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Clinical Trial Details — Status: Not yet recruiting

Administrative data

NCT number NCT04851015
Other study ID # 2021-7386
Secondary ID
Status Not yet recruiting
Phase Phase 3
First received
Last updated
Start date June 2022
Est. completion date March 2026

Study information

Verified date April 2022
Source McGill University Health Centre/Research Institute of the McGill University Health Centre
Contact Sarah Elsayed
Phone 514-934-1934
Email sarah.elsayed@idtrials.com
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


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.


Recruitment information / eligibility

Status Not yet recruiting
Enrollment 300
Est. completion date March 2026
Est. primary completion date December 2025
Accepts healthy volunteers No
Gender All
Age group 18 Years to 100 Years
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
trimethoprim-sulfamethoxazole
10mg/kg/day of TMP component
trimethoprim-sulfamethoxazole
15mg/kg/day of TMP component

Locations

Country Name City State
Canada McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital) Montreal Quebec

Sponsors (1)

Lead Sponsor Collaborator
McGill University Health Centre/Research Institute of the McGill University Health Centre

Country where clinical trial is conducted

Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Other Proportion with all cause mortality All cause mortality 90 days
Other Proportion with at least 1 recurrence of Pneumocystis A subsequent diagnosis of pneumocystis pneumonia occurring between days 22 and 90 90 days
Primary Proportion with Treatment failure Composite of death, new mechanical ventilation or treatment change for presumed inefficacy or severe adverse events 21 days
Secondary Proportion who die All cause mortality 21 days
Secondary Proportion who require new mechanical ventilation A new requirement for mechanical ventilation 21 days
Secondary Proportion with treatment change due to inefficacy Treatment change for presumed inefficacy 21 days
Secondary Proportion with treatment change due to toxicity Treatment change for drug toxicity 21 days
Secondary Proportion with ongoing oxygen need Requirement for oxygen according to guidelines for oxygen use in hospitalized patients Day 7
Secondary Proportion with ongoing oxygen need Requirement for oxygen according to guidelines for oxygen use in hospitalized patients Day 14
Secondary Proportion with ongoing oxygen need Requirement for oxygen according to guidelines for oxygen use in hospitalized patients Day 21
Secondary Proportion requiring new non-invasive ventilation New non-invasive ventilation (e.g. BiPAP, high-flow nasal canulae) 21 days
Secondary 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
Secondary Proportion with hyperkalemia Proportion with Grade 3 or 4 hyperkalemia (non-hemolyzed sample) by Common Terminology Criteria for Adverse Events definition 21 days
Secondary Proportion with drug-induced hepatitis Proportion with Grade 3 or 4 drug-induced hepatitis by Common Terminology Criteria for Adverse Events definition 21 days
Secondary 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
Secondary Proportion with new cytopenias Proportion with development of new Grade 3 or 4 cytopenias by Common Terminology Criteria for Adverse Events definition 21 days
Secondary Proportion with hypoglycemia Proportion with greater than 3 episodes of documented capillary or blood hypoglycemia (=2.5mmol/L) 21 days
Secondary 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
Secondary Quality of life measured by visual analog scale Measured by VAS for quality of life (higher is better from 0-100) Day 28
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