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

NCT04851015 | Recruiting Phase 3 DMC

• 1 other identifier: 2021-7386
• Study Type: interventional
• Target: 416
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Keywords

Pneumocystis; PCP; PJP; immunosuppressed; HIV; TMP-SMX

Outcome Measures

Primary Outcomes (1)

• Hierarchical composite outcome

  Hierarchical composite of Win Ratio at day 30: * death; * new extracorporeal membrane oxygenation (ECMO), * new invasive mechanical ventilation; * severe (CTCAE grade 4) adverse drug event (dermatologic, nephrologic, hematologic, neurologic, and/or endocrinologic) considered at least probable (by Leape and Bates criteria); * new non-invasive ventilation; * change of therapy (i.e., dose or agent) due to presumed treatment failure or probable adverse drug reaction (by Leape and Bates criteria); and * length of stay in hospital (amongst survivors)

  Day 30

Secondary Outcomes (7)

• Proportion of patients that die (death)

  Day 30

• Proportion of patients with a need for new extracorporeal membrane oxygenation (ECMO)

  Day 30

• Proportion of patients requiring new Invasive Mechanical Ventilation

  Day 30

• . Proportion of patients with severe (CTCAE grade 4) adverse drug event

  Day 30

• Proportion of patients with need for new non-invasive ventilation

  Day 30

Other Outcomes (4)

• Tertiary outcome measure of quality of life at day 30

  Day 30

• Tertiary outcome measure of all-cause mortality

  Day 180

• Tertiary Outcome Measure of PCP recurrence

  Day 180

Study Arms (2)

Reduced dose TMP-SMX

EXPERIMENTAL

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.

Drug: trimethoprim-sulfamethoxazole

Standard dose TMP-SMX

ACTIVE COMPARATOR

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.

Drug: trimethoprim-sulfamethoxazole

Interventions

trimethoprim-sulfamethoxazole DRUG

10mg/kg/day of TMP component

Also known as: Reduced dose

Reduced dose TMP-SMX

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Todd C. Lee MD MPH FIDSA: lead

Study Sites (1)

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

Montreal, Quebec, H4A3J1, Canada

RECRUITING

Related Publications (2)

• 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 BACKGROUND

• 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.

  PMID: 35863836 DERIVED

MeSH Terms

Conditions

Pneumonia, Pneumocystis; Pneumocystis Infections; Pneumonia; Infections

Interventions

Trimethoprim, Sulfamethoxazole Drug Combination; Off-Label Use

Condition Hierarchy (Ancestors)

Lung Diseases, Fungal; Mycoses; Bacterial Infections and Mycoses; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Sulfanilamides; Aniline Compounds; Amines; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Trimethoprim; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Drug Combinations; Pharmaceutical Preparations; Drug Prescriptions; Drug Therapy; Therapeutics

Study Officials

• Emily G McDonald, MD MSc

  Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

• Todd C Lee, MD MPH FIDSA

  Research Institute of the McGill University Health Centre

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Babykumari Chitramuthu, PhD

CONTACT

514-934-1934; babykumari.chitramuthu@muhc.mcgill.ca

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Placebo
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: April 12, 2021
• First Posted: April 20, 2021
• Study Start: November 28, 2025
• Primary Completion (Estimated): September 30, 2030
• Study Completion (Estimated): December 31, 2030
• Last Updated: February 20, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, ANALYTIC CODE
• Time Frame: 3-6 months post publication
• Access Criteria: Trial data and analytic code required to replicate any analyses presented in the publication will be shared openly via a website which we will set up at that time. For a copy of the complete de-identified dataset, we will require a formal data sharing agreement (enacted under Quebec law) between the requesting group and the RI-MUHC.

Locations

CA (1)