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

NCT06892951 | Not Yet Recruiting Phase 1 DMC

• 2 other identifiers: 2022-DR329-CaspoNEB2023-508861-34-00
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Pneumocystis Pneumonia; Pneumocystis Jirovecii Infection; Pneumocystis Infections

Keywords

ventilation; Pneumocystis; caspofungin; echinocandin; aerosol; inhalation; nebulization; interstitial pneumonia

Outcome Measures

Primary Outcomes (2)

• Part 1: safety of inhaled caspofungin

  * frequency of adverse events * severity of adverse events

  D-7 (day-7)

• Part 2: proportion of patients alive and with a favorable clinical course* at the seventh day (day-7) after the first administration.

  Composite outcome defined by at least one of the two following items persisting ≥24 hours in alive patients: * Relative reduction (de-escalation or withdrawal) of respiratory assistance due to clinical improvement (depending on the initial support): * extubation, or * weaning of non-invasive ventilatory support, or * weaning of nasal high-flow or low-flow oxygen therapy; (NB: all participating centers will implement uniform protocols for ventilatory assistance weaning) * Occurrence of a +50% increase in oxygenation (PaO2 / FiO2 ratio vs. the worst value observed after inclusion).

  D7 (day-7)

Secondary Outcomes (6)

• Individual components of the composite primary outcome at day-7 (d-7)

  D7 (day-7)

• Safety of nebulized caspofungin in patients with Pneumocystis pneumonia through

  day-1 (d-1), d-2, d-3, d-4, d-5, d-6, and d-7

• Pharmacokinetics of nebulized caspofungin

  0, 2, 4, 6, 12, 24 hours, plus residual concentration at day (d-3) and d-7

• Mortality

  day-28 (d-28) and d-90

• Morbidity

  day-1 (d-1), d-7 and d-21

Study Arms (3)

Part 2 - randomized study (group 1)

EXPERIMENTAL

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

Drug: Caspofungin Acetate 50 MG

Part 2 - randomized study (group 2)

PLACEBO COMPARATOR

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

Drug: Physiologic saline

Part 1 - open study

EXPERIMENTAL

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)

Drug: Caspofungin Acetate 50 MG

Interventions

Caspofungin Acetate 50 MG DRUG

The experimental treatment will be administered once daily for up to seven days, through the nebulization route by the means of a disposable vibrating mesh Aeroneb solo® nebulizer with the valved mask (Galway, Ireland). Before generating aerosol, resuspension of the caspofungin powder will be carried out in the same manner than for the IV route, into 10.5 mL saline serum. Preparation of the experimental drug (re-suspension) will be unblindly carried out in a distinct medical office by a nurse neither involved in the healthcare of the included patients, nor in the other parts of the study, data recording or outcome assessment. Once reconstituted, the suspension is expected to be limpid, with neither odour nor foam. Thereafter, its administration will be blindly completed by the clinical staff in charge of the enrolled patient.

Part 1 - open study; Part 2 - randomized study (group 1)

Physiologic saline DRUG

Procedures will be exactly the same than those described above for the experimental group, but caspofungin will be replaced during the seven days of intervention by 10mL of 0.9% saline nebulized in the control group for a 15 minute-long process of nebulization (from d-1 to d-7).

Part 2 - randomized study (group 2)

Eligibility Criteria

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

You may qualify if:

• 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.
• 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

Sponsors & Collaborators

• University Hospital, Tours: lead
• University Hospital, Angers: collaborator
• Centre Hospitalier Universitaire de Besancon: collaborator
• University Hospital, Bordeaux: collaborator
• University Hospital, Brest: collaborator
• Centre Hospitalier Universitaire Dijon: collaborator
• University Hospital, Grenoble: collaborator
• University Hospital, Lille: collaborator
• University Hospital, Limoges: collaborator
• Hospices Civils de Lyon: collaborator
• University Hospital, Montpellier: collaborator
• Nantes University Hospital: collaborator
• Centre Hospitalier Universitaire de Nice: collaborator
• Hospital Avicenne: collaborator
• Henri Mondor University Hospital: collaborator
• Hopital Foch: collaborator
• Hôpital Necker-Enfants Malades: collaborator
• Pitié-Salpêtrière Hospital: collaborator
• Poitiers University Hospital: collaborator
• Reims University hospital: collaborator
• Ohre Pharma: collaborator
• Aerogen: collaborator
• Wako Diagnostics: collaborator
• Cape Cod Incorporated: collaborator
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator
• Tours university: collaborator
• Amiens University Hospital: collaborator
• Rennes University Hospital: collaborator

