A Double-Blind, Placebo-Controlled Study of Nebulized Bacteriophages in Patients With Ventilator-Associated Pneumonia Due to Pseudomonas Aeruginosa (PYOPHANEB)

Ventilator-associated pneumonia (VAP) complicates the hospital course of up to 40% of mechanically ventilated patients and is associated with mortality rates approaching 30%, despite appropriate antibiotic therapy (ATB). Gram-negative bacteria account for approximately 60% of VAP episodes, with Pseudomonas aeruginosa (Pa) being one of the most common pathogens. Recurrent Pa-VAP occurs in 19-33% of cases outside the COVID-19 setting, whereas recurrence rates as high as 79% have been reported in patients with COVID-19, most often caused by the same pathogen and frequently occurring despite adequate antibiotic therapy.

Several attempts have been made to improve pulmonary antibiotic exposure by combining intravenous therapy with aerosolized antibiotics delivered through conventional nebulizers. However, clinical results have been disappointing, largely because standard jet nebulizers deliver less than 10% of the nominal dose to the lungs owing to high residual volumes, drug deposition within the ventilator circuit and endotracheal tube, and loss through the expiratory limb. Even with more efficient vibrating mesh nebulizers, two recent randomized con-trolled trials failed to demonstrate any clinical benefit of adjunctive nebulized antibiotics in patients with Gram-negative VAP.

Bacteriophages are bacteria-specific viruses that have emerged as a promising therapeutic alternative for difficult-to-treat bacterial infections. Their highly specific host range allows selective targeting of pathogenic bacteria while sparing the commensal microbiota and human cells, thereby minimizing toxicity and off-target effects. An increasing body of preclinical evidence and clinical case reports supports the safety and potential efficacy of anti-P. aeruginosa phage therapy. More recently, a porcine model of Pa-VAP demonstrated that high concentrations of bacteriophages can be efficiently delivered to the lungs by nebulization during mechanical ventilation, resulting in rapid control of the pulmonary infection. The use of phages as compassionate treatment has been authorized in September 2021 in this indication using phages produced by Phagenix- ©.

The aim of this placebo controlled study is to demonstrate the efficacy and safety of nebulized anti-Pa bacteriophages, delivered to the lung using a vi-brating mesh nebulizer, in addition to conventional IV ATB treatment.

Study Overview

• Status: Not yet recruiting
• Conditions: Pseudomonas Aeruginosa Infection; Ventilator Associated Bacterial Pneumonia
• Intervention / Treatment: Biological: Bacteriophages GMP; Drug: saline solution (placebo)

• Study Type: Interventional
• Enrollment (Estimated): 184
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Alexandre BLEIBTREU, MD; Phone Number: + 33 1 84 02 76 92; Email: alexandre.bleibtreu@aphp.fr

Study Locations

• France
  • Amiens, France, 80054
    • CHU Amiens
    • Contact: Stéphanie MALAQUIN, MD
  • Angers, France, 49933
    • CHU Angers
    • Contact: Pierre ASFAR, MD
  • Bobigny, France, 93000
    • Hôpital Avicenne
    • Contact: Sophie NAGLE, MD
  • Clermont-Ferrand, France, 63003
    • CHU Clermont-Ferrand
    • Contact: Renaud GUERIN, MD
  • Colombes, France, 92700
    • Hôpital Louis Mourier
    • Contact: Baptiste GABORIEU, MD
  • Créteil, France, 94000
    • Hopital Henri Mondor
    • Contact: Pierre BAY, MD
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Bicêtre
    • Contact: Nadia ANGUEL, MD
  • Nice, France, 06200
    • CHU Nice
    • Contact: Mathieu JOZWIAK, MD
  • Orléans, France, 45000
    • CHU Orléans
    • Contact: François BARBIER, MD
  • Paris, France, 75013
    • Hôpital Pitié-Salpêtrière
    • Contact: Alexandre BLEIBTREU, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients ≥ 18 years old
2. Intubated and mechanically ventilated for at least 48 hours
3. Mechanical ventilation expected to continue for at least 3 days
4. Clinical diagnosis of VAP
5. VAP due to P. aeruginosa (P. aeruginosa recovered at a significant level from lung sample (≥10^4/ml for BAL or ≥10^5/ml for tracheal aspirate or ≥10^3 CFU/ml for plugged telescopic catheter)
6. Signed informed consent from the patient or the patient's legal representative or a family member or a close relative. According to the legal conditions of emergency inclusion, randomization without the family member or the surrogate consent could be performed if the patient is unable to give his/her consent and if no legal representative/family member or close relative is present. Close relative/ legal representative/family member consent will be asked as soon as possible. The patient will be asked to give his/her consent for continuation of the trial when his/her condition will allow.
7. Patient with childbearing potential* should have reliable contraception for the all duration of the study
8. Affiliation to social security (AME excluded)

