Pneumocystis Pneumonia Clinical Trial
Official title:
Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia
Pneumocystis jirovecii pneumonia (PJP) 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 PJP 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 PJP for the primary outcome of death, new mechanical ventilation, and change of treatment.
Pneumocystis jirovecii pneumonia (PJP) is an opportunistic fungal infection primarily affecting immunocompromised patients. Adults with HIV (particularly CD4 ≤200 cells/µL), solid organ and allogeneic hematopoietic stem cell transplant recipients, as well as patients on certain chemotherapies, immunosuppressant drugs, and systemic corticosteroids are at a highest risk. Although routine primary prophylaxis has diminished its prevalence, PJP still results in significant morbidity and mortality worldwide. Retrospective cohort studies have reported mortality rates between 20-50% among non-HIV populations and 10-20% for patients with HIV. Current guidelines from the National Institutes of Health (NIH), the HIV Medicine Association of the Infectious Diseases Society of America (IDSA), and the American Society of Transplantation (AST) all recommend weight-based trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15-20 mg/kg/day of the trimethoprim component as the standard of care. Yet, higher doses of TMP-SMX are associated with serious adverse events, including hypersensitivity reactions, drug-induced liver injury, cytopenia, and renal failure with adverse drug events (ADEs) reported among 20-60% of patients on treatment. To better inform the optimal dosing strategy for PJP therapy, we recently performed a systematic review and meta-analysis of reduced dose regimens of TMP-SMX in the treatment of PJP among immunocompromised adult patients with and without HIV. When comparing standard doses to reduced doses (≤10mg/kg/day of the TMP component), there was no statistically significant difference in mortality (absolute risk difference: -9% in favor of reduced dose, 95% CI: -27% to 8%) with a corresponding 18% (95% CI: -31% to -5%) absolute risk reduction of Grade III or higher adverse events. These data provide the best available evidence for treatment equipoise and highlight the need for a randomized controlled trial to directly compare dosing strategies. The primary objective of this trial is to determine whether treatment with reduced-dose TMP-SMX (10mg/kg/day) is superior to standard dose (15mg/kg/day) among immunocompromised HIV-infected and uninfected patients with PJP for the composite primary outcome of death, new mechanical ventilation, or change in treatment by Day 21. ;
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