Low-dose trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (LOW-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial.

Pneumocystis jirovecii pneumonia (PJP) is an opportunistic infection of immunocompromised hosts with significant morbidity and mortality. The current standard of care, trimethoprim-sulfamethoxazole (TMP-SMX) at a dose of 15–20 mg/kg/day, is associated with serious adverse drug events (ADE) in 20%–60% of patients. ADEs include hypersensitivity reactions, drug-induced liver injury, cytopenias and renal failure, all of which can be treatment limiting. In a recent meta-analysis of observational studies, reduced dose TMP-SMX for the treatment of PJP was associated with fewer ADEs, without increased mortality. A phase III randomised, placebo-controlled, trial to directly compare the efficacy and safety of low-dose TMP-SMX (10 mg/kg/day of TMP) with the standard of care (15 mg/kg/day of TMP) among patients with PJP, for a composite primary outcome of change of treatment, new mechanical ventilation, or death. The trial will be undertaken at 16 Canadian hospitals. Data will be analysed as intention to treat. Primary and secondary outcomes will be compared using logistic regression adjusting for stratification and presented with 95% CI. This study has been conditionally approved by the McGill University Health Centre; Ethics approval will be obtained from all participating centres. Results will be submitted for publication in a peer-reviewed journal. NCT04851015.

耶氏肺孢子菌肺炎（PJP）是免疫功能低下宿主易患的一种机会性感染，具有较高的发病率和死亡率。目前的标准治疗方案是使用复方磺胺甲恶唑（TMP - SMX），剂量为15 - 20毫克/千克/天，但20% - 60%的患者会出现严重的药物不良事件（ADE）。药物不良事件包括过敏反应、药物性肝损伤、血细胞减少和肾衰竭，所有这些都可能限制治疗的进行。在最近一项对观察性研究的荟萃分析中，降低剂量的TMP - SMX用于治疗PJP时，药物不良事件较少，且未增加死亡率。 一项III期随机、安慰剂对照试验，旨在直接比较低剂量TMP - SMX（TMP剂量为10毫克/千克/天）与标准治疗（TMP剂量为15毫克/千克/天）在PJP患者中的疗效和安全性，主要复合终点为治疗方案改变、开始新的机械通气或死亡。该试验将在加拿大16家医院开展。数据将按意向性治疗分析。主要和次要结局将采用逻辑回归进行比较，并针对分层因素进行调整，结果以95%置信区间呈现。 本研究已获得麦吉尔大学健康中心的有条件批准；伦理审批将从所有参与中心获取。研究结果将提交至同行评审期刊发表。 临床试验编号：NCT04851015 。