Low Dose Trimethoprim-Sulfamethoxazole for the Treatment of Pneumocystis Jirovecii Pneumonia (LOW-DOSE)

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.

Study Overview

• Status: Recruiting
• Conditions: Pneumocystis Infections; Pneumocystis Jirovecii Infection; Pneumocystis; Pneumocystis Pneumonia; Pneumocystis Carinii Infection; Pneumocystosis; Pneumonia (Etiology); Pneumocystis Carinii; Infection, Resulting From HIV Disease; Pneumocystosis Associated With AIDS
• Intervention / Treatment: Drug: trimethoprim-sulfamethoxazole; Drug: trimethoprim-sulfamethoxazole

Detailed Description

Pneumocystis jirovecii pneumonia (PCP) 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, PCP 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 PCP therapy, we recently performed a systematic review and meta-analysis of reduced dose regimens of TMP-SMX in the treatment of PCP 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 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, new mechanical ventilation, or change in treatment by Day 30.

• Study Type: Interventional
• Enrollment (Estimated): 416
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Babykumari Chitramuthu, PhD; Phone Number: 23730 514-934-1934; Email: babykumari.chitramuthu@muhc.mcgill.ca

Study Locations

• Canada
  • Quebec
    • Montreal, Quebec, Canada, H4A3J1
      • Recruiting
      • McGill University Health Centre (Royal Victoria Hospital and Montreal General Hospital)
      • Principal Investigator: Emily G McDonald, MD MSc
      • Principal Investigator: Todd C Lee, MD MPH FIDSA
      • Contact: Kristen Moran; Phone Number: 23730 514-934-1934; Email: kristen.moran@mail.mcgill.ca
      • Contact: Babykumari Chitramuthu, PhD; Phone Number: 23730 514-934-1934; Email: babykumari.chitramuthu@muhc.mcgill.ca
      • Sub-Investigator: Cheng P Matthew, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 96 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18 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.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: trimethoprim-sulfamethoxazole; 10mg/kg/day of TMP component; Other Names: Reduced dose; Drug: trimethoprim-sulfamethoxazole; 15mg/kg/day of TMP component; Other Names: Standard dose
Active Comparator: 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.	Drug: trimethoprim-sulfamethoxazole; 10mg/kg/day of TMP component; Other Names: Reduced dose; Drug: trimethoprim-sulfamethoxazole; 15mg/kg/day of TMP component; Other Names: Standard dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients requiring new Invasive Mechanical Ventilation	Initiation of invasive mechanical ventilation via endotracheal intubation during hospitalization following initiation of the assigned PCP treatment strategy.	Day 30
Proportion of patients requiring escalation or change of PCP -directed therapy	Proportion of patients with escalation or change of PCP -directed therapy due to inadequate clinical response, disease progression, or treatment-limiting toxicity during the treatment or follow-up period.	Day 30
Median length of stay in hospital amongst survivors	Length of hospital stay, measured in days from hospital admission to discharge among participants who survive to hospital discharge.	Day 30
Proportion of patients that die (death)	All cause mortality	Day 30
Proportion of patients with a need for new extracorporeal membrane oxygenation (ECMO)	New initiation of extracorporeal membrane oxygenation during hospitalization following initiation of assigned PCP treatment strategy.	Day 30
. Proportion of patients with severe (CTCAE grade 4) adverse drug event	Proportion of patients with occurence of severe (CTCAE grade 4) adverse drug event (dermatologic, nephrologic, hematologic, neurologic, and/or endocrinologic) considered at least probable (by Leape and Bates criteria).	Day 30
Proportion of patients with need for new non-invasive ventilation	initiation of non-invasive ventilation (including continuous positive airway pressure [CPAP] or bilevel positive airway pressure [BiPAP] during hospitalization following initiation of the assigned PCP treatment strategy.	Day 30

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tertiary outcome measure of quality of life at day 30	Quality of life (EQ-5D-5L) wherein a higher score indicates better quality of life.	Day 30
Tertiary outcome measure of all-cause mortality	All-cause mortality, defined as death from any cause.	Day 180
Tertiary Outcome Measure of PCP recurrence	Recurrence of pneumocystis pneumonia, defined as a new episode of clinically and/or microbiologically confirmed PCP after initial resolution.	Day 180
Tertiary Outcome measure of quality of life at day 180	Quality of life assessed using a EQ-5D-5L questionnaire. High score indicates better quality of life.	Day 180

Collaborators and Investigators

• Sponsor: Todd C. Lee MD MPH FIDSA
• Investigators: Principal Investigator: 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

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2025
• Primary Completion (Estimated): September 30, 2030
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: April 12, 2021
• First Submitted That Met QC Criteria: April 14, 2021
• First Posted (Actual): April 20, 2021

Study Record Updates

• Last Update Posted (Actual): February 20, 2026
• Last Update Submitted That Met QC Criteria: February 18, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: HIV; immunosuppressed; Pneumocystis; PCP; PJP; TMP-SMX
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Bacterial Infections and Mycoses; Lung Diseases, Fungal; Mycoses; Pneumonia; Infections; Pneumonia, Pneumocystis; Pneumocystis Infections; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pharmaceutical Preparations; Therapeutics; Drug Therapy; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amides; Aniline Compounds; Amines; Pyrimidines; Benzene Derivatives; Drug Combinations; Sulfamethoxazole; Benzenesulfonamides; Sulfonamides; Sulfanilamides; Sulfones; Trimethoprim; Drug Prescriptions; Trimethoprim, Sulfamethoxazole Drug Combination; Off-Label Use
• Other Study ID Numbers: 2021-7386

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

A copy of a trial data required to replicate trial publication analyses will be shared within 3-6 months of publication.

After study completion, a fully de-identified copy of the full trial dataset can be made available to other researchers subject to a data sharing agreement enacted under Quebec law.

• IPD Sharing Time Frame: 3-6 months post publication

IPD Sharing 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.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No