Study Sites (1)

CHU Tours

Tours, 37000, France

Location

Related Publications (12)

• Limper AH. Alveolar macrophage and glycoprotein responses to Pneumocystis carinii. Semin Respir Infect. 1998 Dec;13(4):339-47.

  PMID: 9872631 BACKGROUND

• McKinnell JA, Cannella AP, Kunz DF, Hook EW 3rd, Moser SA, Miller LG, Baddley JW, Pappas PG. Pneumocystis pneumonia in hospitalized patients: a detailed examination of symptoms, management, and outcomes in human immunodeficiency virus (HIV)-infected and HIV-uninfected persons. Transpl Infect Dis. 2012 Oct;14(5):510-8. doi: 10.1111/j.1399-3062.2012.00739.x. Epub 2012 May 1.

  PMID: 22548840 BACKGROUND

• Lobo ML, Esteves F, de Sousa B, Cardoso F, Cushion MT, Antunes F, Matos O. Therapeutic potential of caspofungin combined with trimethoprim-sulfamethoxazole for pneumocystis pneumonia: a pilot study in mice. PLoS One. 2013 Aug 5;8(8):e70619. doi: 10.1371/journal.pone.0070619. Print 2013.

  PMID: 23940606 BACKGROUND

• Wong-Beringer A, Lambros MP, Beringer PM, Johnson DL. Suitability of caspofungin for aerosol delivery: physicochemical profiling and nebulizer choice. Chest. 2005 Nov;128(5):3711-6. doi: 10.1378/chest.128.5.3711.

  PMID: 16304338 BACKGROUND

• Ehrmann S, Mercier E, Vecellio L, Ternant D, Paintaud G, Dequin PF. Pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects. Intensive Care Med. 2008 Apr;34(4):755-62. doi: 10.1007/s00134-007-0935-1. Epub 2007 Nov 29.

  PMID: 18046534 BACKGROUND

• Beitler JR, Sarge T, Banner-Goodspeed VM, Gong MN, Cook D, Novack V, Loring SH, Talmor D; EPVent-2 Study Group. Effect of Titrating Positive End-Expiratory Pressure (PEEP) With an Esophageal Pressure-Guided Strategy vs an Empirical High PEEP-Fio2 Strategy on Death and Days Free From Mechanical Ventilation Among Patients With Acute Respiratory Distress Syndrome: A Randomized Clinical Trial. JAMA. 2019 Mar 5;321(9):846-857. doi: 10.1001/jama.2019.0555.

  PMID: 30776290 BACKGROUND

• Desoubeaux G, Lemaignen A, Ehrmann S. Scientific rationale for inhaled caspofungin to treat Pneumocystis pneumonia: A therapeutic innovation likely relevant to investigate in a near future.... Int J Infect Dis. 2020 Jun;95:464-467. doi: 10.1016/j.ijid.2020.03.029. Epub 2020 Mar 16. No abstract available.

  PMID: 32194238 BACKGROUND

• Le Gal S, Toubas D, Totet A, Dalle F, Abou Bacar A, Le Meur Y, Nevez G; Anofel Association. Pneumocystis Infection Outbreaks in Organ Transplantation Units in France: A Nation-Wide Survey. Clin Infect Dis. 2020 May 6;70(10):2216-2220. doi: 10.1093/cid/ciz901.

