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Clinical Trial NCT07357103 (SPIRIT-ALT) for 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) is not yet recruiting. See the Trial Radar Card View and AI discovery tools for all the details. Or ask anything here. | ||
Positioning Second-line Therapies for Pneumocystis Jirovecii Pneumonia (PCP Alternatives) (SPIRIT-ALT) Phase 4 416
This study asks the question:
When TMP-SMX cannot be used, which alternative treatment for PCP provides the best balance of effectiveness and safety?
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, kidne...
Show MorePositioning Second-line Therapies for Pneumocystis Jirovecii Pneumonia (PCP Alternatives) [A Branch of the Initial Treatment Domain of the SPIRIT-PCP Platform]
- SPIRIT-ALT
- 2026-12268
- 527077 (Other Grant/Funding Number) (CIHR)
Pneumocystis jirovecii pneumonia
PCP Alternatives
Clindamycin
Pentamidine
Primaquine
Atovaquone
HIV
Non-HIV
Immunocompromised host
Randomized Control Trial
| Participant Group/Arm | Intervention/Treatment |
|---|---|
ExperimentalSevere PCP-Clindamycin+primaquine Participants with severe PCP will be randomized to receive clindamycin in combination with primaquine as second-line therapy due to intolerance of or contraindications to trimethoprim-sulfamethoxazole. | Clindamycin + 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. |
ExperimentalSevere PCP-Intravenous Pentamidine Participants with severe PCP will be randomized to receive intravenous pentamidine as second-line therapy due to intolerance of or contraindications to trimethoprim-sulfamethoxazole. | Pentamidine 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) |
ExperimentalMild to Moderate PCP- Clindamycin+primaquine Participants with mild to moderate PCP will be randomized to receive clindamycin in combination with primaquine as second-line therapy due to intolerance of or contraindications to trimethoprim-sulfamethoxazole. | Clindamycin + 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. |
ExperimentalMild to moderate PCP- Atovaquone Participants with mild to moderate PCP will be randomized to receive atovaquone as second-line therapy due to intolerance of or contraindications to trimethoprim-sulfamethoxazole. | Atovaquone 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). |
| 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 |
| Outcome Measure | Measure Description | Time Frame |
|---|---|---|
Proportion of patients that die (death) | Mortality at day 30 | 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 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 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 |
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 |
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).
- 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:
Previous severe adverse reaction or hypersensitivity to clindamycin, primaquine, or atovaquone (mild-moderate PCP) or to clindamycin, primaquine, or pentamidine (severe PCP);
More than 7 calendar days of any therapy for PCP (no more than 4 can involve a study drug).
Known pregnancy or breastfeeding (pregnancy test will be offered)
Drug specific exclusion criteria:
For clindamycin-primaquine:
- Known G6PD deficiency OR family history of G6PD deficiency without excluding by testing*
- Known diagnosis of porphyria
- Concomitant use of methotrexate or cyclophosphamide which cannot be held *G6PD deficiency is an X-linked recessive genetic disease. Female patients without a family history are very unlikely to have this disease and so therapy can start while waiting for the test in the absence of a family history. Male patients should wait for test results prior to receiving primaquine even if they do not have a family history. For those without G6PD testing at diagnosis, it is a reasonable standard of care to order testing.
For pentamidine:
- Absence of adequate intravenous access as determined by treating team and site investigator. In the event of loss of IV, up to 2 consecutive doses can be given intramuscularly if the patient is not systemically anticoagulated and does not have a coagulopathy.
- Hypotension defined as systolic blood pressure below 90mmHg without pharmacologic support
- Personal history of Torsade de Pointes or presence of a corrected QTc of greater than 490ms on ECG on date of enrollment
For atovaquone:
- Receipt of PCP Prophylaxis (≥3 doses per week) for ≥ 4 weeks with atovaquone
- inability to tolerate atovaquone with a meal or enteral feeding (e.g., prolonged NPO status is an exclusion as atovaquone must be taken with food for proper absorption)
- Concurrent use of rifampin, rifabutin, or tetracycline (that cannot be stopped)
- Reduced gastric absorption (patient must not have a medical condition which the treating team and/or site investigator believes will interfere with atovaquone absorption, e.g., total gastrectomy)
Administrative:
1. Trial site not participating in PCP Alternatives branch of the initial therapy domain