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DIAgnostics for Multidrug Resistant Tuberculosis in Africa (DIAMA)

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ClinicalTrials.gov Identifier: NCT03303963
Recruitment Status : Recruiting
First Posted : October 6, 2017
Last Update Posted : October 5, 2020
Sponsor:
Collaborators:
Rwanda Biomedical Center (RBC), Kigali, Rwanda
The Tuberculosis Reference Laboratory Bamenda
Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo
Jimma University
Service de Pneumophtisiologie, Hôpital Ignace Deen
University of the Sciences, Techniques and Technologies of Bamako
Damien Foundation
Cheikh Anta Diop University, Senegal
Institute of Tropical Medicine, Belgium
World Health Organization
London School of Hygiene and Tropical Medicine
Genoscreen
Information provided by (Responsible Party):
Dissou AFFOLABI, Laboratoire de Référence des Mycobactéries

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.

Condition or disease Intervention/treatment
Tuberculosis, Multidrug-Resistant Diagnostic Test: Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line Diagnostic Test: Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis

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.

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Study Type : Observational
Estimated Enrollment : 2840 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Culture Free Diagnosis and Follow-up of Multidrug Resistant Tuberculosis Patients
Actual Study Start Date : May 4, 2017
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Group/Cohort Intervention/treatment
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

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
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




Primary Outcome Measures :
  1. Validation of Deeplex test [ Time Frame: 4 years ]
    Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results

  2. Validation of GeneXpert 2nd line [ Time Frame: 4 years ]
    Concordance between WGS, Deeplex results and GeneXpert 2nd line results

  3. Validation of InSilixa chip assay [ Time Frame: 4 years ]
    Concordance between WGS, Deeplex results and MolBioTrueNat results

  4. Validation of FDA microscopy [ Time Frame: 4 years ]
    Concordance between Culture results and FDA microscopy results

  5. Validation of GeneXpert Ct value [ Time Frame: 4 years ]
    Concordance between Culture results and GeneXpert Ct value results


Secondary Outcome Measures :
  1. Estimation of proportion of additional resistance in patients resistant to Rifampicin [ Time Frame: 4 years ]
    Evaluation to be done with the Deeplex test

  2. Measurement of the association of specific mutations against some drugs with programmatic treatment outcome [ Time Frame: 4 years ]
    Evaluation to be done with the Deeplex test

  3. Evaluation of the add value of Connectivity system in the management of Multi Drug Resistant-Tuberculosis patients [ Time Frame: 2 years ]
    Evaluation to be done with Data2Care connectivity system


Biospecimen Retention:   Samples With DNA

Sputum.

At the enrôlment, 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   15 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03303963


Contacts
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Contact: Dissou AFFOLABI, MD, MSc, PhD 66614862 ext 00229 affolabi_dissou@yahoo.fr
Contact: Faridath MASSOU, PharmD 67244944 ext 00229 abenimas@gmail.com

Locations
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Belgium
Institute of Tropical Medecine Active, not recruiting
Antwerp, Belgium
Benin
Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou Recruiting
Cotonou, Atlantique/Littoral, Benin, 01BP321
Contact: Dissou AFFOLABI, MD PhD Prof    66614862 ext 00229    affolabi_dissou@yahoo.fr   
Contact: Faridath MASSOU, PharmD    67244944 ext 00229    abenimas@gmail.com   
Cameroon
The Tuberculosis Reference Laboratory Bamenda Recruiting
Bamenda, Cameroon
Contact: Melissa SANDER, MSc, PhD    694721484 ext 00237    melissa.sander@gmail.com   
Congo, The Democratic Republic of the
Institut National de Recherche Biomédicale (INRB) Recruiting
Kinshasa, Congo, The Democratic Republic of the
Contact: Michel KASWA, MD MSc MPH    999928694 ext 00243    meckkay2002@yahoo.fr   
Ethiopia
Jimma University Terminated
Jīma, Ethiopia
Guinea
Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry Recruiting
Conakry, Guinea
Contact: Lansana Younoussa Camara, MD, Prof    622440635/ 624406335 ext 00224    camaralmady@yahoo.fr   
Mali
Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO Recruiting
Bamako, Mali
Contact: Bassirou DIARRA, MD MSc PhD Student    66807491 ext 00223    bdiarra@icermali.org   
Nigeria
Damien Fundation Recruiting
Ibadan, Nigeria
Contact: Othman EL TAYEB, BSc MSc    8023683356 ext 00234    osman.eltayeb@dfbnigeria.org   
Rwanda
Rwanda Biomedical Center (RBC) Recruiting
Kigali, Rwanda
Contact: Jean-Claude SEMUTO NGABONZIZA, MSc PhD student    788740490 ext 00250    cldsemuto@gmail.com   
Senegal
Université Cheick Anta Diop (UCAD) Completed
Dakar, Senegal
Sponsors and Collaborators
Dissou AFFOLABI
Rwanda Biomedical Center (RBC), Kigali, Rwanda
The Tuberculosis Reference Laboratory Bamenda
Institut National de Recherche Biomédicale. Kinshasa, République Démocratique du Congo
Jimma University
Service de Pneumophtisiologie, Hôpital Ignace Deen
University of the Sciences, Techniques and Technologies of Bamako
Damien Foundation
Cheikh Anta Diop University, Senegal
Institute of Tropical Medicine, Belgium
World Health Organization
London School of Hygiene and Tropical Medicine
Genoscreen
Investigators
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Principal Investigator: Dissou AFFOLABI, MD, MSc, PhD Laboratoire de Référence des Mycobactéries
  Study Documents (Full-Text)

Documents provided by Dissou AFFOLABI, Laboratoire de Référence des Mycobactéries:
Publications of Results:
Other Publications:
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Responsible Party: Dissou AFFOLABI, Professor (Deputy Head of the Laboratory), Laboratoire de Référence des Mycobactéries
ClinicalTrials.gov Identifier: NCT03303963    
Other Study ID Numbers: DRIA2014-326
First Posted: October 6, 2017    Key Record Dates
Last Update Posted: October 5, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dissou AFFOLABI, Laboratoire de Référence des Mycobactéries:
culture-free
tuberculosis
multidrug resistant
diagnosis
follow-up
africa
molecular tools
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections