Clinical trial NCT03303963: DIAgnostics for Multidrug Resistant Tuberculosis in Africa
Official title: Culture Free Diagnosis and Follow-up of Multidrug Resistant Tuberculosis Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis, Multidrug-Resistant
Keywords: culture-free
tuberculosis
multidrug resistant
diagnosis
follow-up
africa
molecular tools
Lead sponsor: Laboratoire de Référence des Mycobactéries
Sponsor class: OTHER_GOV
Collaborators: name: Rwanda Biomedical Centre
name: The Tuberculosis Reference Laboratory Bamenda
name: Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo
name: Jimma University
name: Service de Pneumophtisiologie, Hôpital Ignace Deen
name: University of the Sciences, Techniques and Technologies of Bamako
name: Damien Foundation
name: Cheikh Anta Diop University, Senegal
name: Institute of Tropical Medicine, Belgium
name: World Health Organization
name: London School of Hygiene and Tropical Medicine
name: Genoscreen
First posted: 2017-10-06
Enrollment: 3356
Sex: ALL
Minimum age (years): 15
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Two multi center observational studies will be conducted:

Study 1: Cross sectional study for Tuberculosis(TB) cases aged ≥ 15 (all Rifampicin resistant (RR) ones (new cases or retreatment patients) and equal number of Rifampicin sensitive retreatment patients from the same country) with comparison of TB resistance diagnostic test performance at baseline. There are 2 phases in this project; phase 1 is the comparison of Deeplex results against the phenotypic results and WGS (Gold standard), phase 2 is the comparison of MolBio TrueNat and GeneXpert 2nd generation results against Deeplex and WGS (gold standard).

Study 2: Cohort study of RR-TB patients (recruited in Study 1) under treatment with comparison of the performance of FDA and GeneXpert compared to solid culture

Brief summary: Recent advances in molecular diagnostics of tuberculosis, especially the GeneXpert Mycobacterium tuberculosis/Rifampicin test have reduced the time to diagnose Rifampicin Resistant Tuberculosis (RR-TB) but only rifampicin resistance is diagnosed, leading to presumptive diagnosis of resistance to isoniazid and maybe other drugs. Thus in low and middle income countries, most drug sensitivity testing relies on phenotypic drug resistance testing, which takes up to 4 months. In addition, currently, culture on monthly sputum samples is recommended by the World Health Organization for follow-up of Rifampicin Resistant Tuberculosis patients under treatment. Unfortunately, culture is often not locally available and samples need to be transported from field to culture laboratories. The associated transport delays lead to high rates of contamination and false negative culture, particularly in laboratories in low resource settings. Many gaps for the diagnosis and management of RR-TB patients still need to be addressed and the DIAMA project (DIAgnostics for Multidrug resistant tuberculosis in Africa) study aims to address some of them.

Detailed description: The proposed DIAMA (DIAgnostics for Multidrug resistant tuberculosis in Africa) study aims to address current gaps in the diagnosis and management of patients with Multi-Drug-Resistant (MDR) tuberculosis. Building on existing networks and research collaborations previously funded by the European \& Developing Countries Clinical Trials Partnership (EDCTP), this project involved partners in West, Central, and East Africa. It aims to evaluate and implement rapid and accurate molecular tests for several anti Tuberculosis drugs, to replace the current dependency on phenotypic drug resistance testing, which takes up to 4 months and is technically so demanding that few laboratories can perform it correctly.

The project builds on the continuous surveillance of Tuberculosis retreatment patients for rifampicin resistance. Two African partners (Benin and Rwanda) with advanced molecular laboratories are establishing reference laboratories for the 'Deeplex' assay, a novel multiplex deep sequencing-based drug resistance diagnostic platform that simultaneously provides sequence information of genes that confer resistance to several key anti tuberculosis drugs. Partners are recruiting all patients with rifampicin resistant Tuberculosis, and a subset of those with rifampicin sensitive Tuberculosis. In a first phase, sputum will be shipped for the Deeplex assay, for comparison against phenotypic DST, the reference method for detecting resistance to 1st and 2nd line drugs. In addition, since Whole Genome Sequencing is the "reference" of molecular tests, Deeplex assay will also be validated again this test. In a second phase, Cepheid 2nd line Xpert and Molbio Truenat test, two 'lower tech' tests at the last stages of laboratory validations, will also be validated. The Cepheid Xpert 2nd line cartridge can be implemented in existing Xpert machines used for the Xpert MTB/Rif assays. These tests will be compared versus the Deeplex assay and versus WGS

Using the latest advances in DataTocare software developed by one of the project partners, molecular results will be communicated in real time to the National Tuberculosis Programmes, so that Multi Drug Resistant Tuberculosis patients can swiftly start appropriate treatment. The added-value of this system will be evaluated as a pilot study in some sites.

Lastly, once patients have initiated MDR treatment, they will be monitored for treatment success by faster alternative approaches to the WHO recommended monthly cultures: serial sputum samples will have Fluorescein DiAcetate (FDA) vital stain microscopy, measurement of the bacterial load using the Xpert MTB/Rif as well as precursor of ribosomal RNA measurement (pre-rRNA).

Together, these advances are expected to dramatically improve the currently dismal prognosis of MDR-TB in health systems in resource-poor settings.

Eligibility criteria: Inclusion criteria:

* Being ≥ 15 year old
* Having a positive test on GeneXpert (M. tuberculosis) with or without resistance detected to rifampicin
* Willing and able to provide written informed consent, or for minors: assent from and consent from a legal representative

Exclusion Criteria: None

Primary outcomes:
measure: Validation of Deeplex test
timeFrame: 4 years
measure: Validation of GeneXpert 2nd line
timeFrame: 4 years
measure: Validation of MolBio TrueNat for INH, FQ and BDQ
timeFrame: 4 years
measure: Validation of FDA microscopy
timeFrame: 4 years
measure: Validation of GeneXpert Ct value
timeFrame: 4 years
Secondary outcomes:
measure: Estimation of proportion of additional resistance in patients resistant to Rifampicin
timeFrame: 4 years
measure: Measurement of the association of specific mutations against some drugs with programmatic treatment outcome
timeFrame: 4 years
measure: Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients
timeFrame: 2 years
Other outcomes:
Locations:
city: Antwerp
country: Belgium
facility: Institute of Tropical Medecine
city: Cotonou
country: Benin
facility: Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou
state: Atlantique/Littoral
city: Bamenda
country: Cameroon
facility: The Tuberculosis Reference Laboratory Bamenda
city: Kinshasa
country: Congo, The Democratic Republic of the
facility: Institut National de Recherche Biomédicale (INRB)
city: Jīma
country: Ethiopia
facility: Jimma University
city: Conakry
country: Guinea
facility: Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry
city: Bamako
country: Mali
facility: Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO
city: Ibadan
country: Nigeria
facility: Damien Fundation
city: Kigali
country: Rwanda
facility: Rwanda Biomedical Center (RBC)
city: Dakar
country: Senegal
facility: Université Cheick Anta Diop (UCAD)
Study officials:
affiliation: Laboratoire de Référence des Mycobactéries
name: Dissou AFFOLABI, MD, MSc, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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