Clinical trial NCT02170441: Global Consortium for Drug-resistant Tuberculosis Diagnostics
Official title: Global Consortium for Drug-resistant Tuberculosis Diagnostics
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis
Tuberculosis, Multidrug-Resistant
Keywords: Tuberculosis
Multi-drug resistant tuberculosis
Extensively drug-resistant tuberculosis
Drug-resistant tuberculosis
Mycobacterial Growth Indicator Tube Drug Susceptibility Test
Line Probe Assay
Microscopic Observation Drug Susceptibility Assay
Pyrosequencing
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2014-06-23
Enrollment: 1128
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with newly diagnosed or previously treated tuberculosis who are at risk for drug-resistant tuberculosis

Brief summary: The goal of this study is to evaluate time to diagnosis for three assays (line probe, pyrosequencing, and Microscopic Observation Drug Susceptibility Assay \[MODS\]) to detect resistance to first and second-line anti-tuberculosis (TB) drugs in Mycobacterium tuberculosis (Mtb) strains in 7 days or less, allowing for rapid diagnosis of extensively drug-resistant TB (XDR-TB).

Detailed description: The goals of this study are to test, fine tune, and compare three tests (line probe, pyrosequencing, MODS assays) to rapidly detect Mycobacterium tuberculosis (Mtb) strains that are resistant to first and second-line anti-tuberculosis (TB) drugs allowing for rapid diagnosis of Extensively Drug-Resistant Tuberculosis (XDR-TB).

Primary Specific Aims

Aim 1: To reduce the average XDR-TB detection time from months to a week.

Aim 2: To determine agreement between rapid tests and standard drug susceptibility testing (DST) results.

Aim 3: To identify the genetic basis of discordant results from Aim 2.

Aim 4: To characterize genotypic, phenotypic and epidemiological features, as well as geographical relationships, of XDR-TB strains compared to other drug-resistant and susceptible strains.

Secondary Aims Aim 1: Cost-effectiveness study. The costs associated with rapid-test implementation will be compared with the performance of the new tests to rapidly and accurately detect drug resistance and XDR-TB.

Aim 2: To determine the predictive value of resistance-associated mutations in determining sputum culture conversion.

The investigators hypothesize that analysis of the genotypic basis of anti-TB drug resistance will allow for the development of improved rapid molecular drug susceptibility tests that will detect resistance to fluoroquinolones and injectable anti-TB drugs and reduce the current XDR-TB diagnosis time of up to three months to less than seven days.

Eligibility criteria: Inclusion Criteria:

* At least 5 years of age
* Known to be acid fast bacilli (AFB) sputum smear-positive, 1+ or greater (within prior 14 days), positive on GeneXpert, or present clinically with high suspicion of active TB and:
* Had previously received \>1 month of treatment for a prior TB episode or
* Were failing TB treatment with positive sputum smear or culture after ≥3 months of a standard TB treatment or
* Had had close contact with a known drug-resistant TB case or
* Were newly diagnosed with multi-drug resistant TB (MDR-TB) within the last 30 days or
* Were 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
* Provided informed consent or had ability and willingness of subject or legal guardian/representative to provide informed consent

Exclusion Criteria:

* Institutionalized
* Unable to provide at least 7.5ml sputum (1st and 2nd samples combined)
* Had results from second line DST performed within the last 3 months

Primary outcomes:
measure: Time to completion of rapid diagnostic assays
timeFrame: Up to 83 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Mumbai
country: India
facility: P.D. Hinduja National Hospital and Medical Research Centre
city: Chisinau
country: Moldova, Republic of
facility: Phthisiopneumology Institute
city: Cape Town
country: South Africa
facility: Department of Biomedical Sciences, Stellenbosch University
Study officials:
affiliation: University of California, San Diego
name: Antonino Catanzaro, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Groessl EJ, Ganiats TG, Hillery N, Trollip A, Jackson RL, Catanzaro DG, Rodwell TC, Garfein RS, Rodrigues C, Crudu V, Victor TC, Catanzaro A. Cost analysis of rapid diagnostics for drug-resistant tuberculosis. BMC Infect Dis. 2018 Mar 2;18(1):102. doi: 10.1186/s12879-018-3013-0.
citation: Seifert M, Georghiou SB, Garfein RS, Catanzaro D, Rodwell TC. Impact of Fluoroquinolone Use on Mortality Among a Cohort of Patients With Suspected Drug-Resistant Tuberculosis. Clin Infect Dis. 2017 Sep 1;65(5):772-778. doi: 10.1093/cid/cix422.
citation: Georghiou SB, Seifert M, Catanzaro DG, Garfein RS, Rodwell TC. Increased Tuberculosis Patient Mortality Associated with Mycobacterium tuberculosis Mutations Conferring Resistance to Second-Line Antituberculous Drugs. J Clin Microbiol. 2017 Jun;55(6):1928-1937. doi: 10.1128/JCM.00152-17. Epub 2017 Apr 12.
citation: Catanzaro DG, Trollip AP, Seifert M, Georghiou SB, Garfein RS, Rodwell TC, Catanzaro A, Eisenach KD. Evaluation of the microscopic observation drug susceptibility assay for the detection of first- and second-line drug susceptibility for Mycobacterium tuberculosis. Eur Respir J. 2017 Apr 5;49(4):1602215. doi: 10.1183/13993003.02215-2016. Print 2017 Apr.
citation: Georghiou SB, Seifert M, Lin SY, Catanzaro D, Garfein RS, Jackson RL, Crudu V, Rodrigues C, Victor TC, Catanzaro A, Rodwell TC. Shedding light on the performance of a pyrosequencing assay for drug-resistant tuberculosis diagnosis. BMC Infect Dis. 2016 Aug 31;16(1):458. doi: 10.1186/s12879-016-1781-y.
citation: Georghiou SB, Seifert M, Catanzaro D, Garfein RS, Valafar F, Crudu V, Rodrigues C, Victor TC, Catanzaro A, Rodwell TC. Frequency and Distribution of Tuberculosis Resistance-Associated Mutations between Mumbai, Moldova, and Eastern Cape. Antimicrob Agents Chemother. 2016 Jun 20;60(7):3994-4004. doi: 10.1128/AAC.00222-16. Print 2016 Jul.
citation: Hillery N, Groessl EJ, Trollip A, Catanzaro D, Jackson L, Rodwell TC, Garfein RS, Lin SY, Eisenach K, Ganiats TG, Park D, Valafar F, Rodrigues C, Crudu V, Victor TC, Catanzaro A. The Global Consortium for Drug-resistant Tuberculosis Diagnostics (GCDD): design of a multi-site, head-to-head study of three rapid tests to detect extensively drug-resistant tuberculosis. Trials. 2014 Nov 6;15:434. doi: 10.1186/1745-6215-15-434.