DIAgnostics for Multidrug Resistant Tuberculosis in Africa

Tuberculosis, Multidrug-Resistant Clinical Trial

— DIAMA  

Official title:

Culture Free Diagnosis and Follow-up of Multidrug Resistant Tuberculosis Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03303963
• Other study ID #: DRIA2014-326
• Status: Completed
• Start date: May 4, 2017
• Est. completion date: November 30, 2022

Study information

• Verified date: March 2023
• Source: Laboratoire de Référence des Mycobactéries
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3356
• Est. completion date: November 30, 2022
• Est. primary completion date: June 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

Diagnostic Test:
• 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)
• 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

Locations

Country	Name	City	State
Belgium	Institute of Tropical Medecine	Antwerp
Benin	Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou	Cotonou	Atlantique/Littoral
Cameroon	The Tuberculosis Reference Laboratory Bamenda	Bamenda
Congo, The Democratic Republic of the	Institut National de Recherche Biomédicale (INRB)	Kinshasa
Ethiopia	Jimma University	Jima
Guinea	Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry	Conakry
Mali	Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO	Bamako
Nigeria	Damien Fundation	Ibadan
Rwanda	Rwanda Biomedical Center (RBC)	Kigali
Senegal	Université Cheick Anta Diop (UCAD)	Dakar

Sponsors (13)

Lead Sponsor

Collaborator

Dissou AFFOLABI

Cheikh Anta Diop University, Senegal, Damien Foundation, Genoscreen, Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo, Institute of Tropical Medicine, Belgium, Jimma University, London School of Hygiene and Tropical Medicine, Rwanda Biomedical Centre, Service de Pneumophtisiologie, Hôpital Ignace Deen, The Tuberculosis Reference Laboratory Bamenda, University of the Sciences, Techniques and Technologies of Bamako, World Health Organization

Countries where clinical trial is conducted

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

References & Publications (5)

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. — View Citation

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 Patien — View Citation

Boehme CC, Nabeta P, Hillemann D, Nicol MP, Shenai S, Krapp F, Allen J, Tahirli R, Blakemore R, Rustomjee R, Milovic A, Jones M, O'Brien SM, Persing DH, Ruesch-Gerdes S, Gotuzzo E, Rodrigues C, Alland D, Perkins MD. Rapid molecular detection of tuberculosis and rifampin resistance. N Engl J Med. 2010 Sep 9;363(11):1005-15. doi: 10.1056/NEJMoa0907847. Epub 2010 Sep 1. — View Citation

Piubello A, Harouna SH, Souleymane MB, Boukary I, Morou S, Daouda M, Hanki Y, Van Deun A. High cure rate with standardised short-course multidrug-resistant tuberculosis treatment in Niger: no relapses. Int J Tuberc Lung Dis. 2014 Oct;18(10):1188-94. doi: — View Citation

Van Deun A, Maug AK, Salim MA, Das PK, Sarker MR, Daru P, Rieder HL. Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med. 2010 Sep 1;182(5):684-92. doi: 10.1164/rccm.201001-0077OC. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Validation of Deeplex test	Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results	4 years
Primary	Validation of GeneXpert 2nd line	Concordance between WGS, Deeplex results and GeneXpert 2nd line results	4 years
Primary	Validation of MolBio TrueNat for INH, FQ and BDQ	Concordance between WGS, Deeplex results and MolBioTrueNat results	4 years
Primary	Validation of FDA microscopy	Concordance between Culture results and FDA microscopy results	4 years
Primary	Validation of GeneXpert Ct value	Concordance between Culture results and GeneXpert Ct value results	4 years
Secondary	Estimation of proportion of additional resistance in patients resistant to Rifampicin	Evaluation to be done with the Deeplex test	4 years
Secondary	Measurement of the association of specific mutations against some drugs with programmatic treatment outcome	Evaluation to be done with the Deeplex test	4 years
Secondary	Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients	Evaluation to be done with Data2Care connectivity system	2 years