Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 416
- 试验地点
- 1
- 主要终点
- Hierarchical composite outcome
研究概览
简要总结
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.
详细描述
Pneumocystis jirovecii pneumonia (PCP) 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, PCP 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 PCP therapy, we recently performed a systematic review and meta-analysis of reduced dose regimens of TMP-SMX in the treatment of PCP 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 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, new mechanical ventilation, or change in treatment by Day 30.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
盲法说明
Placebo
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •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
研究组 & 干预措施
Reduced dose TMP-SMX
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.
干预措施: trimethoprim-sulfamethoxazole (Drug)
Standard dose TMP-SMX
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.
干预措施: trimethoprim-sulfamethoxazole (Drug)
结局指标
主要结局
Hierarchical composite outcome
时间窗: Day 30
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)
次要结局
- Proportion of patients that die (death)(Day 30)
- Proportion of patients with a need for new extracorporeal membrane oxygenation (ECMO)(Day 30)
- Proportion of patients requiring new Invasive Mechanical Ventilation(Day 30)
- . Proportion of patients with severe (CTCAE grade 4) adverse drug event(Day 30)
- Proportion of patients with need for new non-invasive ventilation(Day 30)
- Proportion of patients requiring escalation or change of PCP -directed therapy(Day 30)
- Median length of stay in hospital amongst survivors(Day 30)
研究者
Todd C. Lee MD MPH FIDSA
Professor of Medicine
McGill University Health Centre/Research Institute of the McGill University Health Centre