Clinical trial NCT04851015: Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia
Official title: Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE3
Conditions: Pneumocystis
Pneumocystis Pneumonia
Pneumocystis Jirovecii Infection
Pneumocystis Infections
Pneumocystis Carinii Infection
Pneumocystosis; Pneumonia (Etiology)
Pneumocystis Carinii; Infection, Resulting From HIV Disease
Pneumocystosis Associated With AIDS
Keywords: Pneumocystis
PCP
PJP
Lead sponsor: McGill University Health Centre/Research Institute of the McGill University Health Centre
Sponsor class: OTHER
First posted: 2021-04-20
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Proportion with Treatment failure
timeFrame: 21 days
Secondary outcomes:
measure: Proportion who die
timeFrame: 21 days
measure: Proportion who require new mechanical ventilation
timeFrame: 21 days
measure: Proportion with treatment change due to inefficacy
timeFrame: 21 days
measure: Proportion with treatment change due to toxicity
timeFrame: 21 days
measure: Proportion with ongoing oxygen need
timeFrame: Day 7
measure: Proportion with ongoing oxygen need
timeFrame: Day 14
measure: Proportion with ongoing oxygen need
timeFrame: Day 21
measure: Proportion requiring new non-invasive ventilation
timeFrame: 21 days
measure: Proportion with new renal failure
timeFrame: 21 days
measure: Proportion with hyperkalemia
timeFrame: 21 days
measure: Proportion with drug-induced hepatitis
timeFrame: 21 days
measure: Proportion with Skin rash
timeFrame: 21 days
measure: Proportion with new cytopenias
timeFrame: 21 days
measure: Proportion with hypoglycemia
timeFrame: 21 days
measure: EQ-5D-5L
timeFrame: Day 28
measure: Quality of life measured by visual analog scale
timeFrame: Day 28
Other outcomes:
measure: Proportion with all cause mortality
timeFrame: 90 days
measure: Proportion with at least 1 recurrence of Pneumocystis
timeFrame: 90 days
Locations:
city: Montreal
country: Canada
facility: McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
state: Quebec
Study officials:
affiliation: Research Institute of the McGill University Health Centre
name: Emily G McDonald, MD MSc
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute of the McGill University Health Centre
name: Todd C Lee, MD MPH FIDSA
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Institute of the McGill University Health Centre
name: Zahra N Sohani, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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-TMP): protocol for a phase III randomised, placebo-controlled, dose-comparison trial. BMJ Open. 2022 Jul 21;12(7):e053039. doi: 10.1136/bmjopen-2021-053039.