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

NCT ID: NCT04851015

Last Updated: 2024-11-19

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 300 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-01-31
• Study Completion Date: 2028-06-30

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.

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Reduced dose TMP-SMX

Trimethoprim-Sulfamethoxazole at a total dose of 10mg/kg/day. Oral or intravenous drug will be administered at discretion of treating team. This will be given as a dose of 10mg/kg/day open label with additional placebo tablets or intravenous placebo solution given to simulate 15mg/kg/day. All doses will be adjusted for obesity and renal function.

Group Type: EXPERIMENTAL

trimethoprim-sulfamethoxazole

Intervention Type: DRUG

10mg/kg/day of TMP component

Standard dose TMP-SMX

Trimethoprim-Sulfamethoxazole at a total dose of 15mg/kg/day. Oral or intravenous drug will be administered at discretion of treating team. This will be given as 10mg/kg/day open label plus an extra masked 5mg/kg/day of tablets or intravenous solution. All doses will be adjusted for obesity and renal function.

Group Type: ACTIVE_COMPARATOR

trimethoprim-sulfamethoxazole

Intervention Type: DRUG

15mg/kg/day of TMP component

Interventions

trimethoprim-sulfamethoxazole

10mg/kg/day of TMP component

Intervention Type: DRUG

trimethoprim-sulfamethoxazole

15mg/kg/day of TMP component

Intervention Type: DRUG

Other Intervention Names

Reduced dose; Standard dose

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 100 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

McGill University Health Centre/Research Institute of the McGill University Health Centre

OTHER

Sponsor Role: lead

Responsible Party

Todd C. Lee MD MPH FIDSA

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Emily G McDonald, MD MSc

Role: PRINCIPAL_INVESTIGATOR

Research Institute of the McGill University Health Centre

Todd C Lee, MD MPH FIDSA

Role: PRINCIPAL_INVESTIGATOR

Research Institute of the McGill University Health Centre

Zahra N Sohani, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Research Institute of the McGill University Health Centre

Locations

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

Montreal, Quebec, Canada

Countries

Canada

Central Contacts

Kristen Moran

Role: CONTACT

kristen.moran@mail.mcgill.ca

514-934-1934 ext. 23730

References

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.

Reference Type: BACKGROUND

PMID: 32391402 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 35863836 (View on PubMed)

Other Identifiers

2021-7386

Identifier Type: -

Identifier Source: org_study_id