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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат trimethoprim-sulfamethoxazole
  10mg/kg/day of TMP component
• Препарат trimethoprim-sulfamethoxazole
  15mg/kg/day of TMP component

Первичные конечные точки

• Hierarchical composite outcome [Срок оценки: Day 30]

Вторичные конечные точки (7)

• Proportion of patients that die (death) [Срок оценки: Day 30]
• Proportion of patients with a need for new extracorporeal membrane oxygenation (ECMO) [Срок оценки: Day 30]
• Proportion of patients requiring new Invasive Mechanical Ventilation [Срок оценки: Day 30]
• . Proportion of patients with severe (CTCAE grade 4) adverse drug event [Срок оценки: Day 30]
• Proportion of patients with need for new non-invasive ventilation [Срок оценки: Day 30]
• Proportion of patients requiring escalation or change of PCP -directed therapy [Срок оценки: Day 30]
• Median length of stay in hospital amongst survivors [Срок оценки: Day 30]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Четверное слепое

Основная цель

Лечение

Центры проведения

Канада · 1 центр

• McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital) — Montreal

Публикации

• 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. PMID 32391402
• Sohani ZN, Butler-Laporte G, Aw A, Belga S, Benedetti A, Carignan A, Cheng MP, Coburn B, Costiniuk CT, Ezer N, Gregson D, Johnson A, Khwaja K, Lawandi A, Leung V, Lother S, MacFadden D, McGuinty M, Parkes L, Qureshi S, Roy V, Rush B, Schwartz I, So M, Somayaji R, Tan D, Trinh E, Lee TC, McDonald EG. Low-dose trimethoprim-sulfamethoxazole for the treatment of Pneumocystis jirovecii pneumonia (LOW-T PMID 35863836

Идентификаторы

NCT: NCT04851015 · 2021-7386

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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