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Trial of Point-of-treatment Xpert MTB/RIF Assay (TBNEATXpert)

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ClinicalTrials.gov Identifier: NCT01554384
Recruitment Status : Completed
First Posted : March 15, 2012
Last Update Posted : June 6, 2013
Information provided by (Responsible Party):

Study Description
Brief Summary:
Xpert MTB/RIF assay is a novel automated molecular tool for the diagnosis of TB. Xpert can detect TB genetic material in sputum samples as well as test for genetic resistance to rifampicin providing results within 2 hours. Xpert received WHO endorsement in December 2010. There is limited data on the impact of Xpert on time-to-treatment and TB-related patient morbidity in primary care clinics. No studies have yet evaluated Xpert performed at the point-of-treatment (POT) i.e. in primary care clinic location. The investigators hypothesize that one sputum GeneXpert MTB/RIF assay performed at the POT will improve time-to-diagnosis, time-to-treatment and TB related patient morbidity for patients with suspected TB presenting to primary level TB clinics in high HIV prevalent settings.

Condition or disease Intervention/treatment
Tuberculosis Procedure: Xpert MTB/RIF assay Procedure: Smear microscopy

Detailed Description:

Tuberculosis (TB) is one of the world's most important infectious causes of mortality and continues to kill 1.8 million people annually. Despite intensified standard measure of TB control, TB case detection rates are low, posing major hurdles for TB control. It is estimated that approximately 50% of patients with TB are still not diagnosed and treated appropriately. The problem is compounded by the increasing prevalence of multi drug resistant (MDR) and extensively drug resistant (XDR) TB and the close association between TB and HIV infection.

Diagnostic tools introduced 100 years ago are still in routine use and increasingly inaccurate if the face of the HIV and TB syndemics. Consequently, many patients with active TB remain undiagnosed and continue to spread the disease within the community. Thus, missed or delayed diagnosis results in ongoing transmission, patient morbidity and mortality, and social and economic consequences. Currently, there is no available point-of-care, or even point-of-treatment test that allows early detection of active tuberculosis at the peripheral health clinic level. Lack of rapid, simple and accurate diagnostic tests at this level is a major hurdle in controlling the global burden of TB. A number of promising new TB diagnostics have shown initial promise but there remains an urgent need to assess their impact when used at the point-of-treatment in primary care level.

In 2009, Cepheid released the Xpert® MTB/RIF Assay, which is the only system able to deliver answers directly from unprocessed samples by combining on-board preparation of the sample with real-time polymerase chain reaction (PCR) in less than 2 hours. Additionally, the Xpert® MTB/RIF Assay allows for simultaneous on-demand molecular testing for the detection of mycobacterium tuberculosis (M.tb) and rifampicin (frontline anti-TB drug) resistance. . The GeneXpert™ system consists of a GeneXpert instrument, personal computer and disposable fluidic cartridges. The system combines cartridge-based sample preparation with amplification and detection in a fully integrated and automated nucleic acid analysis instrument. Xpert has now been shown to be an accurate tool for the rapid diagnosis of tuberculosis in both smear-positive and smear-negative samples in both a multicentre evaluation and demonstration study with a sensitivity of approximately 70% in smear negative culture positive TB. Xpert testing in both these studies was performed at microscopy laboratories. In December 2010, on the basis of these results, Xpert was endorsed for TB diagnosis by the World Health Organisation (WHO) but is yet to be integrated into national tuberculosis control programmes.

Limited data is available on the impacts of Xpert on patient important outcomes such as TB-related morbidity. No data is available about the feasibility and robustness of performing Xpert in primary care clinics at the POT using minimally trained nursing staff. The objective of this study will be to examine the feasibility and impact of a single point-of-treatment Gene Xpert MTB/RIF Assay performed by clinic staff compared to standard microscopy-centre based diagnostics. Special focus will be on the patient-related outcomes of time-to-treatment initiation, drop out rates and the mean difference in TB-morbidity scores in patients diagnosed with Xpert.

The Xpert POT study will be a multicentre patient-level randomised controlled trial comparing a single sputum GeneXpert MTB/RIF Assay performed at point-of-treatment with same-day standard fluorescent smear microscopy for TB diagnosis at the primary level of care. A single liquid MGIT culture performed a regional laboratory will be used as the reference standard.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 1472 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Multicentre Randomised Control Trial of Point-of-treatment (Clinic-based) Xpert MTB/RIF Assay
Study Start Date : October 2010
Primary Completion Date : July 2012
Study Completion Date : July 2012

