DIAgnostics for Multidrug Resistant Tuberculosis in Africa

NCT ID: NCT03303963

Last Updated: 2023-03-14

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 3356 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2017-05-04
• Study Completion Date: 2022-11-30

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.

Conditions

Tuberculosis, Multidrug-Resistant

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Rifampicin resistant and susceptible patients

Study 1: Patients detected positive by the GeneXpert Mycobacterium tuberculosis/Rifampicin (susceptible and resistant to rifampicin)

Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line

Intervention Type: DIAGNOSTIC_TEST

Improvement of the diagnosis of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to diagnose Tuberculosis resistance to 1st and 2nd line drugs through novel molecular multiplex assays (Study 1) by:

• Validating the Deeplex test and establish a network for shipment of sputum samples in ethanol to regional reference laboratories (Study 1 - phase 1)
• Validating the Molbio Truenat test as a point of care test (Study 1 - phase 2)
• Validating the Cepheid GeneXpert 2nd line cartridge at the district level (Study 1 -phase2)

Rifampicin resistant patients

Study 2: Follow up of the rifampicin resistant patients included in the study 1 during their treatment

Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis

Intervention Type: DIAGNOSTIC_TEST

Improvement of the management of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to set up alternative culture-free approaches for the monitoring of patients' response to Multi Drug Resistant-Tuberculosis treatment (Study 2), with:

• FDA microscopy
• Measurement of bacterial load by following Cycle threshold (Ct) values in GeneXpert Mycobacterium tuberculosis/Rifampicin
• Measurement of pre-rRNA synthesis

Interventions

Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line

Improvement of the diagnosis of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to diagnose Tuberculosis resistance to 1st and 2nd line drugs through novel molecular multiplex assays (Study 1) by:

• Validating the Deeplex test and establish a network for shipment of sputum samples in ethanol to regional reference laboratories (Study 1 - phase 1)
• Validating the Molbio Truenat test as a point of care test (Study 1 - phase 2)
• Validating the Cepheid GeneXpert 2nd line cartridge at the district level (Study 1 -phase2)

Intervention Type: DIAGNOSTIC_TEST

Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis

Improvement of the management of Multi Drug Resistant-Tuberculosis patients with culture-free approaches. We have planned to set up alternative culture-free approaches for the monitoring of patients' response to Multi Drug Resistant-Tuberculosis treatment (Study 2), with:

• FDA microscopy
• Measurement of bacterial load by following Cycle threshold (Ct) values in GeneXpert Mycobacterium tuberculosis/Rifampicin
• Measurement of pre-rRNA synthesis

Intervention Type: DIAGNOSTIC_TEST

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

• Minimum Eligible Age: 15 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rwanda Biomedical Centre

OTHER

Sponsor Role: collaborator

The Tuberculosis Reference Laboratory Bamenda

UNKNOWN

Sponsor Role: collaborator

Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo

OTHER

Sponsor Role: collaborator

Jimma University

OTHER

Sponsor Role: collaborator

Service de Pneumophtisiologie, Hôpital Ignace Deen

UNKNOWN

Sponsor Role: collaborator

University of the Sciences, Techniques and Technologies of Bamako

OTHER

Sponsor Role: collaborator

Damien Foundation

OTHER

Sponsor Role: collaborator

Cheikh Anta Diop University, Senegal

OTHER

Sponsor Role: collaborator

Institute of Tropical Medicine, Belgium

OTHER

Sponsor Role: collaborator

World Health Organization

OTHER

Sponsor Role: collaborator

London School of Hygiene and Tropical Medicine

OTHER

Sponsor Role: collaborator

Genoscreen

OTHER

Sponsor Role: collaborator

Dissou AFFOLABI

OTHER_GOV

Sponsor Role: lead

Responsible Party

Dissou AFFOLABI

Professor (Deputy Head of the Laboratory)

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Dissou AFFOLABI, MD, MSc, PhD

Role: PRINCIPAL_INVESTIGATOR

Laboratoire de Référence des Mycobactéries

Locations

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, , Democratic Republic of the Congo

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

Countries

Belgium; Benin; Cameroon; Democratic Republic of the Congo; Ethiopia; Guinea; Mali; Nigeria; Rwanda; Senegal

References

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Reference Type: BACKGROUND

PMID: 20825313 (View on PubMed)

Bastos ML, Hussain H, Weyer K, Garcia-Garcia L, Leimane V, Leung CC, Narita M, Pena JM, Ponce-de-Leon A, Seung KJ, Shean K, Sifuentes-Osornio J, Van der Walt M, Van der Werf TS, Yew WW, Menzies D; Collaborative Group for Meta-analysis of Individual Patient Data in MDR-TB. Treatment outcomes of patients with multidrug-resistant and extensively drug-resistant tuberculosis according to drug susceptibility testing to first- and second-line drugs: an individual patient data meta-analysis. Clin Infect Dis. 2014 Nov 15;59(10):1364-74. doi: 10.1093/cid/ciu619. Epub 2014 Aug 5.

Reference Type: RESULT

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Aung KJ, Van Deun A, Declercq E, Sarker MR, Das PK, Hossain MA, Rieder HL. Successful '9-month Bangladesh regimen' for multidrug-resistant tuberculosis among over 500 consecutive patients. Int J Tuberc Lung Dis. 2014 Oct;18(10):1180-7. doi: 10.5588/ijtld.14.0100.

Reference Type: RESULT

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Reference Type: RESULT

PMID: 25216832 (View on PubMed)

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Reference Type: RESULT

PMID: 20442432 (View on PubMed)

Inbaraj LR, Daniel J, Sathya Narayanan MK, Srinivasalu VA, Bhaskar A, Scandrett K, Rajendran P, Kirubakaran R, Shewade HD, Malaisamy M, Padmapriyadarsini C, Takwoingi Y. Truenat MTB assays for pulmonary tuberculosis and rifampicin resistance in adults and adolescents. Cochrane Database Syst Rev. 2025 Mar 24;3(3):CD015543. doi: 10.1002/14651858.CD015543.pub2.

Reference Type: DERIVED

PMID: 40122135 (View on PubMed)

Pillay S, Steingart KR, Davies GR, Chaplin M, De Vos M, Schumacher SG, Warren R, Theron G. Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin. Cochrane Database Syst Rev. 2022 May 18;5(5):CD014841. doi: 10.1002/14651858.CD014841.pub2.

Reference Type: DERIVED

PMID: 35583175 (View on PubMed)

Provided Documents

Document Type: Study Protocol, Statistical Analysis Plan, and Informed Consent Form

View Document

Other Identifiers

DRIA2014-326

Identifier Type: -

Identifier Source: org_study_id