Pneumocystis Pneumonia Clinical Trial
— LOW-TMPOfficial 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.
Status | Not yet recruiting |
Enrollment | 300 |
Est. completion date | March 2026 |
Est. primary completion date | December 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years to 100 Years |
Eligibility | Inclusion Criteria: - 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. Exclusion 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 |
Country | Name | City | State |
---|---|---|---|
Canada | McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital) | Montreal | Quebec |
Lead Sponsor | Collaborator |
---|---|
McGill University Health Centre/Research Institute of the McGill University Health Centre |
Canada,
Butler-Laporte G, Smyth E, Amar-Zifkin A, Cheng MP, McDonald EG, Lee TC. Low-Dose TMP-SMX in the Treatment of Pneumocystis jirovecii Pneumonia: A Systematic Review and Meta-analysis. Open Forum Infect Dis. 2020 Apr 2;7(5):ofaa112. doi: 10.1093/ofid/ofaa112. eCollection 2020 May. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | Proportion with all cause mortality | All cause mortality | 90 days | |
Other | Proportion with at least 1 recurrence of Pneumocystis | A subsequent diagnosis of pneumocystis pneumonia occurring between days 22 and 90 | 90 days | |
Primary | Proportion with Treatment failure | Composite of death, new mechanical ventilation or treatment change for presumed inefficacy or severe adverse events | 21 days | |
Secondary | Proportion who die | All cause mortality | 21 days | |
Secondary | Proportion who require new mechanical ventilation | A new requirement for mechanical ventilation | 21 days | |
Secondary | Proportion with treatment change due to inefficacy | Treatment change for presumed inefficacy | 21 days | |
Secondary | Proportion with treatment change due to toxicity | Treatment change for drug toxicity | 21 days | |
Secondary | Proportion with ongoing oxygen need | Requirement for oxygen according to guidelines for oxygen use in hospitalized patients | Day 7 | |
Secondary | Proportion with ongoing oxygen need | Requirement for oxygen according to guidelines for oxygen use in hospitalized patients | Day 14 | |
Secondary | Proportion with ongoing oxygen need | Requirement for oxygen according to guidelines for oxygen use in hospitalized patients | Day 21 | |
Secondary | Proportion requiring new non-invasive ventilation | New non-invasive ventilation (e.g. BiPAP, high-flow nasal canulae) | 21 days | |
Secondary | Proportion with new renal failure | 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. | 21 days | |
Secondary | Proportion with hyperkalemia | Proportion with Grade 3 or 4 hyperkalemia (non-hemolyzed sample) by Common Terminology Criteria for Adverse Events definition | 21 days | |
Secondary | Proportion with drug-induced hepatitis | Proportion with Grade 3 or 4 drug-induced hepatitis by Common Terminology Criteria for Adverse Events definition | 21 days | |
Secondary | Proportion with Skin rash | 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. | 21 days | |
Secondary | Proportion with new cytopenias | Proportion with development of new Grade 3 or 4 cytopenias by Common Terminology Criteria for Adverse Events definition | 21 days | |
Secondary | Proportion with hypoglycemia | Proportion with greater than 3 episodes of documented capillary or blood hypoglycemia (=2.5mmol/L) | 21 days | |
Secondary | EQ-5D-5L | 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) | Day 28 | |
Secondary | Quality of life measured by visual analog scale | Measured by VAS for quality of life (higher is better from 0-100) | Day 28 |
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