DIAgnostics for Multidrug Resistant Tuberculosis in Africa

Completed

• Conditions: Tuberculosis, Multidrug-Resistant

• Registration Number: NCT03303963
• Lead Sponsor: Dissou AFFOLABI

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.

Study Timeline

• Study Start: 2017-05-04
• Study First Submitted: 2017-09-24
• Study First Submitted QC: 2017-10-02
• Study First Posted: 2017-10-06
• Primary Completion: 2022-06-30
• Study Completion: 2022-11-30
• Status Verified: 2023-03
• Last Update Submitted: 2023-03-13
• Last Update Posted: 2023-03-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 3356

Inclusion Criteria

Not provided

Exclusion Criteria

None

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Validation of MolBio TrueNat for INH, FQ and BDQ	4 years	Concordance between WGS, Deeplex results and MolBioTrueNat results
Validation of GeneXpert Ct value	4 years	Concordance between Culture results and GeneXpert Ct value results
Validation of GeneXpert 2nd line	4 years	Concordance between WGS, Deeplex results and GeneXpert 2nd line results
Validation of Deeplex test	4 years	Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results
Validation of FDA microscopy	4 years	Concordance between Culture results and FDA microscopy results

Secondary Outcome Measures

Name	Time	Method
Measurement of the association of specific mutations against some drugs with programmatic treatment outcome	4 years	Evaluation to be done with the Deeplex test
Estimation of proportion of additional resistance in patients resistant to Rifampicin	4 years	Evaluation to be done with the Deeplex test
Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients	2 years	Evaluation to be done with Data2Care connectivity system

Trial Locations

Locations (10)

Institute of Tropical Medecine; 🇧🇪 Antwerp, Belgium

Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou; 🇧🇯 Cotonou, Atlantique/Littoral, Benin

The Tuberculosis Reference Laboratory Bamenda; 🇨🇲 Bamenda, Cameroon

Institut National de Recherche Biomédicale (INRB); 🇨🇩 Kinshasa, Congo, The Democratic Republic of the

Jimma University; 🇪🇹 Jīma, Ethiopia

Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry; 🇬🇳 Conakry, Guinea

Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO; 🇲🇱 Bamako, Mali

Damien Fundation; 🇳🇬 Ibadan, Nigeria

Rwanda Biomedical Center (RBC); 🇷🇼 Kigali, Rwanda

Université Cheick Anta Diop (UCAD); 🇸🇳 Dakar, Senegal