Xpert MTB/RIF Test in the Diagnosis of Pulmonary Tuberculosis

Xpert MTB/RIF Test as the Initial Diagnostic Test in the Diagnosis of Pulmonary Tuberculosis: a Pragmatic Trial

Currently in Taiwan, most clinicians use sputum smear and culture for the diagnosis of pulmonary tuberculosis (TB) and apply nucleic acid amplification (NAA) test in a selected manner. In 2013, the World Health Organization issued conditional recommendation that Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all adults suspected of having TB. The newly published Taiwan guidelines for TB diagnosis and treatment has recommended NAA test, together with smear and culture, as the initial diagnostic test in individuals suspected of having TB. The investigators conduct a prospective study to investigate the use of Xpert MTB/RIF as the initial diagnostic test of pulmonary TB under a pragmatic trial design.

Study Overview

• Status: Active, not recruiting
• Conditions: Pulmonary Tuberculosis Confirmation by Culture
• Intervention / Treatment: Diagnostic test: Xpert MTB/RIF test

Detailed Description

In this study the investigators will respect current practice in the use of NAA in the diagnosis of pulmonary TB. Clinicians may have ordered NAA as the initial diagnostic test in adults suspected of having pulmonary TB (group A, Immediate NAA by clinician), and the investigators will not intervene. For patients who do not have NAA as the initial diagnostic test, the investigators will use random permuted blocks to randomize these participants into two groups. One group will have immediate Xpert test (intervention group) as the initial diagnostic test and another group will continue usual care without immediate Xpert test (control group).

Group A (Immediate NAA by clinician): NAA as the initial diagnostic test for pulmonary TB requested by clinicians.

Group B (Immediate NAA as intervention): NAA as the initial diagnostic test for pulmonary TB not requested by clinicians, but is performed as intervention in this study (intervention group).

Group C (No immediate NAA): NAA as the initial diagnostic test for pulmonary TB not requested by clinicians, and is not performed as the initial diagnostic test in this study (control group). NAA may be ordered at a later point in time by clinicians as an add-on test after sputum smear microscopy.

The investigators will assess pulmonary TB cases detected in all groups regarding

1. The interval between sputum examinations and initiation of ant-TB treatment.
2. The proportion of culture confirmed pulmonary TB among all pulmonary TB cases notified.
3. The proportion of TB patients who are advised to stop anti-TB treatment before completion of a treatment course.
4. Outcome of tuberculosis treatment, including patients who die before anti-TB treatment.

Among patients with NAA as the initial diagnostic test (Group A and Group B), the investigators will investigate

1. Performance (sensitivity, specificity and predictive values) of NAA in the diagnosis of culture positive pulmonary TB.
2. The incremental yield of the second and third smear in patients who have both NAA test and smear microscopy as the initial diagnostic test, aiming to determine the contribution of the second and third smear in the diagnosis of pulmonary TB.
3. The proportion of NAA positive cases who were culture negative.

• Study Type: Interventional
• Enrollment (Anticipated): 6900
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Taiwan
  • Chang-Hua, Taiwan, 513
    • Chang-Hua Hospital
  • Hualien City, Taiwan
    • Buddhist Tzu Chi General Hospital
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Tainan, Taiwan, 717
    • Chest Hospital, Ministry of Health and Welfare
  • Taipei, Taiwan, 111
    • Wan Fang Hospital, Taipei Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All presumptive tuberculosis cases who have sputum examinations for the diagnosis of pulmonary TB

Exclusion Criteria:

• Tuberculosis cases who have been on treatment for 14 or more days who have sputum examinations for follow-up

