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

Pneumocystis Pneumonia Clinical Trial

— LOW-TMP  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04851015
• Other study ID #: 2021-7386
• Status: Not yet recruiting
• Phase: Phase 3
• 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
• 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

Related Conditions & MeSH terms

• Communicable Diseases
• Infections
• Pneumocystis
• Pneumocystis Carinii Infection
• Pneumocystis Carinii; Infection, Resulting From HIV Disease
• Pneumocystis Infections
• Pneumocystis Jirovecii Infection
• Pneumocystis Pneumonia
• Pneumocystosis Associated With AIDS
• Pneumocystosis; Pneumonia (Etiology)
• Pneumonia
• Pneumonia, Pneumocystis

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