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  • Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study): protocol for a randomised controlled clinical trial

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Infectious diseases
Protocol
Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study): protocol for a randomised controlled clinical trial
  1. Titus Henry Divala1,2,3,
  2. Katherine L Fielding1,4,
  3. Derek J Sloan5,
  4. Neil French6,
  5. Marriott Nliwasa1,2,
  6. Peter MacPherson3,7,
  7. Chikondi Charity Kandulu2,3,
  8. Lingstone Chiume2,3,
  9. Sanderson Chilanga2,3,
  10. Masiye John Ndaferankhande3,
  11. Elizabeth L Corbett1,2,3
  1. 1TB Centre, London School of Hygiene and Tropical Medicine, London, UK
  2. 2Helse Nord Tuberculosis Initiative, University of Malawi College of Medicine, Blantyre, Malawi
  3. 3Malawi-Liverpool Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi
  4. 4School of Public Health, University of the Witwatersrand, Johannesburg-Braamfontein, Gauteng, South Africa
  5. 5School of Medicine, University of Saint Andrews, Saint Andrews, Fife, UK
  6. 6Institute of Infection and Global Health, University of Liverpool Faculty of Health and Life Sciences, Liverpool, UK
  7. 7Clinical Sciences, Liverpool School of Tropical Medicine, Liverpool, UK
  1. Correspondence to Dr Titus Henry Divala; titus.divala{at}lshtm.ac.uk

Abstract

Introduction Over 40% of global tuberculosis case notifications are diagnosed clinically without mycobacteriological confirmation. Standard diagnostic algorithms include ‘trial-of-antibiotics’—empirical antibiotic treatment given to mycobacteriology-negative individuals to treat infectious causes of symptoms other than tuberculosis, as a ‘rule-out’ diagnostic test for tuberculosis. Potentially 26.5 million such antibiotic courses/year are prescribed globally for the 5.3 million/year mycobacteriology-negative patients, making trial-of-antibiotics the most common tuberculosis diagnostic, and a global-scale risk for antimicrobial resistance (AMR). Our systematic review found no randomised controlled trial (RCT) to support use of trial-of-antibiotic. The RCT aims to determine the diagnostic and clinical value and AMR consequences of trial-of-antibiotics.

Methods and analysis A three-arm, open-label, RCT randomising (1:1:1) Malawian adults (≥18 years) seeking primary care for cough into: (a) azithromycin 500 mg one time per day for 3 days or (b) amoxicillin 1 g three times per day for 5 days or (c) standard-of-care (no immediate antibiotic). We will perform mycobacteriology tests (microscopy, Xpert MTB/RIF (Mycobacterium tuberculosis/rifampicin) and Mycobacterium tuberculosis culture) at baseline. We will use audiocomputer-assisted self-interview to assess clinical improvement at day 8. First primary outcome will be proportion of patients reporting day 8 improvement out of those with negative mycobacteriology (specificity). Second primary outcome will be day 29 incidence of a composite endpoint of either death or hospitalisation or missed tuberculosis diagnosis. To determine AMR impact we compare proportion of resistant nasopharyngeal Streptococcus pneumoniae isolates on day 29. 400 mycobacteriology-negative participants/arm will be required to detect a ≥10% absolute difference in diagnostic specificity with 80% power. We will estimate measures of effect by comparing outcomes in antibiotic arms (combined and individually) to standard-of-care.

Ethics and dissemination The study has been reviewed and approved by Malawi College of Medicine Research and Ethics Committee, London School of Hygiene & Tropical Medicine (LSHTM) Research Ethics Committee and Regional Committee for Health and Research Ethics – Norway, and Malawi Pharmacy, Medicines and Poisons Board. We will present abstracts at relevant conferences, and prepare a manuscript for publication in a peer-reviewed journal.

Trial registration number The clinical trial is registered with ClinicalTrials.gov, NCT03545373

  • trial-of-antibiotics
  • tuberculosis
  • TB
  • antimicrobial resistance
  • diagnostic performance
  • antibiotics
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2019-033999

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    Footnotes

    • Twitter @TDivala

    • Contributors THD, KF and ELC are the main contributors to the conception, and design of the study. DS, MN and PM contributed to the general study planning and clinical design. NF contributed to the general study planning and antimicrobial resistance design. CK, LC, SC, and MJN contributed to the design, piloting and refining of study and clinical procedures. THD developed the first draft of the manuscript. All authors carefully reviewed and substantially contributed to the development of the trial protocol and this manuscript. All authors read and approved the final manuscript. THD is the guarantor for this work.

    • Funding The clinical trial is funded by the Commonwealth Scholarship Commission and the Helse Nord RHF grant awarded to THD. This work is part of THD’s PhD work at London School of Hygiene & Tropical Medicine (LSHTM). LSHTM is the sponsor of this clinical trial (sponsor address: Keppel Street, Bloomsbury, London WC1E 7HT). ELC is funded by a Wellcome Trust Senior Research Fellowship in Clinical Science: WT200901.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting or dissemination plans of this research. Refer to the Methods section for further details.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.