Pneumocystis jirovecii pneumonia (PCP) is an opportunistic fungal infection of immunocompromised hosts which causes in significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day of TMP, is associated with serious adverse events, including hypersensitivity reactions, drug-induced liver injury, cytopenia, and renal failure occurring among 20-60% of patients. The frequency of adverse events increases in a dose dependent manner and commonly limits the use of TMP-SMX.
Reduced treatment doses of TMP-SMX for PCP reduced ADEs without mortality differences in a recent meta-analysis of observational studies. We therefore propose a Phase III randomized, placebo-controlled trial to directly compare the efficacy and safety of low dose (10 mg/kg/day of TMP) compared to the standard-of-care (15 mg/kg/day) among patients with PCP for the primary outcome of Win Ratio hierarchical composite of death, ECMO, invasive ventilation, grade 4 toxicity, non-invasive ventilation, change of therapy and length of stay.
18 years or older
Immunocompromised (including but not limited to HIV, solid organ transplant, solid tumors, hematological stem cell transplant and malignancies, systemic diseases, chemotherapy, long term corticosteroid use, and immunosuppressive therapies, as well as primary immunodeficiencies
Presentation to a day hospital, emergency department, or admitted to hospital
Proven or probable diagnosis of PCP using an adapted version of the 2021 EORTC/MSGERC criteria.
Previous severe adverse reaction to TMP-SMX, any sulfa drug, or any component of formulation
Compliant with PCP prophylaxis for ≥4 weeks with TMP-SMX at enrollment
More than 96 hours of any therapy for PCP
Hepatic impairment marked by alanine aminotransferase levels ≥5 times the upper limit of normal
Parallel
trimethoprim-sulfamethoxazole
Drug10mg/kg/day of TMP component
trimethoprim-sulfamethoxazole
Drug15mg/kg/day of TMP component
Hierarchical composite outcome
Hierarchical composite of Win Ratio at day 30: * death; * new extracorporeal membrane oxygenation (ECMO), * new invasive mechanical ventilation; * severe (CTCAE grade 4) adverse drug event (dermatologic, nephrologic, hematologic, neurologic, and/or endocrinologic) considered at least probable (by Leape and Bates criteria); * new non-invasive ventilation; * change of therapy (i.e., dose or agent) due to presumed treatment failure or probable adverse drug reaction (by Leape and Bates criteria); and * length of stay in hospital (amongst survivors)
Proportion of patients that die (death)
All cause mortality
Proportion of patients with a need for new extracorporeal membrane oxygenation (ECMO)
New initiation of extracorporeal membrane oxygenation during hospitalization following initiation of assigned PCP treatment strategy.
Proportion of patients requiring new Invasive Mechanical Ventilation
Initiation of invasive mechanical ventilation via endotracheal intubation during hospitalization following initiation of the assigned PCP treatment strategy.
. Proportion of patients with severe (CTCAE grade 4) adverse drug event
Proportion of patients with occurence of severe (CTCAE grade 4) adverse drug event (dermatologic, nephrologic, hematologic, neurologic, and/or endocrinologic) considered at least probable (by Leape and Bates criteria).
Tertiary outcome measure of quality of life at day 30
Quality of life (EQ-5D-5L) wherein a higher score indicates better quality of life.
Tertiary outcome measure of all-cause mortality
All-cause mortality, defined as death from any cause.
Tertiary Outcome Measure of PCP recurrence
Recurrence of pneumocystis pneumonia, defined as a new episode of clinically and/or microbiologically confirmed PCP after initial resolution.
Tertiary Outcome measure of quality of life at day 180
Quality of life assessed using a EQ-5D-5L questionnaire. High score indicates better quality of life.
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Todd C. Lee MD MPH FIDSA
Lead sponsor
McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor institution
