1 van den Elsen SHJ, et al. BMJ Open 2020;10:e035350. doi:10.1136/bmjopen-2019-035350 Open access Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study Simone HJ van den Elsen, 1 Marieke GG Sturkenboom, 1 Onno Akkerman, 2,3 Linda Barkane, 4 Judith Bruchfeld, 5,6 Geoffrey Eather, 7 Scott K Heysell, 8 Henadz Hurevich, 9 Liga Kuksa, 4 Heinke Kunst, 10 Johanna Kuhlin, 5,6 Katerina Manika, 11 Charalampos Moschos, 12 Stellah G Mpagama, 13 Marcela Muñoz Torrico, 14 Alena Skrahina, 9 Giovanni Sotgiu, 15 Marina Tadolini, 16 Simon Tiberi, 17 Francesca Volpato, 16 Tjip S van der Werf, 2,18 Malcolm R Wilson, 7 Joaquin Zúñiga, 19,20 Daan J Touw, 1 Giovanni B Migliori, 21 Jan-Willem Alffenaar 1,22 To cite: van den Elsen SHJ, Sturkenboom MGG, Akkerman O, et al. Prospective evaluation of improving fluoroquinolone exposure using centralised therapeutic drug monitoring (TDM) in patients with tuberculosis (PERFECT): a study protocol of a prospective multicentre cohort study. BMJ Open 2020;10:e035350. doi:10.1136/ bmjopen-2019-035350 ► Prepublication history and additional material for this paper are available online. To view these files, please visit the journal online (http://dx.doi. org/10.1136/bmjopen-2019- 035350). DJT, GBM and J-WA contributed equally. Received 29 October 2019 Revised 06 March 2020 Accepted 21 May 2020 For numbered affiliations see end of article. Correspondence to Dr Jan-Willem Alffenaar; j.w.c.alffenaar@umcg.nl Protocol © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. ABSTRACT Introduction Global multidrug-resistant tuberculosis (MDR-TB) treatment success rates remain suboptimal. Highly active WHO group A drugs moxifloxacin and levofloxacin show intraindividual and interindividual pharmacokinetic variability which can cause low drug exposure. Therefore, therapeutic drug monitoring (TDM) of fluoroquinolones is recommended to personalise the drug dosage, aiming to prevent the development of drug resistance and optimise treatment. However, TDM is considered laborious and expensive, and the clinical benefit in MDR-TB has not been extensively studied. This observational multicentre study aims to determine the feasibility of centralised TDM and to investigate the impact of fluoroquinolone TDM on sputum conversion rates in patients with MDR-TB compared with historical controls. Methods and analysis Patients aged 18 years or older with sputum smear and culture-positive pulmonary MDR- TB will be eligible for inclusion. Patients receiving TDM using a limited sampling strategy (t=0 and t=5 hours) will be matched to historical controls without TDM in a 1:2 ratio. Sample analysis and dosing advice will be performed in a centralised laboratory. Centralised TDM will be considered feasible if >80% of the dosing recommendations are returned within 7 days after sampling and 100% within 14 days. The number of patients who are sputum smear and culture-negative after 2 months of treatment will be determined in the prospective TDM group and will be compared with the control group without TDM to determine the impact of TDM. Ethics and dissemination Ethical clearance was obtained by the ethical review committees of the 10 participating hospitals according to local procedures or is pending (online supplementary file 1). Patients will be included after obtaining written informed consent. We aim to publish the study results in a peer-reviewed journal. Trial registration number ClinicalTrials.gov Registry (NCT03409315). INTRODUCTION Tuberculosis (TB) is one of the major infec- tious diseases worldwide with an estimated number of 10 million new cases in 2017. 1 In addition, multidrug-resistant TB (MDR-TB) Strengths and limitations of this study ► To our knowledge, this is the first study that investi- gates the impact of fluoroquinolone therapeutic drug monitoring (TDM) on sputum smear and culture con- version rates in prospective patients with multidrug- resistant tuberculosis (MDR-TB) versus historical controls without TDM. ► The feasibility for centralised TDM will be evaluated due to the participation of multiple healthcare cen- tres located in differently-resourced countries from multiple regions in the world. ► The use of limited sampling strategies will reduce the burden of TDM for patients and healthcare pro- viders while still providing a reliable estimation of drug exposure. ► A limitation is that this study focuses on TDM for moxifloxacin and levofloxacin only, being core drugs in MDR-TB treatment, without assessing other (core) anti-TB drugs. on February 23, 2022 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2019-035350 on 16 June 2020. Downloaded from