Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP)

David Ekqvist; Anna Bornefall; Daniel Augustinsson; Martina Sönnerbrandt; Michaela Jonsson Nordvall; Mats Fredrikson; Björn Carlsson; Mårten Sandstedt; Ulrika S H Simonsson; Jan-Willem C Alffenaar; Jakob Paues; Katarina Niward

doi:10.1136/bmjopen-2021-054788

Safety and pharmacokinetics-pharmacodynamics of a shorter tuberculosis treatment with high-dose pyrazinamide and rifampicin: a study protocol of a phase II clinical trial (HighShort-RP)

BMJ Open. 2022 Mar 10;12(3):e054788. doi: 10.1136/bmjopen-2021-054788.

Affiliations

¹ Department of Infectious Diseases, Region Östergötland, Linköping University, Linköping, Sweden.
² Department of Infectious Diseases, Region Östergötland, Linköping, Sweden.
³ Department of Infectious Diseases, Region Östergötland, Norrköping, Sweden.
⁴ Department of Clinical Microbiology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁵ Forum Östergötland, Linköping University, Linköping, Sweden.
⁶ Department of Clinical Pharmacology, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
⁷ Department of Radiology in Linköping, and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden.
⁸ Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
⁹ School of Pharmacy, The University of Sydney Faculty of Medicine and Health, Sydney, New South Wales, Australia.
¹⁰ Sydney Institute for Infectious Diseases, The University of Sydney, Sydney, New South Wales, Australia.
¹¹ Westmead Hospital, Sydney, New South Wales, Australia.
¹² Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Linköping University, Linkoping, Sweden.
¹³ Department of Infectious Diseases, and Department of Biomedical and Clinical Sciences, Linköping University, Linkoping, Sweden katarina.niward@liu.se.

Abstract

Introduction: Increased dosing of rifampicin and pyrazinamide seems a viable strategy to shorten treatment and prevent relapse of drug-susceptible tuberculosis (TB), but safety and efficacy remains to be confirmed. This clinical trial aims to explore safety and pharmacokinetics-pharmacodynamics of a high-dose pyrazinamide-rifampicin regimen.

Methods and analysis: Adult patients with pulmonary TB admitted to six hospitals in Sweden and subjected to receive first-line treatment are included. Patients are randomised (1:3) to either 6-month standardised TB treatment or a 4-month regimen based on high-dose pyrazinamide (40 mg/kg) and rifampicin (35 mg/kg) along with standard doses of isoniazid and ethambutol. Plasma samples for measurement of drug exposure determined by liquid chromatography tandem-mass spectrometry are obtained at 0, 1, 2, 4, 6, 8, 12 and 24 hours, at day 1 and 14. Maximal drug concentration (C_max) and area under the concentration-time curve (AUC_0-24h) are estimated by non-compartmental analysis. Conditions for early model-informed precision dosing of high-dose pyrazinamide-rifampicin are pharmacometrically explored. Adverse drug effects are monitored throughout the study and graded according to Common Terminology Criteria for Adverse Events V.5.0. Early bactericidal activity is assessed by time to positivity in BACTEC MGIT 960 of induced sputum collected at day 0, 5, 8, 15 and week 8. Minimum inhibitory concentrations of first-line drugs are determined using broth microdilution. Disease severity is assessed with X-ray grading and a validated clinical scoring tool (TBscore II). Clinical outcome is registered according to WHO definitions (2020) in addition to occurrence of relapse after end of treatment. Primary endpoint is pyrazinamide AUC_0-24h and main secondary endpoint is safety.

Ethics and dissemination: The study is approved by the Swedish Ethical Review Authority and the Swedish Medical Products Agency. Informed written consent is collected before study enrolment. The study results will be submitted to a peer-reviewed journal.

Trial registration number: NCT04694586.

Keywords: adverse events; clinical pharmacology; clinical trials; tuberculosis.

Publication types

Clinical Trial Protocol
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Antitubercular Agents / therapeutic use
Clinical Trials, Phase II as Topic
Drug Therapy, Combination
Humans
Isoniazid / therapeutic use
Pyrazinamide*
Randomized Controlled Trials as Topic
Recurrence
Rifampin
Tuberculosis* / chemically induced
Tuberculosis* / drug therapy

Substances

Antitubercular Agents
Pyrazinamide
Isoniazid
Rifampin

Associated data

ClinicalTrials.gov/NCT04694586