Xpert MTB/XDR Clinical Evaluation Trial

Multicentre Clinical Trial to Assess the Performance of the Xpert MTB/XDR Assay for INH- and Second-line Resistance Detection

FIND and partners intend to address the need for a multi- and extensively drug-resistant tuberculosis (M/XDR-TB) diagnostic solution for patients in settings with a high burden of drug-resistant tuberculosis (DR-TB) though the development, evaluation and introduction of an Xpert MTB/XDR assay

Study Overview

• Status: Completed
• Conditions: Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant
• Intervention / Treatment: Device: Cepheid Gene Xpert MTB/XDR

• Study Type: Observational
• Enrollment (Actual): 710

Contacts and Locations

Study Locations

• Moldova, Republic of
  • Chisinau, Moldova, Republic of
    • Institute of Pthisiopenumology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Individuals who have one or more risk factors for DR-TB presenting to participating centres will be screened by Xpert MTB/RIF or Ultra. Those who test MTB-positive by Xpert MTB/RIF or Ultra at the study sites will be asked to participate. Individuals will be recruited at outpatient clinic settings and inpatient hospital settings. HIV-positive individuals and HIV-negative individuals will be included in this study.

Description

Inclusion Criteria:

• • Age 18 years or above;

  • Symptoms suggesting pulmonary TB, i.e. persistent cough (generally ≥3 weeks or as per local definition of TB suspect), and at least one of the following:

    • Previously received >1 month of treatment for a prior TB episode or
    • Failing TB treatment with positive sputum smear or culture after ≥3 months of a standard TB treatment or
    • Had close contact with a known drug-resistant TB case or
    • Newly diagnosed with MDR-TB within the last 30 days or
    • Previously diagnosed with MDR-TB and failed TB treatment with positive sputum smear or culture after ≥3 months of a standard MDR-TB treatment regimen

Patients meeting the above criteria will be screened by Xpert MTB/RIF or Xpert MTB/RIF Ultra. TB patients meeting the following criteria will be included in the study:

• A clear Mtb-positive and RIF-resistant or RIF-sensitive result by Xpert MTB/RIF or Xpert MTB/RIF Ultra
• Provision of informed consent;
• Production of an adequate quantity (>3mL) of sputum

Exclusion Criteria:

• Participants will be excluded from the study if informed consent is not provided.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
TB case detection Group; Patients with pulmonary TB symptoms and at least one DR-TB risk factor will be screened by Xpert MTB/RIF or Ultra. Patients with a clear TB-positive and RIF-resistant or RIF-sensitive result by Xpert MTB/RIF or Ultra and who consent to study procedures will be tested by Xpert MTB/XDR.	Device: Cepheid Gene Xpert MTB/XDR; The Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA) is an integrated, automated, cartridge-based system for MDR-TB diagnosis that uses the GeneXpert instrument platform. WHO confirmed evidence to support the widespread use of the Xpert MTB/RIF assay in 2010 and the assay has since been widely used in TB programs, but it is only capable of identifying Mycobacterium tuberculosis (Mtb) and detecting RIF resistance. The Xpert MTB/XDR assay will be evaluated for INH and second-line resistance detection, and to recommend its use in diverse clinical settings. The focus of this protocol is the multicentre clinical evaluation.
RIF-resistance MTB Group; An anticipated 316 additional RIF-resistant patients, as detected by Xpert MTB. /RIF, will be enrolled in this study to evaluate sensitivity and specificity of the Xpert MTB/XDR test against strains with other potential drug-resistance mutations.	Device: Cepheid Gene Xpert MTB/XDR; The Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA) is an integrated, automated, cartridge-based system for MDR-TB diagnosis that uses the GeneXpert instrument platform. WHO confirmed evidence to support the widespread use of the Xpert MTB/RIF assay in 2010 and the assay has since been widely used in TB programs, but it is only capable of identifying Mycobacterium tuberculosis (Mtb) and detecting RIF resistance. The Xpert MTB/XDR assay will be evaluated for INH and second-line resistance detection, and to recommend its use in diverse clinical settings. The focus of this protocol is the multicentre clinical evaluation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Estimate the diagnostic accuracy of the Xpert MTB/XDR assay for INH and ETH resistance detection	Sensitivity and specificity estimates for INH and ETH resistance detection	Day 1
Estimate the diagnostic accuracy of the Xpert MTB/XDR assay for fluoroquinolone resistance detection	Sensitivity and specificity estimates for fluoroquinolone resistance detection	Day 1
Estimate the diagnostic accuracy of the Xpert MTB/XDR assay for second-line injectable resistance detection	Sensitivity and specificity estimates for second-line injectable resistance detection	Day 1

Collaborators and Investigators

• Sponsor: Foundation for Innovative New Diagnostics, Switzerland
• Collaborators: University of Witwatersrand, South Africa; PD Hinduja Hospital and Medical Research Centre, Mumbai, India; Cepheid; Phthisiopneumology Institute, Chisinau, Moldova; National Institute of Tuberculosis and Respiratory Disease, New Delhi, India

Publications and helpful links

General Publications

• Penn-Nicholson A, Georghiou SB, Ciobanu N, Kazi M, Bhalla M, David A, Conradie F, Ruhwald M, Crudu V, Rodrigues C, Myneedu VP, Scott L, Denkinger CM, Schumacher SG; Xpert XDR Trial Consortium. Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study. Lancet Infect Dis. 2022 Feb;22(2):242-249. doi: 10.1016/S1473-3099(21)00452-7. Epub 2021 Oct 7.

Study record dates

Study Major Dates

• Study Start (Actual): July 11, 2019
• Primary Completion (Actual): August 18, 2020
• Study Completion (Actual): August 18, 2020

Study Registration Dates

• First Submitted: October 5, 2018
• First Submitted That Met QC Criteria: November 1, 2018
• First Posted (Actual): November 2, 2018

Study Record Updates

• Last Update Posted (Actual): May 19, 2021
• Last Update Submitted That Met QC Criteria: May 17, 2021
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: 7162-02/2

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data sharing statement Individual, de-identified participant data will be shared, including data dictionaries. Other documents that have been made available include the study protocol and statistical analysis plan. Templates of the informed consent forms may be shared upon request. The data will be available immediately following publication with no end date. The data will be shared with anyone who wishes to access the data. The data will be available for any purpose of analyses. For data, please contact the corresponding author.
• IPD Sharing Time Frame: Upon publication of final study results
• IPD Sharing Access Criteria: The data will be shared with anyone who wishes to access the data.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No