Low-dose trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (LOW-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial

Zahra N Sohani, Guillaume Butler-Laporte, Andrew Aw, Sara Belga, Andrea Benedetti, Alex Carignan, Matthew P Cheng, Bryan Coburn, Cecilia T Costiniuk, Nicole Ezer, Dan Gregson, Andrew Johnson, Kosar Khwaja, Alexander Lawandi, Victor Leung, Sylvain Lother, Derek MacFadden, Michaeline McGuinty, Leighanne Parkes, Salman Qureshi, Valerie Roy, Barret Rush, Ilan Schwartz, Miranda So, Ranjani Somayaji, Darrell Tan, Emilie Trinh, Todd C Lee, Emily G McDonald, Zahra N Sohani, Guillaume Butler-Laporte, Andrew Aw, Sara Belga, Andrea Benedetti, Alex Carignan, Matthew P Cheng, Bryan Coburn, Cecilia T Costiniuk, Nicole Ezer, Dan Gregson, Andrew Johnson, Kosar Khwaja, Alexander Lawandi, Victor Leung, Sylvain Lother, Derek MacFadden, Michaeline McGuinty, Leighanne Parkes, Salman Qureshi, Valerie Roy, Barret Rush, Ilan Schwartz, Miranda So, Ranjani Somayaji, Darrell Tan, Emilie Trinh, Todd C Lee, Emily G McDonald

Abstract

Introduction: Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%-60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality.

Methods and analysis: A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI.

Ethics and dissemination: This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal.

Trial registration number: NCT04851015.

Keywords: Bone marrow transplantation; EPIDEMIOLOGY; HIV & AIDS; INFECTIOUS DISEASES; Protocols & guidelines; TRANSPLANT MEDICINE.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study design diagram. *50% dose reduction if CrCl 16–30 mL/min; 75% dose reduction if ≤15 mL/min. †Day 1 will represent first dose of study drug. PJP, Pneumocystis jirovecii pneumonia; TMP-SMX, trimethoprim-sulfamethoxazole. (uploaded separately).

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