF or Ultra, who are also at risk for or proven to have drug resistant TB, will be invited to participate in the trial. Interested individuals meeting these criteria will be referred to study personnel for screening. Both HIV-positive individuals and HIV-negative individuals will be included in this study. Depending on the sites individuals may be recruited at outpatient clinic settings as well as inpatient hospital settings.
Criteria

Inclusion Criteria:

  1. A TB-positive result by Xpert MTB/RIF OR Xpert MTB/RIF Ultra (i.e. "MTB DETECTED") at or prior to enrollment, AND
  2. At risk for drug resistant TB based on at least one of the following risk factors:

    A. A positive RIF-resistance result by Xpert MTB/RIF OR Xpert MTB/RIF Ultra (i.e."RIF resistance DETECTED") OR B. Not responding TB treatment with positive sputum smear or culture after ≥ 3 months of standard TB treatment. OR C. Previously diagnosed with Rif-resistant/MDR-TB and failed TB treatment with positive sputum smear or culture after ≥ 3months of a standard MDR-TB regimen OR D. Previously received >1 month of treatment for a prior TB episode OR E. Close contact with a known drug-resistant TB case AND

  3. Willing to provide sputum AND
  4. 18 years of age and older (or legal adult age corresponding to the site) AND
  5. Provision of signed informed consent

Exclusion Criteria:

  1. Have started treatment for current TB episode more than 7 days prior to date of enrolment (i.e. must have been on treatment for less than 7 days for this TB treatment episode at enrolment) OR
  2. Are pregnant or institutionalized or imprisoned

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): NCT04239326


Contacts
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Contact: Pamela Nabeta, MD +41 22 710 27 87 Pamela.Nabeta@finddx.org
Contact: Andres De la Rossa, PhD +41 79 881 47 05 Andres.DelaRossa@finddx.org

Locations
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Georgia
National Center for Tuberculosis and Lung Diseases
Tbilisi, Georgia, 380060
Contact: Nestan Tukvadze, PhD    +995 032 291 0251    marikushane@yahoo.com   
India
Hinduja Hospital and Medical Research Centre
Mumbai, Maharashtra, India, 40016
Contact: Camilla Rodrigues       dr_crodrigues@hindujahospital.com   
South Africa
National Institute for Communicable Diseases & Wits Health Consortium
Johannesburg, Sandringham, South Africa, 2192
Contact: Shaheed Omar, PhD    +27 118855343    shaheedvo@nicd.ac.za   
Sponsors and Collaborators
Foundation for Innovative New Diagnostics, Switzerland
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Responsible Party: Foundation for Innovative New Diagnostics, Switzerland
ClinicalTrials.gov Identifier: NCT04239326    
Other Study ID Numbers: TB038
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: July 22, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections