DIAgnostics for Multidrug Resistant Tuberculosis in Africa

NCT03303963 | Completed

• 1 other identifier: DRIA2014-326
• Study Type: observational
• Target: 3,356
• Locations: 9 countries
• Sites: 9

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.

Conditions

Tuberculosis, Multidrug-Resistant

Keywords

culture-free; tuberculosis; multidrug resistant; diagnosis; follow-up; africa; molecular tools

Outcome Measures

Primary Outcomes (5)

• Validation of Deeplex test

  Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results

  4 years

• Validation of GeneXpert 2nd line

  Concordance between WGS, Deeplex results and GeneXpert 2nd line results

  4 years

• Validation of MolBio TrueNat for INH, FQ and BDQ

  Concordance between WGS, Deeplex results and MolBioTrueNat results

  4 years

• Validation of FDA microscopy

  Concordance between Culture results and FDA microscopy results

  4 years

• Validation of GeneXpert Ct value

  Concordance between Culture results and GeneXpert Ct value results

  4 years

Secondary Outcomes (3)

• Estimation of proportion of additional resistance in patients resistant to Rifampicin

  4 years

• Measurement of the association of specific mutations against some drugs with programmatic treatment outcome

  4 years

• Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients

  2 years

Study Arms (2)

Rifampicin resistant and susceptible patients

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

Diagnostic Test: Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line

Rifampicin resistant patients

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

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

Interventions

Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line 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 and susceptible patients

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

Rifampicin resistant patients

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (10)

Institute of Tropical Medecine

Antwerp, Belgium

Location

Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou

Cotonou, Atlantique/Littoral, 01BP321, Benin

Location

The Tuberculosis Reference Laboratory Bamenda

Bamenda, Cameroon

Location

Institut National de Recherche Biomédicale (INRB)

Kinshasa, Democratic Republic of the Congo

Location

Jimma University

Jīma, Ethiopia

Location

Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry

Conakry, Guinea

Location

Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO

Bamako, Mali

Location

Damien Fundation

Ibadan, Nigeria

Location

Rwanda Biomedical Center (RBC)

Kigali, Rwanda

Location

Université Cheick Anta Diop (UCAD)

Dakar, Senegal

Location

Related Publications (7)

• 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.

  PMID: 20825313 BACKGROUND

• 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.

  PMID: 25097082 RESULT

• 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.

  PMID: 25216831 RESULT

• 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: 10.5588/ijtld.13.0075.

  PMID: 25216832 RESULT

• 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. Epub 2010 May 4.

  PMID: 20442432 RESULT

• 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.

  PMID: 40122135 DERIVED

• 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.

  PMID: 35583175 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Sputum. At the enrolment, three samples (spot-overnight-spot) will be collected for the comparison of phenotypic results against molecular results. During the treatment, two monthly samples (overnight-spot) will be collected for the comparison of culture result against FDA Microscopy and GeneXpert Ct values.

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Tuberculosis; Disease

Interventions

Microscopy

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Dissou AFFOLABI, MD, MSc, PhD

  Laboratoire de Référence des Mycobactéries

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor (Deputy Head of the Laboratory)

Study Record Dates

• First Submitted: September 24, 2017
• First Posted: October 6, 2017
• Study Start: May 4, 2017
• Primary Completion: June 30, 2022
• Study Completion: November 30, 2022
• Last Updated: March 14, 2023

Record last verified: 2023-03

Locations

BE (1); ET (1); SE (1); DE (1); GU (1); MA (1); CA (1); NG (1); RW (1)