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Immediate NAA by clinician; Nucleic acid amplification test requested by clinicians as the initial diagnostic test for the diagnosis of pulmonary TB	Diagnostic test: Xpert MTB/RIF test; Xpert MTB/RIF performed as the initial diagnostic test for the diagnosis of pulmonary TB; Other Names: nucleic acid amplification test
Experimental: Immediate NAA as intervention; Nucleic acid amplification test not requested by clinicians as the initial diagnostic test for the diagnosis of pulmonary TB, but Xpert MTB/RIF is performed as intervention in this study (intervention group)	Diagnostic test: Xpert MTB/RIF test; Xpert MTB/RIF performed as the initial diagnostic test for the diagnosis of pulmonary TB; Other Names: nucleic acid amplification test
No Intervention: No immediate NAA; Nucleic acid amplification test not requested by clinicians as the initial diagnostic test for the diagnosis of pulmonary TB, and Xpert MTB/RIF is not performed as the initial diagnostic test in this study (control group). Nucleic acid amplification test may be ordered at a later point in time by clinicians as an add-on test after sputum smear microscopy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
diagnostic turnaround time	The interval between sputum examinations and initiation of ant-TB treatment	through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
culture positive pulmonary TB	The proportion of culture confirmed pulmonary TB among pulmonary TB cases notified	through study completion, an average of 1 year
change diagnosis	The proportion of TB patients who are advised to stop anti-TB treatment before completion of a treatment course	12 months after the initiation of anti-tuberculosis treatment
treatment outcomes	The proportion of patients who die before anti-TB treatment, who are successfully treated, who died during treatment, who are loss-to-follow-up, who have treatment failure and who are transferred out	12 months after the initiation of anti-tuberculosis treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
performance of nucleic acid amplification test	sensitivity, specificity and predictive values of nucleic acid amplification test in the diagnosis of culture positive pulmonary TB	through study completion, an average of 1 year
incremental yield	The incremental yield of the second and third smear in patients who have both NAA test and smear microscopy as the initial diagnostic test, aiming to determine the contribution of the second and third smear in the diagnosis of pulmonary TB	through study completion, an average of 1 year
NAA false positive	The proportion of nucleic acid amplification test positive cases who were culture negative	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Taipei Medical University WanFang Hospital
• Collaborators: Buddhist Tzu Chi General Hospital; Taichung Veterans General Hospital; Chang-Hua Hospital; Chest Hospital, Ministry of Health and Welfare, Taiwan
• Investigators: Principal Investigator: Chen-Yuan Chiang, MD,DrPhilos, Wan Fang Hospital, Taipei Medical University, Taiwan

Publications and helpful links

General Publications

• Calligaro GL, Zijenah LS, Peter JG, Theron G, Buser V, McNerney R, Bara W, Bandason T, Govender U, Tomasicchio M, Smith L, Mayosi BM, Dheda K. Effect of new tuberculosis diagnostic technologies on community-based intensified case finding: a multicentre randomised controlled trial. Lancet Infect Dis. 2017 Apr;17(4):441-450. doi: 10.1016/S1473-3099(16)30384-X. Epub 2017 Jan 5.
• Ford I, Norrie J. Pragmatic Trials. N Engl J Med. 2016 Aug 4;375(5):454-63. doi: 10.1056/NEJMra1510059. No abstract available.
• Chiang CY, Enarson DA, Bai KJ, Suo J, Wu YC, Lin TP, Luh KT. Factors associated with a clinician's decision to stop anti-tuberculosis treatment before completion. Int J Tuberc Lung Dis. 2008 Apr;12(4):441-6.
• Chiang CY, Chang CT, Chang RE, Li CT, Huang RM. Patient and health system delays in the diagnosis and treatment of tuberculosis in Southern Taiwan. Int J Tuberc Lung Dis. 2005 Sep;9(9):1006-12.
• Chen CC, Chiang CY, Pan SC, Wang JY, Lin HH. Health system delay among patients with tuberculosis in Taiwan: 2003-2010. BMC Infect Dis. 2015 Nov 2;15:491. doi: 10.1186/s12879-015-1228-x.
• Pan SC, Chen YC, Wang JY, Sheng WH, Lin HH, Fang CT, Chang SC. Tuberculosis in Healthcare Workers: A Matched Cohort Study in Taiwan. PLoS One. 2015 Dec 17;10(12):e0145047. doi: 10.1371/journal.pone.0145047. eCollection 2015.
• Boehme CC, Nicol MP, Nabeta P, Michael JS, Gotuzzo E, Tahirli R, Gler MT, Blakemore R, Worodria W, Gray C, Huang L, Caceres T, Mehdiyev R, Raymond L, Whitelaw A, Sagadevan K, Alexander H, Albert H, Cobelens F, Cox H, Alland D, Perkins MD. Feasibility, diagnostic accuracy, and effectiveness of decentralised use of the Xpert MTB/RIF test for diagnosis of tuberculosis and multidrug resistance: a multicentre implementation study. Lancet. 2011 Apr 30;377(9776):1495-505. doi: 10.1016/S0140-6736(11)60438-8. Epub 2011 Apr 18.
• Hermans S, Caldwell J, Kaplan R, Cobelens F, Wood R. The impact of the roll-out of rapid molecular diagnostic testing for tuberculosis on empirical treatment in Cape Town, South Africa. Bull World Health Organ. 2017 Aug 1;95(8):554-563. doi: 10.2471/BLT.16.185314. Epub 2017 Apr 28.
• Cox H, Dickson-Hall L, Ndjeka N, Van't Hoog A, Grant A, Cobelens F, Stevens W, Nicol M. Delays and loss to follow-up before treatment of drug-resistant tuberculosis following implementation of Xpert MTB/RIF in South Africa: A retrospective cohort study. PLoS Med. 2017 Feb 21;14(2):e1002238. doi: 10.1371/journal.pmed.1002238. eCollection 2017 Feb.
• Cox HS, Mbhele S, Mohess N, Whitelaw A, Muller O, Zemanay W, Little F, Azevedo V, Simpson J, Boehme CC, Nicol MP. Impact of Xpert MTB/RIF for TB diagnosis in a primary care clinic with high TB and HIV prevalence in South Africa: a pragmatic randomised trial. PLoS Med. 2014 Nov 25;11(11):e1001760. doi: 10.1371/journal.pmed.1001760. eCollection 2014 Nov.
• Naidoo P, Dunbar R, Lombard C, du Toit E, Caldwell J, Detjen A, Squire SB, Enarson DA, Beyers N. Comparing Tuberculosis Diagnostic Yield in Smear/Culture and Xpert(R) MTB/RIF-Based Algorithms Using a Non-Randomised Stepped-Wedge Design. PLoS One. 2016 Mar 1;11(3):e0150487. doi: 10.1371/journal.pone.0150487. eCollection 2016.
• Mbonze NB, Tabala M, Wenzi LK, Bakoko B, Brouwer M, Creswell J, Van Rie A, Behets F, Yotebieng M. Xpert((R)) MTB/RIF for smear-negative presumptive TB: impact on case notification in DR Congo. Int J Tuberc Lung Dis. 2016 Feb;20(2):240-6. doi: 10.5588/ijtld.15.0177.
• Automated Real-Time Nucleic Acid Amplification Technology for Rapid and Simultaneous Detection of Tuberculosis and Rifampicin Resistance: Xpert MTB/RIF Assay for the Diagnosis of Pulmonary and Extrapulmonary TB in Adults and Children: Policy Update. Geneva: World Health Organization; 2013. Available from http://www.ncbi.nlm.nih.gov/books/NBK258608/
• Lin HH, Dowdy D, Dye C, Murray M, Cohen T. The impact of new tuberculosis diagnostics on transmission: why context matters. Bull World Health Organ. 2012 Oct 1;90(10):739-747A. doi: 10.2471/BLT.11.101436. Epub 2012 Jul 16.
• Steingart KR, Schiller I, Horne DJ, Pai M, Boehme CC, Dendukuri N. Xpert(R) MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst Rev. 2014 Jan 21;2014(1):CD009593. doi: 10.1002/14651858.CD009593.pub3.
• Mase SR, Ramsay A, Ng V, Henry M, Hopewell PC, Cunningham J, Urbanczik R, Perkins MD, Aziz MA, Pai M. Yield of serial sputum specimen examinations in the diagnosis of pulmonary tuberculosis: a systematic review. Int J Tuberc Lung Dis. 2007 May;11(5):485-95.
• Lombardi G, Di Gregori V, Girometti N, Tadolini M, Bisognin F, Dal Monte P. Diagnosis of smear-negative tuberculosis is greatly improved by Xpert MTB/RIF. PLoS One. 2017 Apr 21;12(4):e0176186. doi: 10.1371/journal.pone.0176186. eCollection 2017.
• Rieder HL, Chiang CY, Rusen ID. A method to determine the utility of the third diagnostic and the second follow-up sputum smear examinations to diagnose tuberculosis cases and failures. Int J Tuberc Lung Dis. 2005 Apr;9(4):384-91.

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2020
• Primary Completion (Actual): October 31, 2021
• Study Completion (Anticipated): December 31, 2022

Study Registration Dates

• First Submitted: June 9, 2020
• First Submitted That Met QC Criteria: June 11, 2020
• First Posted (Actual): June 16, 2020

Study Record Updates

• Last Update Posted (Actual): May 12, 2022
• Last Update Submitted That Met QC Criteria: May 10, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Tuberculosis; Xpert MTB/RIF; diagnostic turnaround time
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Pulmonary
• Other Study ID Numbers: N202002038

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: individual participant data will be available on request for researchers who meet the criteria for access to confidential data
• IPD Sharing Time Frame: 1 year after publication of findings
• IPD Sharing Access Criteria: researchers who have been trained for research, are interested in diagnostic turnaround time of pulmonary TB, and will not use the data for commercial or publication purpose.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes