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

• Difference in TB-related Morbidity [ Time Frame: 2 months ] [ Designated as safety issue: No ]

  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

  
  
• Difference in TB-related Morbidity [ Time Frame: 6 months ] [ Designated as safety issue: No ]

  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

  
  

• Time-to-diagnosis [ Time Frame: 6 months ] [ Designated as safety issue: No ]

  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

  
  
• Drop-out and lost-to-follow up rates [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  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
  
  
• Feasibility of clinic-based performance of Xpert MTB/RIF assay performed by nursing staff without formal research training [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  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.
  
  
• Individual patient-level cost analysis, cost-effectiveness evaluation and quality of health indices evaluation [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  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.
  
  
• Time-to-treatment initiation [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  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
  
  

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.