  PMID: 31633150 BACKGROUND

• Desoubeaux G, Dominique M, Morio F, Thepault RA, Franck-Martel C, Tellier AC, Ferrandiere M, Hennequin C, Bernard L, Salame E, Bailly E, Chandenier J. Epidemiological Outbreaks of Pneumocystis jirovecii Pneumonia Are Not Limited to Kidney Transplant Recipients: Genotyping Confirms Common Source of Transmission in a Liver Transplantation Unit. J Clin Microbiol. 2016 May;54(5):1314-20. doi: 10.1128/JCM.00133-16. Epub 2016 Mar 2.

  PMID: 26935726 BACKGROUND

• Alanio A, Desoubeaux G, Sarfati C, Hamane S, Bergeron A, Azoulay E, Molina JM, Derouin F, Menotti J. Real-time PCR assay-based strategy for differentiation between active Pneumocystis jirovecii pneumonia and colonization in immunocompromised patients. Clin Microbiol Infect. 2011 Oct;17(10):1531-7. doi: 10.1111/j.1469-0691.2010.03400.x. Epub 2011 Apr 12.

  PMID: 20946413 BACKGROUND

• Nevez G, Le Gal S. Caspofungin and Pneumocystis Pneumonia: It Is Time To Go Ahead. Antimicrob Agents Chemother. 2019 Sep 23;63(10):e01296-19. doi: 10.1128/AAC.01296-19. Print 2019 Oct. No abstract available.

  PMID: 31548210 BACKGROUND

• Peghin M, Fishman JA, Grossi PA. Pneumocystis jiroveci: still troublesome to diagnose and treat. Curr Opin Infect Dis. 2025 Oct 18. doi: 10.1097/QCO.0000000000001155. Online ahead of print.

  PMID: 41151592 DERIVED

Related Links

• Supplier of the device
• Supplier of the drug
• Supplier of the diagnostic kit
• Supplier of the diagnostic kit

MeSH Terms

Conditions

Pneumonia, Pneumocystis; Pneumocystis Infections; Respiratory Aspiration; Lung Diseases, Interstitial

Interventions

Caspofungin

Condition Hierarchy (Ancestors)

Lung Diseases, Fungal; Mycoses; Bacterial Infections and Mycoses; Infections; Respiratory Tract Infections; Pneumonia; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Lipopeptides; Lipids; Peptides; Amino Acids, Peptides, and Proteins; Echinocandins; Peptides, Cyclic

Study Officials

• Guillaume DESOUBEAUX, Prof

  University Hospital of TOURS

  STUDY DIRECTOR

• Stephan EHRMANN, Prof

  University Hospital of TOURS

  STUDY DIRECTOR

• Adrien LEMAIGNEN, Dr

  University Hospital of TOURS

  STUDY DIRECTOR

Central Study Contacts

Guillaume DESOUBEAUX, Prof

CONTACT

+33(0)2 34 37 89 26; guillaume.desoubeaux@univ-tours.fr

Stephan EHRMANN, Prof

CONTACT

+33(0)6 71 10 33 02; stephanehrmann@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: To ensure the blind administration during the part 2, the following procedures will be carried out: * Central randomization by an independent statistician * Packaging and labelling of the intervention medications, nebulizers and tubing in such a manner that there is no way to determine to which treatment group (experimental or control) the participant is assigned
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The protocol will be carried out in a sequential manner to first provide safety data and the optimal dosing regimen on inhaled caspofungin, prior to inclusion of all the other patients: 1. Part 1: open-label, one arm, non-randomized, three centres study including six patients with ascending scheme regarding the rhythm of administration over one week, depending on the tolerance and closely monitored in intensive care unit to ensure that caspofungin is well tolerated via the inhaled route and to provide data supporting the proposed dose for part 2 (PK modeling) 2. Part 2: comparative, two arms, add-on, multicenter, individually-randomized placebo-controlled trial

Study Record Dates

• First Submitted: January 18, 2024
• First Posted: March 25, 2025
• Study Start: June 1, 2025
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): December 1, 2028
• Last Updated: March 25, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: At the end of the study (2028)
• Access Criteria: Upon request

Locations

FR (1)