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Tuberculosis, Multidrug-ResistantDIAMANCT03303963

DIAgnostics for Multidrug Resistant Tuberculosis in Africa

An observational study of Tuberculosis, Multidrug-Resistant, run by Dissou AFFOLABI at 10 sites in 10 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages 15 years and older
Conditions the study is for
Tuberculosis, Multidrug-Resistant
What is being tested?
Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line and Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis
How many people
3,356 participants
Where
10 sitesin 10 countries
Study dates
4 May 2017to 30 Nov 2022
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 15 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

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

Who may be able to join

  • 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

Who cannot join

None listed.

Trial locations and contacts

10 sites in 10 countries.

10 sites in 10 countries

Belgium1 site
  • Institute of Tropical Medecine

    Antwerp

Other trials in Belgium

Benin1 site
  • Centre National Hospitalier Universitaire de Pneumo-Phtisiologie de Cotonou

    Cotonou, Atlantique/Littoral, 01BP321

Other trials in Benin

Cameroon1 site
  • The Tuberculosis Reference Laboratory Bamenda

    Bamenda

Other trials in Cameroon

Democratic Republic of the Congo1 site
  • Institut National de Recherche Biomédicale (INRB)

    Kinshasa

Other trials in Democratic Republic of the Congo

Ethiopia1 site
  • Jimma University

    Jīma

Other trials in Ethiopia

Guinea1 site
  • Service de Pneumophtisiologie, Hôpital Ignace Deen, Conakry

    Conakry

Other trials in Guinea

Mali1 site
  • Université des Sciences, des Techniques et des Technologies de Bamako, SEREFO

    Bamako

Other trials in Mali

Nigeria1 site
  • Damien Fundation

    Ibadan

Other trials in Nigeria

Rwanda1 site
  • Rwanda Biomedical Center (RBC)

    Kigali

Other trials in Rwanda

Senegal1 site
  • Université Cheick Anta Diop (UCAD)

    Dakar

Other trials in Senegal

About this study

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

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.

Read the 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.

Being tested
Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line, Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis
Keywords
culture-free, tuberculosis, multidrug resistant, diagnosis, follow-up, africa, molecular tools
Medical subject headings
Tuberculosis, Multidrug-Resistant, Tuberculosis, Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd lineDiagnostic 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)
  • Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesisDiagnostic 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
Study groups in NCT03303963
Study groupRoleWhat they receive
Rifampicin resistant and susceptible patientsStudy 1: Patients detected positive by the GeneXpert Mycobacterium tuberculosis/Rifampicin (susceptible and resistant to rifampicin)
Receives: Diagnostic Test: Deeplex test, MolBio TrueNat for 2nd line, GeneXpert 2nd line
Rifampicin resistant patientsStudy 2: Follow up of the rifampicin resistant patients included in the study 1 during their treatment
Receives: Diagnostic Test: Fluorescein DiAcetate (FDA) Microscopy,GeneXpert Ct value, pre-rRNA synthesis

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Validation of Deeplex test

    Concordance between phenotypic Drug Susceptibility Test, WGS and Deeplex results

    Measured: 4 years

  2. Validation of GeneXpert 2nd line

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

    Measured: 4 years

  3. Validation of MolBio TrueNat for INH, FQ and BDQ

    Concordance between WGS, Deeplex results and MolBioTrueNat results

    Measured: 4 years

  4. Validation of FDA microscopy

    Concordance between Culture results and FDA microscopy results

    Measured: 4 years

  5. Validation of GeneXpert Ct value

    Concordance between Culture results and GeneXpert Ct value results

    Measured: 4 years

Secondary outcomes (3)
  1. Estimation of proportion of additional resistance in patients resistant to Rifampicin

    Evaluation to be done with the Deeplex test

    Measured: 4 years

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

    Evaluation to be done with the Deeplex test

    Measured: 4 years

  3. 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

    Measured: 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Oct 2017
  2. Study start4 May 2017
  3. Primary completion30 Jun 2022
  4. Study completion30 Nov 2022

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
3,356 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03303963
Sponsor's protocol ID
DRIA2014-326
Acronym
DIAMA
Status last verified
Mar 2023
First submitted
24 Sep 2017
Last updated
14 Mar 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 20825313
  • 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.

    PubMed 25097082
  • 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.

    PubMed 25216831
  • 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.

    PubMed 25216832
  • 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.

    PubMed 20442432
  • 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.

    PubMed 40122135
  • 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.

    PubMed 35583175

Questions about this trial

What is this clinical trial studying?

An observational study of Tuberculosis, Multidrug-Resistant, run by Dissou AFFOLABI at 10 sites in 10 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Belgium, Benin, Cameroon, Democratic Republic of the Congo, Ethiopia and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Validation of Deeplex test (time frame: 4 years). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03303963, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Mar 2023.

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