Pneumocystis, Pneumocystis Infection, Pneumocystis Carinii Infection, Pneumocystis Carinii; Infection, Resulting From HIV Disease, Pneumocystis Jirovecii Pneumonia, Pneumocystis Jirovecii Infection, Pneumocystosis Associated With AIDS, Pneumocystosis; Pneumonia (Etiology)
Conditions
Keywords
PCP, Pneumocystis jirovecii pneumonia, PCP Alternatives, Clindamycin, Pentamidine, Primaquine, Atovaquone, HIV, Non-HIV, Immunocompromised host, Randomized Control Trial
Brief summary
The usual first treatment for Pneumocystis jirovecii pneumonia (PCP) is an antibiotic called trimethoprim-sulfamethoxazole (TMP-SMX). However, some patients cannot take this medication because of allergies, side effects, or lack of response. This study asks the question: When TMP-SMX cannot be used, which alternative treatment for PCP provides the best balance of effectiveness and safety?
Detailed description
Pneumocystis jirovecii pneumonia (PCP) is a serious lung infection that affects people with weakened immune systems (e.g., patients with cancer, organ transplants, autoimmune diseases, or HIV). Without timely treatment, PCP can lead to respiratory failure and death. TMP-SMX is the standard first-line treatment, but 20-30% of patients cannot receive the treatment or cannot tolerate it due to allergic reactions, kidney problems, low blood counts, drug interactions, or treatment failure. In these situations, doctors use alternative medications such as clindamycin with primaquine, pentamidine, or atovaquone. Although these alternative treatments are widely used, there is limited modern research directly comparing them. As a result, treatment choices vary between hospitals and physicians. The main objective of this study is to determine which alternative treatment works best for patients with PCP who cannot receive TMP-SMX. Eligible participants in the PCP alternatives therapy are enrolled and randomized centrally 1:1 in the MUHC Research Electronic Data Capture (REDCap) system. The primary outcome is a Hierarchical composite Win Ratio Outcome at day 30: death; new extracorporeal membrane oxygenation (ECMO), new invasive mechanical ventilation; severe (CTCAE grade 4) adverse drug event; and length of stay in hospital (amongst survivors). Secondary endpoints include individual components of the composite outcome, and tertiary endpoints include quality of life and longer-term outcomes through day 180.
Interventions
DRUGClindamycin + primaquine
Participants randomized to this intervention will receive clindamycin in combination with primaquine as second-line therapy for the treatment of PCP. This regimen may be used for participants with Severe PCP or mild to moderate PCP in acccordance with protocol-defined disease severity and standard clinical practice.
DRUGPentamidine
Participants randomized to this intervention will receive pentamidine, administered intravenously, as second-line therapy for the treatment of PCP in patients with severe disease who are unable to tolerate or have contraindications to trimethoprim-sulfamethoxazole (TMP/SMX)
DRUGAtovaquone
Participants randomized to. this intervention will receive atovaquone, administered orally, as second-line therapy for the treatment of PCP in participants with mild to moderate disease who are unable to tolerate or have contraindications to trimethoprim-sulfamethozaxole (TMP/SMX).
Sponsors
McGill University Health Centre/Research Institute of the McGill University Health Centre
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Immunocompromised patients (including but not limited to HIV, solid organ transplant, solid tumors, hematological transplant and malignancies, systemic diseases, chemotherapy, long term corticosteroid use, and immunosuppressive therapies, as well as primary immunodeficiencies) in an emergency department, cliinic, or hospital * Age ≥18 years * Proven or probable Pneumocystis jirovecii pneumonia * Inability to receive trimethoprim-sulfamethoxazole due to contraindication, intolerance, toxicity, or treatment failure * Immunocompromised status * Ability to provide informed consent (or per local regulations) While participants may be enrolled in multiple domains of the SPIRIT-PCP Platform over time (if they are eligible and a domain is active), they may only be enrolled to single question once (e.g., they can be part PCP Alternatives and an eventual secondary prophylaxis domain; however, if they have a recurrence, they cannot be included in PCP Alternatives again).
Exclusion criteria
* The Platform will exclude: patients where we are unable to obtain informed consent, where patients or their proxy have declined to consent, where the treating team has declined participation, where follow up cannot be reliably obtained (e.g., lack of means of communication, patient non-resident of jurisdiction), where treatment with antibiotics is not in keeping with a patient's advanced care directives, and where death is deemed imminent (\<48h) as determined by the treating team and site investigator. Clinical: 1. Previous severe adverse reaction or hypersensitivity to clindamycin, primaquine, or atovaquone (mild-moderate PCP) or to clindamycin, primaquine, or pentamidine (severe PCP); 2. More than 7 calendar days of any therapy for PCP (no more than 4 can involve a study drug). 3. Known pregnancy or breastfeeding (pregnancy test will be offered) Drug specific
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hierarchical composite outcome | Day 30 | 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) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients that die (death) | Day 30 | Mortality at day 30 |
| Proportion of patients with a need for new extracorporeal membrane oxygenation (ECMO), | Day 30 | New initiation of extracorporeal membrane oxygenation during hospitalization following initiation of assigned PCP treatment strategy. |
| Proportion of patients requiring new Invasive Mechanical Ventilation | Day 30 | Initiation of invasive mechanical ventilation via endotracheal intubation during hospitalization following initiation of the assigned PCP treatment strategy. |
| Proportion of patients with severe (CTCAE grade 4) adverse drug event | Day 30 | 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). |
| Proportion of patients with need for new non-invasive ventilation; | Day 30 | 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. |
| Proportion of patients requiring escalation or change of PCP -directed therapy | Day 30 | 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. |
| Median length of stay in hospital amongst survivors | Day 30 | Length of hospital stay, measured in days from hospital admission to discharge among participants who survive to hospital discharge. |
Contacts
CONTACTBabykumari Chitramuthu, PhD
PRINCIPAL_INVESTIGATOREmily G McDonald, MD MSc
McGill University Health Centre/Research Institute of the McGill University Health Centre
PRINCIPAL_INVESTIGATORTodd C Lee, MD MPH
McGill University Health Centre/Research Institute of the McGill University Health Centre
PRINCIPAL_INVESTIGATORMatthew P Cheng, MD FRCPC
McGill University Health Centre/Research Institute of the McGill University Health Centre
Outcome results
None listed