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis
U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
Experimental: Xpert MTB/RIF
Patients in this arm will receive 1 sputum Xpert MTB/RIF test (point-of-treatment) and 1 sputum sample for MGIT liquid TB culture (regional lab)
Procedure: Xpert MTB/RIF assay
Automated nucleic-acid amplification test (fully integrated) test for TB
Other Name: Cepheid Xpert MTB/RIF assay
Active Comparator: Sputum smear microscopy
Patients in this study arm will receive 2 sputum samples for same-day smear microscopy and 1 of the sputum samples will have a MGIT Liquid culture (regional lab).
Procedure: Smear microscopy
Smear microscopy involve sputum smear with either ziehl-neelsen or auramine-O staining of slides and light or fluorescence microscopy reading

Outcome Measures

Primary Outcome Measures :
  1. Difference in TB-related Morbidity [ Time Frame: 2 months ]

    Time-specific (2 month) difference in morbidity between the Xpert MTB/RIF and smear microscopy study arms.

    Morbidity will be assessed using the TB Score and Karnosky performance scale

  2. Difference in TB-related Morbidity [ Time Frame: 6 months ]

    Time-specific (6 month) difference in morbidity between the Xpert MTB/RIF and smear microscopy study arms.

    Morbidity will be assessed using the TB Score and Karnosky performance scale

Secondary Outcome Measures :
  1. Time-to-diagnosis [ Time Frame: 6 months ]

    Time from study enrollment to TB diagnosis in each study arm

    A diagnosis of TB will include:

    i) Smear microscopy: WHO classification for smear grading considered positive ii) Xpert MTB/RIF positive (mtb detected) iii) MGIT liquid culture positive

  2. Drop-out and lost-to-follow up rates [ Time Frame: 1 year ]
    Number of patients that are enrolled, randomized to a study arm, and then do not return to receive a positive test result, and Number of patients that are enrolled, randomized to a study arm, diagnosed with TB, and then are lost-to-follow up prior to completion of prescribed standard TB treatment

  3. Feasibility of clinic-based performance of Xpert MTB/RIF assay performed by nursing staff without formal research training [ Time Frame: 6 months ]
    Feasibility indicators for the performance of Xpert at POT will be recorded. These include indeterminate rates, turn-around-time, user appraisal and assessments and performance comparisons between laboratory and clinic-based Xpert MTB/RIF.

  4. Individual patient-level cost analysis, cost-effectiveness evaluation and quality of health indices evaluation [ Time Frame: 1 year ]
    Detailed documentation of patient and health system costs for TB diagnosis and treatment will be done at baseline, 2 month and 6 month time-points as well as quality of life health questionaires.

  5. Time-to-treatment initiation [ Time Frame: 6 months ]
    The time-to-treatment initiation for TB culture positive patients in each study arm will be compared Treatment commencement will be considered as the initiation of the first dose of anti-TB treatment at a registered DOTs facility

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Able and willing to give informed consent
  2. Ambulant patient presenting to TB clinic

    IF HIV negative requires 2 or more of the following:

    • Cough ≥ 2 weeks
    • loss of weight
    • persistent fever ≥ 2 weeks and/or
    • a single recorded temp > 38°C
    • night sweats
    • generalized fatigue
    • hemoptysis or
    • chest pain

    OR if HIV positive - any one of the following:

    • current cough
    • night sweats
    • fever
    • loss of weight
  3. Patient 18 years or above

Exclusion Criteria:

  1. Inability to provide informed consent (e.g. mentally impaired)
  2. Unable to produce 2 sputa of ≥ 1ml
  3. TB treatment within the last 60 days
  4. Unable to potentially return for study follow-up at 2 and 6 months (i.e. leaving community)
  5. Patient not meeting inclusion criteria
Contacts and Locations

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): NCT01554384

South Africa
Medical Research Council
Durban, Kwazulu-Natal, South Africa
University of Cape Town
Cape Town, Western Cape, South Africa, 7945
University Teaching Hospital of Zambia
Lusaka, Zambia
University of Zimbabwe
Harare, Zimbabwe
Sponsors and Collaborators
University of Cape Town
Biomedical Research and Training Institute
University of Zimbabwe
University of Zambia
Medical Research Council, South Africa
Mbeya medical research program
McGill University
Radboud University
University of Cape Town Lung Institute
Principal Investigator: Keertan Dheda, MD PhD University of Cape Town
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Keertan Dheda, Professor and Head, Lung Infection and Immunity unit, University of Cape Town
ClinicalTrials.gov Identifier: NCT01554384     History of Changes
Other Study ID Numbers: TBNEATXpertRCT
IP.09.32040.009 ( Other Grant/Funding Number: EDCTP )
First Posted: March 15, 2012    Key Record Dates
Last Update Posted: June 6, 2013
Last Verified: June 2013

Keywords provided by Keertan Dheda, University of Cape Town:
randomized controlled trial

Additional relevant MeSH terms:
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections