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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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.
Divala , T H , Fielding , K L , Sloan , D J , French , N , Nliwasa , M , MacPherson , P , Kandulu , C C , Chiume , L , Chilanga , S , Ndaferankhande , M J & Corbett , E L 2020 , ' Accuracy and consequences of using trial-of-antibiotics for TB diagnosis (ACT-TB study) : protocol for a randomised controlled clinical trial ' , BMJ Open , vol. 10 , no. 3 , e033999 . https://doi.org/10.1136/bmjopen-2019-033999
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DescriptionThe 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.
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