Clinical trial NCT04397536: New Genomic Techniques and Management of Multidrug-resistant Tuberculosis
Official title: Impact of New Genomic Tools on the Management of Patients With Multidrug-resistant Tuberculosis
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Multi-Drug Resistant Tuberculosis
Keywords: Tuberculosis
Multi-Drug Resistance
Diagnosis
Whole Genome
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-05-21
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: All the patients diagnosed with MDR-TB in France during the frame time of the project

Brief summary: In the context of the emergence of cases of multidrug-resistant tuberculosis (MDR-TB) it is crucial to improve patient's management. Therefore, assessing the place of innovative strategies enabling the diagnosis of those cases (e.g. WGS and Deeplex-MycTB) in the personalized care of patients with MDR-TB and the rationalization of medical biology procedures is a major issue. This project participates to these goals since the investigators will : (i) assess the diagnostic qualities and the performance of the different innovatives strategies enabling detection of resistance to anti-tuberculosis drugs, (ii) assess the impact of these strategies in the implementation of personalized treatments for MDR-TB patients, and (iii) assess the overall costs of these strategies.

Detailed description: Non-interventional monocentric study on the evaluation of the reliability and validity of a diagnostic test based on a biological collection of M. tuberculosis MDR strains received at the NRC-MyRMA. The study will apply to all strains and samples of multidrug-resistant M. tuberculosis detected in France. These strains are all sent to NRC-MyRMA (National Reference Center for Mycobacteria and resistance to anti-tuberculosis drugs) for Drug Susceptibility testing (DST) to first and second line anti-tuberculosis drugs in accordance with the national guidelines.

Currently, a genotypic and phenotypic diagnosis of antibiotic resistance is carried out upon receipt of a strain of M. tuberculosis MDR at CNR-MyRMA, respectively by PCR-sequence techniques and commercial kits and by phenotypic antibiogram by the method of reference called proportions. In the case of a sample, only the genotypic diagnosis is immediately feasible, the realization of the phenotypic diagnosis can only be carried out from a strain, so the investigators must wait for a positive culture to be obtained.

In addition to this current strategy, two innovative strategies based on the sequencing of the complete genome of the strains (WGS and Deeplex-MycTB) will be implemented. These analyzes will not require an additional patient's samples.

The sensitivities and specificities and the area under the ROC curve of the different tests, with respect to each resistance, will be calculated and their confidence interval will be estimated by bootstrap. The comparison of the sensitivities, specificities and areas under the curve between the different techniques will be carried out by a Gaussian test based on a bootstrap. The agreement between the different tests will be measured by calculating a Cohen kappa. A Kappa confidence interval will be estimated by bootstrap. The Kappa between each genotypic method and the phenotypic method will be compared by a Gaussian test based on a bootstrap.

The comparison of the results reporting times will be done by a comparison test of the symmetry of the rows with respect to the median value (Mann Whithney Wilcoxon test.

In general, the quantitative variables will be described by the classic position measurements (mean, median, 1st and 3rd quartile, minimum and maximum) and dispersion measures (standard deviation). Qualitative variables will be described in terms of absolute value and percentage.

Degree of statistical significance:

The significance level for the tests will be set for an alpha of 0.05.

Software:

All analyzes will be done at the URC on SAS software or R software in their latest version available at the time they are performed.

Eligibility criteria: Inclusion Criteria:

* age ≥ 18 years ;
* patient with bacteriologically proven tuberculosis due to a multidrug resistance strain (i.e. resistant to rifampin and isoniazid)
* patient informed of the study and not opposed to participating in the research

Exclusion Criteria:

* Patient with non MDR tuberculosis ;
* Impossibility of carrying out a phenotypic antibiogram (absence of bacterial culture, contaminated culture)

Primary outcomes:
measure: Sensitivity for the detection of bedaquiline resistance
timeFrame: At the end enrollment
Secondary outcomes:
measure: Performances (deadlines to obtain results, sensitivity, specificity) to identify the species within the tuberculosis complex, and to diagnose resistance to anti-tuberculosis drugs
timeFrame: At the end enrollment
measure: Number of anti-tuberculosis days
timeFrame: At the end enrollment
measure: Performances (sensitivity, specificity) of the WGS strategy by using different pipelines
timeFrame: At the end enrollment
measure: Number of laboratory procedures
timeFrame: At the end enrollment
measure: Costs of personal time and laboratory procedures
timeFrame: At the end enrollment
Other outcomes:
Locations:
city: Paris
country: France
facility: Pitié Salpêtrière Hospital
Study officials:
affiliation: Pitié-Salpêtrière Hospital (AP-HP)
name: Alexandra AUBRY, Pr
role: PRINCIPAL_INVESTIGATOR
References: