Improving TB Diagnosis and Treatment Through Basic, Applied and Health Systems Research

NCT03356925 | Completed

• 1 other identifier: N14/10/13
• Study Type: interventional
• Target: 1,549
• Locations: 1 country
• Sites: 2

Brief Summary

TB is a global health problem and in South Africa rates as the second most important problem in terms of Burden of Disease. There are many reasons for this, among which are diagnostic difficulties, extended treatments, drug resistance and health care provision. This application is concerned with all these drivers and will focus activities on a clinic which provides basic care in a very deprived socio-economic area of greater Cape Town, South Africa. Patients studied in routine, but demanding environments are our focus as these clinics are representative of many areas where TB (and HIV) are found at high prevalence. If the constraints of working in such areas can be understood and appropriate changes that work made, the investigators believe the outputs and policy changes generated in this study will contribute to future success in other settings. The investigators wish to study the implementation of the Xpert®MTB/RIF (Xpert) and Xpert Ultra (Ultra) systems in situ using a randomised controlled trial design, as opposed to a remote site (central laboratory), to assess whether time to diagnosis can be improved using point of care (POC). The investigators wish to maximise this opportunity by collecting biological samples from a patient population experiencing a TB epidemic for the evaluation of future TB diagnostics. Using human DNA, the investigators will attempt to determine reasons for poor or no treatment response. Two possibilities exist for this: a) the M. tuberculosis strain is resistant to the drug in question or b) the patient is highly susceptible to the bacterium. The investigators will determine the exome sequences of study participants with susceptible M. tuberculosis strains who show poor or no response, and compare this with rapid responders. Using 16S rRNA sequencing, the investigators will also observe how the microbiome of TB patients is altered during TB treatment and how this is associated with treatment outcome, as well as after TB treatment. This project will set the foundation for the implementation of new POC TB diagnostic technologies in clinics in South Africa. The biobanked specimens collected can be rapidly utilised for nascent technologies. Studying the patient microbiome will provide insights into what makes some patients more susceptible to TB and what microbiological changes occur during the course of anti-TB treatment.

Conditions

Tuberculosis

Keywords

Xpert®MTB/RIF; Xpert®MTB/RIF Ultra

Outcome Measures

Primary Outcomes (1)

• Treatment time

  Time-specific proportion of patients starting TB treatment (all patients and confirmed cases) in centralised diagnosis and treatment arm compared to POC arm.

  Up to 8 weeks

Secondary Outcomes (3)

• TB diagnosis time

  Up to 8 weeks

• Time specific yield of Xpert Ultra

  Up to 8 weeks

• Airway and gut microbiome composition before, during, and after TB treatment

  Up to 18 months

Study Arms (2)

Centralised Xpert®Ultra testing

NO INTERVENTION

Patients are selected to receive the standard of care for TB diagnosis at a centralised laboratory facility

Xpert Ultra Point of Care testing

ACTIVE COMPARATOR

Patients are selected to receive the point of care for TB diagnosis at the clinic facility they are visiting

Diagnostic Test: Xpert Ultra Point of Care testing

Interventions

Xpert Ultra Point of Care testing DIAGNOSTIC_TEST

The intervention is the point of care Xpert Ultra TB diagnostic compared to the standard of care centralised TB testing at a centralised facility

Xpert Ultra Point of Care testing

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient is willing to provide specimens (urine, blood, stool, respiratory tract specimens and swabs)
• The patient is clinically suspected of having TB (Two WHO TB symptoms for HIV negative patients and one WHO TB symptom if HIV positive)

You may not qualify if:

• The patient is under the age of 18 years old
• The patient declines consent
• The patient has too few clinical symptoms for TB

Sponsors & Collaborators

• University of Stellenbosch: lead

Study Sites (2)

Scottsdene Clinic

Cape Town, Western Cape, 7570, South Africa

Location

Wallacedene Clinic

Cape Town, Western Cape, 7570, South Africa

Location

Related Publications (16)

• Theron G, Zijenah L, Chanda D, Clowes P, Rachow A, Lesosky M, Bara W, Mungofa S, Pai M, Hoelscher M, Dowdy D, Pym A, Mwaba P, Mason P, Peter J, Dheda K; TB-NEAT team. Feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing for tuberculosis in primary-care settings in Africa: a multicentre, randomised, controlled trial. Lancet. 2014 Feb 1;383(9915):424-35. doi: 10.1016/S0140-6736(13)62073-5. Epub 2013 Oct 28.

  PMID: 24176144 BACKGROUND

• Johnson R, Warren R, Strauss OJ, Jordaan AM, Falmer AA, Beyers N, Schaaf HS, Murray M, Cloete K, van Helden PD, Victor TC. An outbreak of drug-resistant tuberculosis caused by a Beijing strain in the western Cape, South Africa. Int J Tuberc Lung Dis. 2006 Dec;10(12):1412-4.

  PMID: 17167961 BACKGROUND

• Petti CA, Polage CR, Quinn TC, Ronald AR, Sande MA. Laboratory medicine in Africa: a barrier to effective health care. Clin Infect Dis. 2006 Feb 1;42(3):377-82. doi: 10.1086/499363. Epub 2005 Dec 20.

  PMID: 16392084 BACKGROUND

• Detjen AK, DiNardo AR, Leyden J, Steingart KR, Menzies D, Schiller I, Dendukuri N, Mandalakas AM. Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in children: a systematic review and meta-analysis. Lancet Respir Med. 2015 Jun;3(6):451-61. doi: 10.1016/S2213-2600(15)00095-8. Epub 2015 Mar 24.

  PMID: 25812968 BACKGROUND

• Theron G, Peter J, Dowdy D, Langley I, Squire SB, Dheda K. Do high rates of empirical treatment undermine the potential effect of new diagnostic tests for tuberculosis in high-burden settings? Lancet Infect Dis. 2014 Jun;14(6):527-32. doi: 10.1016/S1473-3099(13)70360-8. Epub 2014 Jan 15.

  PMID: 24438820 BACKGROUND

• Marais BJ, Brittle W, Painczyk K, Hesseling AC, Beyers N, Wasserman E, van Soolingen D, Warren RM. Use of light-emitting diode fluorescence microscopy to detect acid-fast bacilli in sputum. Clin Infect Dis. 2008 Jul 15;47(2):203-7. doi: 10.1086/589248.

  PMID: 18532893 BACKGROUND

• Ling DI, Zwerling AA, Pai M. GenoType MTBDR assays for the diagnosis of multidrug-resistant tuberculosis: a meta-analysis. Eur Respir J. 2008 Nov;32(5):1165-74. doi: 10.1183/09031936.00061808. Epub 2008 Jul 9.

  PMID: 18614561 BACKGROUND

• Hillemann D, Rusch-Gerdes S, Richter E. Feasibility of the GenoType MTBDRsl assay for fluoroquinolone, amikacin-capreomycin, and ethambutol resistance testing of Mycobacterium tuberculosis strains and clinical specimens. J Clin Microbiol. 2009 Jun;47(6):1767-72. doi: 10.1128/JCM.00081-09. Epub 2009 Apr 22.

  PMID: 19386845 BACKGROUND

• Kiet VS, Lan NT, An DD, Dung NH, Hoa DV, van Vinh Chau N, Chinh NT, Farrar J, Caws M. Evaluation of the MTBDRsl test for detection of second-line-drug resistance in Mycobacterium tuberculosis. J Clin Microbiol. 2010 Aug;48(8):2934-9. doi: 10.1128/JCM.00201-10. Epub 2010 Jun 23.

  PMID: 20573868 BACKGROUND

• 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.

  PMID: 20825313 BACKGROUND

• 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.

  PMID: 21507477 BACKGROUND

• Theron G, Peter J, van Zyl-Smit R, Mishra H, Streicher E, Murray S, Dawson R, Whitelaw A, Hoelscher M, Sharma S, Pai M, Warren R, Dheda K. Evaluation of the Xpert MTB/RIF assay for the diagnosis of pulmonary tuberculosis in a high HIV prevalence setting. Am J Respir Crit Care Med. 2011 Jul 1;184(1):132-40. doi: 10.1164/rccm.201101-0056OC. Epub 2011 Apr 14.

  PMID: 21493734 BACKGROUND

• Warren RM, Streicher EM, Gey van Pittius NC, Marais BJ, van der Spuy GD, Victor TC, Sirgel F, Donald PR, van Helden PD. The clinical relevance of Mycobacterial pharmacogenetics. Tuberculosis (Edinb). 2009 May;89(3):199-202. doi: 10.1016/j.tube.2009.03.001. Epub 2009 May 1.

  PMID: 19409848 BACKGROUND

• Jacobson KR, Theron D, Kendall EA, Franke MF, Barnard M, van Helden PD, Victor TC, Streicher EM, Murray MB, Warren RM. Implementation of genotype MTBDRplus reduces time to multidrug-resistant tuberculosis therapy initiation in South Africa. Clin Infect Dis. 2013 Feb;56(4):503-8. doi: 10.1093/cid/cis920. Epub 2012 Oct 22.

  PMID: 23090928 BACKGROUND

• Theron G, Peter J, Calligaro G, Meldau R, Hanrahan C, Khalfey H, Matinyenya B, Muchinga T, Smith L, Pandie S, Lenders L, Patel V, Mayosi BM, Dheda K. Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments. Sci Rep. 2014 Jul 11;4:5658. doi: 10.1038/srep05658.

  PMID: 25014250 BACKGROUND

• Zifodya JS, Kreniske JS, Schiller I, Kohli M, Dendukuri N, Schumacher SG, Ochodo EA, Haraka F, Zwerling AA, Pai M, Steingart KR, Horne DJ. Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis. Cochrane Database Syst Rev. 2021 Feb 22;2(2):CD009593. doi: 10.1002/14651858.CD009593.pub5.

  PMID: 33616229 DERIVED

Related Links

• WHO Global tuberculosis report 2016
• WHO Global tuberculosis report 2012
• WHO Xpert MTB/RIF implementation manual 2014
• WHO Expert group meeting report. The use of molecular line probe assay for the detection of resistance to second-line anti-tuberculosis drugs. 2013

MeSH Terms

Conditions

Tuberculosis

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Grant Theron, PhD

  University of Stellenbosch

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: DIAGNOSTIC
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: October 26, 2017
• First Posted: November 29, 2017
• Study Start: February 6, 2018
• Primary Completion: June 30, 2022
• Study Completion: June 30, 2022
• Last Updated: November 2, 2022

Record last verified: 2022-11

Locations

ZA (2)