Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia
- Conditions
- PneumocystisPneumocystis PneumoniaPneumocystis Jirovecii InfectionPneumocystis InfectionsPneumocystis Carinii InfectionPneumocystosis; Pneumonia (Etiology)Pneumocystis Carinii; Infection, Resulting From HIV DiseasePneumocystosis Associated With AIDS
- Interventions
- Drug: trimethoprim-sulfamethoxazole
- Registration Number
- NCT04851015
- Lead Sponsor
- McGill University Health Centre/Research Institute of the McGill University Health Centre
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 300
- 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 PJP 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 PJP prophylaxis for ≥4 weeks with TMP-SMX at enrollment
- More than 72 hours of any therapy for PJP
- Hepatic impairment marked by alanine aminotransferase levels ≥5 times the upper limit of normal
- Known G6PD deficiency
- Known diagnosis of porphyria
- Known pregnancy or breastfeeding (as per Health Canada)
- Unable to provide informed consent and no available healthcare proxy (with ethics approval for deferred consent in cases of critical illness); refusal of consent; no reliable means of outpatient contact (telephone/email/text);
- Previously enrolled
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Reduced dose TMP-SMX trimethoprim-sulfamethoxazole Trimethoprim-Sulfamethoxazole at a total dose of 10mg/kg/day. Oral or intravenous drug will be administered at discretion of treating team. This will be given as a dose of 10mg/kg/day open label with additional placebo tablets or intravenous placebo solution given to simulate 15mg/kg/day. All doses will be adjusted for obesity and renal function. Standard dose TMP-SMX trimethoprim-sulfamethoxazole Trimethoprim-Sulfamethoxazole at a total dose of 15mg/kg/day. Oral or intravenous drug will be administered at discretion of treating team. This will be given as 10mg/kg/day open label plus an extra masked 5mg/kg/day of tablets or intravenous solution. All doses will be adjusted for obesity and renal function.
- Primary Outcome Measures
Name Time Method Proportion with Treatment failure 21 days Composite of death, new mechanical ventilation or treatment change for presumed inefficacy or severe adverse events
- Secondary Outcome Measures
Name Time Method Proportion who die 21 days All cause mortality
Proportion who require new mechanical ventilation 21 days A new requirement for mechanical ventilation
Proportion with treatment change due to inefficacy 21 days Treatment change for presumed inefficacy
Proportion with treatment change due to toxicity 21 days Treatment change for drug toxicity
Proportion with ongoing oxygen need Day 21 Requirement for oxygen according to guidelines for oxygen use in hospitalized patients
Proportion requiring new non-invasive ventilation 21 days New non-invasive ventilation (e.g. BiPAP, high-flow nasal canulae)
Proportion with new renal failure 21 days New grade 3 or 4 renal failure by Common Terminology Criteria for Adverse Events definition and by modified KDIGO: increase in serum creatinine by≳26.5 umol/l within 48 hours; or increase in serum creatinine to ≳1.5 times baseline, which is known or presumed to have occurred within the prior 7 days; or new hemodialysis, wherein hemodialysis was not previously required.
Proportion with drug-induced hepatitis 21 days Proportion with Grade 3 or 4 drug-induced hepatitis by Common Terminology Criteria for Adverse Events definition
EQ-5D-5L Day 28 Quality of life as measured by EQ-5D-5L and interpreted based on Canadian value set (see Med Care. 2016 Jan;54(1):98-105)
Proportion with hyperkalemia 21 days Proportion with Grade 3 or 4 hyperkalemia (non-hemolyzed sample) by Common Terminology Criteria for Adverse Events definition
Proportion with Skin rash 21 days Proportion with development of a Grade 3 or 4 skin rash (by Common Terminology Criteria for Adverse Events definition) that was intolerable to the patient, persisted unabated for 48 hours or more, or had bullae or mucous-membrane involvement.
Proportion with new cytopenias 21 days Proportion with development of new Grade 3 or 4 cytopenias by Common Terminology Criteria for Adverse Events definition
Proportion with hypoglycemia 21 days Proportion with greater than 3 episodes of documented capillary or blood hypoglycemia (≤2.5mmol/L)
Quality of life measured by visual analog scale Day 28 Measured by VAS for quality of life (higher is better from 0-100)
Trial Locations
- Locations (1)
McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
🇨🇦Montreal, Quebec, Canada