CaspoNEB: Efficacy and Safety of Caspofungin Aerosols for the Curative Treatment of Pneumocystis Pneumonia

Regional University Hospital Center (CHRU)

Status and phase: Not yet enrolling; Phase 2; Phase 1

Conditions: Pneumocystis Infections; Pneumocystis Pneumonia; Pneumocystis Jirovecii Infection

Treatments: Drug: Physiologic saline; Drug: Caspofungin Acetate 50 MG

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT06892951

2023-508861-34-00 (EU Trial (CTIS) Number)

2022-DR329-CaspoNEB

Details and patient eligibility

About

To assess the efficacy of administrating daily caspofungin aerosols versus placebo for seven days, in adjunction of conventional systemic antifungal therapy during curative treatment of Pneumocystis pneumonia, on the clinical outcome at the end of the nebulized therapy, in order to support a "GO / NO GO" decision towards a phase III trial of nebulized caspofungin in those patients.

Full description

Pneumocystis jirovecii is an airborne-transmissible fungus which can induce pneumonia with severely impaired lung function, especially in immunocompromised patients. At least 1,000 new cases of Pneumocystis pneumonia occur each year in France with approximately 50% of cases suffering from hypoxemia. Around 15% HIV+ and 50% HIV- subjects require mechanical ventilation, and mean duration of hospitalization is about 30 days. Average mortality rate is ≈20% at 3 months, higher for critically ill patients (30%-60%).

To date, cotrimoxazole represents the gold standard anti-Pneumocystis treatment commonly associated with systemic corticosteroids in case of moderate-to-severe infection. However, treatment is long (several weeks) to achieve clearance of the fungus, which might favor lung sequelae like persistent inflammation or post-infectious fibrosis. Furthermore, therapeutic failures have been reported as high as 9-44% of patients. Five other drugs have been commonly used as curative alternatives to cotrimoxazole against P. jirovecii: pentamidine, primaquine + clindamycin, dapsone and atovaquone. Some are responsible for serious side effects, while others are complex to administer or less efficient. All exhibit clinically important drug-drug interactions. Therefore, in such a context, it is important to test new drugs and/or alternative delivery routes for existing therapies.

Echinocandin drugs, including caspofungin, are usually administered daily to treat invasive candidiasis and aspergillosis. They target the fungal cell wall, thus inhibiting the β-(1,3)-D glucan synthase enzyme. Intravenous (IV) echinocandins are generally well tolerated and are not responsibles for major drug-drug interactions. IV caspofungin was also proven effective in animal models of Pneumocystis infection and significantly improve the overall survival. Two human studies showed that in-hospital and 3-month mortality rates were similar between patients receiving daily IV echinocandin and those receiving co-trimoxazole alone. Several case reports also showed 47 successful outcomes with IV caspofungin, alone or in combination with standard treatment. A recent study reported better response and lower in-hospital mortality in patients receiving the combination of cotrimoxazole + IV caspofungin with no severe adverse events. Therefore, IV echinocandins are now recommended in the European therapeutic guidelines for non-HIV patients as a salvage therapy (CII-grade) in association with co-trimoxazole.

However, high molecular weight and elevated protein binding hamper optimal diffusion of IV caspofungin towards the lung alveoli (<5% plasma concentration), where P. jirovecii thrives. Administration through an aerosol directly delivered into the lung may circumvent this limitation. Technical feasibility of echinocandin nebulization was demonstrated in vitro with several commercial nebulizers that provided aerosol particles with adequat size and pH to ensure lung tolerance. In vivo, nebulized caspofungin, at a dosage equivalent to the usual IV dosage, showed an excellent safety profile in rats. It also reduced the fungal burden by -99% and induced elevated and prolonged concentrations of the drug in the lungs (almost 50% of the total amounts of caspofungin initially deposited into the lungs of infected rats were still detectable at 48 hours) - largely above the usual minimal inhibitory concentrations of fungal pathogens -, while caspofungin detection was almost null in other organs and blood.

Therefore, we hypothesize herein the therapeutic interest of caspofungin aerosols in adjunction with conventional antifungal therapy, as first-line curative treatment, to enhance the clinical recovery and to reduce the morbidity due to Pneumocystis pneumonia. As no clinical trials have been worldwide initiated, human efficacy and safety data of nebulized caspofungin are still lacking and will be first investigated in this study in patients. Thus organized in two successive parts, this phase I/II clinical trial represents a mandatory prelude for this original administration modality of caspofungin.

Enrollment: 100 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion criteria:

• Male and female ≥18 years

• Medical management of Pneumocystis pneumonia based on :

  • Microbiological diagnosis of Pneumocystis pneumonia
  • Respiratory support (oxygen therapy or ventilatory assistance)
  • Systemic co-trimoxazole therapy or systemic second-line anti-Pneumocystis salvage therapy (switch to another anti-Pneumocystis drug is possible, but should be notified) (initiated within 48 hours or less before enrolment)

• Person affiliated to a French social security system or equivalent

• Written informed consent obtained from the participant or, if the patient is not able to give consent from representative (trusted person, family member) or if the delay in obtaining the consent is assumed not compatible with the enrollment requirements, a temporary approval can be obtained from the investigator. In all cases, the patient's written informed consent will have to be obtained as soon as possible.

Non-inclusion criteria:

• Persons covered by articles L1121-5 to L1121-8 of the CSP (corresponding to all protected persons: pregnant women, parturients, nursing mothers, persons deprived of their liberty by judicial or administrative decision, minors, and persons subject to a legal protection measure: guardianship or trusteeship). Pregnancy test to be performed in all women from 15 to 45 years old who have not had an ovariectomy.
• Other indication(s) for systemic administration of an echinocandin drug
• Known allergy to echinocandin drugs
• Absolute contraindication to aerosol therapy
• Concomitant co-infection at time of diagnosis (except HIV infection)
• Severe liver impairment (i.e. documented severe liver cirrhosis (Child C), or Factor-V protein < 50% and/or INR for prothrombin time of blood coagulation > 1.5)
• history of toxic epidermal necrosis (TEN) and Steven-Johnson syndrome (SJS)
• Participation in other pharmacological study that focuses on echinocandins and/or anti-infectious aerosol therapy or other anti-pneumocystis treatment
• Participation in a trial with an investigational product known to have pulmonary toxicity or of which the safety is not known

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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100 participants in 3 patient groups, including a placebo group

Part 2 - randomized study (group 1)

Experimental group

Description:

Conventional systemic antifungal treatment (systemic co-trimoxazole or systemic second line anti-Pneumocystis salvage therapy) + aerosols of echinocandin (50 mg caspofungin) during one to seven days (according to the regimen retained from the results of part 1 from day-1 to d-7) using vibrating mesh nebulization device

Treatment:

Drug: Caspofungin Acetate 50 MG

Part 2 - randomized study (group 2)

Placebo Comparator group

Description:

Control group: (in part 2 only) Conventional systemic antifungal treatment (systemic co-trimoxazole or systemic second-line anti-Pneumocystis salvage therapy) + aerosols of placebo (0.9% saline in a volume equivalent to the experimental group) during one to seven days (according to the regimen retained from part 1 results) using vibrating mesh nebulization device

Treatment:

Drug: Physiologic saline

Part 1 - open study

Experimental group

Description:

open-label non-randomized group, with ascending scheme regarding the dose and rhythm of administration over one week, depending on the tolerance, and closely monitored in ICU to ensure that caspofungin is well tolerated via the inhaled route, and to provide data supporting the proposed administration scheme for part 2. * the first two patients (included one by one) will receive two aerosols (5 mg) during the first week, four days apart on d-1 and d-5 (level 1); * the third and fourth will receive two aerosols (15 mg) during the first week, four days apart on d-1 and d-5 (level 2); * the fifth and sixth will receive two aerosols (50 mg) during the first week, four days apart on d-1 and d-5 (level 3); * the seventh and eighth patients will receive four aerosols (50 mg) two days apart during one week, at d-1, then d-3, d-5 and d-7 (level 4); * the last two patients will have daily aerosols during the first week, from d-1 to d-7 (level 5)

Treatment:

Drug: Caspofungin Acetate 50 MG