Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia

Study Overview
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Brief Summary
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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
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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.

Official Title
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Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia

Conditions
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Pneumocystis Jirovecii Infection, Pneumocystis, Pneumocystis Pneumonia, Pneumocystis Infections, Pneumocystis Carinii Infection, Pneumocystosis; Pneumonia (Etiology), Pneumocystis Carinii; Infection, Resulting From HIV Disease, Pneumocystosis Associated With AIDS

Intervention / Treatment
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* Drug: trimethoprim-sulfamethoxazole
* Drug: trimethoprim-sulfamethoxazole


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced dose TMP-SMX<br>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. | Drug: trimethoprim-sulfamethoxazole<br>* 10mg/kg/day of TMP component<br>* Other names: Reduced dose;|
| Active Comparator: Standard dose TMP-SMX<br>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. | Drug: trimethoprim-sulfamethoxazole<br>* 15mg/kg/day of TMP component<br>* Other names: Standard dose;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion with Treatment failure | Composite of death, new mechanical ventilation or treatment change for presumed inefficacy or severe adverse events | 21 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion who die | All cause mortality | 21 days | 
| Proportion who require new mechanical ventilation | A new requirement for mechanical ventilation | 21 days | 
| Proportion with treatment change due to inefficacy | Treatment change for presumed inefficacy | 21 days | 
| Proportion with treatment change due to toxicity | Treatment change for drug toxicity | 21 days | 
| Proportion with ongoing oxygen need | Requirement for oxygen according to guidelines for oxygen use in hospitalized patients | Day 7 | 
| Proportion with ongoing oxygen need | Requirement for oxygen according to guidelines for oxygen use in hospitalized patients | Day 14 | 
| Proportion with ongoing oxygen need | Requirement for oxygen according to guidelines for oxygen use in hospitalized patients | Day 21 | 
| Proportion requiring new non-invasive ventilation | New non-invasive ventilation (e.g. BiPAP, high-flow nasal canulae) | 21 days | 
| 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 | 
| Proportion with hyperkalemia | Proportion with Grade 3 or 4 hyperkalemia (non-hemolyzed sample) by Common Terminology Criteria for Adverse Events definition | 21 days | 
| Proportion with drug-induced hepatitis | Proportion with Grade 3 or 4 drug-induced hepatitis by Common Terminology Criteria for Adverse Events definition | 21 days | 
| 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 | 
| Proportion with new cytopenias | Proportion with development of new Grade 3 or 4 cytopenias by Common Terminology Criteria for Adverse Events definition | 21 days | 
| Proportion with hypoglycemia | Proportion with greater than 3 episodes of documented capillary or blood hypoglycemia (≤2.5mmol/L) | 21 days | 
| 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 | 
| Quality of life measured by visual analog scale | Measured by VAS for quality of life (higher is better from 0-100) | Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PCP, Pneumocystis, PJP