Exclusion Criteria:

1. Severe hypoxemia as defined by PaO2/FiO2 < 100 mmHg, except if the patient is on ECMO (extracorporeal membrane oxygenation)
2. Impossibility to set a tidal volume of 6 ml/kg of ideal body weight during nebulization without risk of barotrauma
3. Patients with cystic fibrosis, lung cancer, lung resection, known bronchial obstruction, or active tuberculosis
4. Patient not expecting to survive 48 hours after randomization
5. Polymicrobial VAP (presence of pathogens other than P. aeruginosa at a significant level in lung samples (≥10^4/ml for BAL or ≥10^5/ml for tracheal aspirate). If the culture retrieves oropharyngeal flora, even at a significant threshold, in addition to Pseudomonas aeruginosa, the patient is eligible.
6. Contraindication to nebulization
7. Participation in another interventional study evaluating drugs for VAP or being in the exclusion period following the end of a previous interventional study evaluating drugs for VAP
8. Pregnancy or breastfeeding
9. Patients under guardianship or curatorship

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bacteriophages GMP; Nebulization of bacteriophages PP1450, PP1777, PP1792 and PP1797 will be performed using a vibrating mesh nebulizer (Aerogen). The aerosol generator will be placed upstream of the heated humidifier, which will remain active during administration. The nebulizer chamber will be filled immediately prior to dosing. When clinically feasible, mechanical ventilation settings will be standardized (volume-controlled mode, tidal volume 6-8 mL/kg ideal body weight, respiratory rate 16-20/min, inspiratory flow <40 L/min), with no specific adjustments for PEEP or FiO₂. Sedation may be used to minimize patient-ventilator asynchrony. Nebulization is expected to last approximately 45-60 minutes. These settings are recommended but not mandatory.	Biological: Bacteriophages GMP; Five administrations of phages daily from D1 to D5
Placebo Comparator: Saline solution; Nebulization of saline solution will be performed using a vibrating mesh nebulizer (Aerogen). The aerosol generator will be placed upstream of the heated humidifier, which will remain active during administration. The nebulizer chamber will be filled immediately prior to dosing. When clinically feasible, mechanical ventilation settings will be standardized (volume-controlled mode, tidal volume 6-8 mL/kg ideal body weight, respiratory rate 16-20/min, inspiratory flow <40 L/min), with no specific adjustments for PEEP or FiO₂. Sedation may be used to minimize patient-ventilator asynchrony. Nebulization is expected to last approximately 45-60 minutes. These settings are recommended but not mandatory.	Drug: saline solution (placebo); Five administrations of saline solution daily from D1 to D5

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients alive and cured at D28 and without any recurrence of Pa-VAP between the initial episode and D28.	Cure is defined as : Resolution of signs and symptoms of infection; Improvement of PaO2/FiO2 ratio as compared to value the day VAP is diagnosed; No appearance of new signs of sepsis All 3 criteria must be fulfilled 7 to 10 days after antibiotic initiation Recurrence is defined as: -a clinically suspected VAP (fever, radiological opacity, increase in ventilation need) A microbiological confirmation with Pa recovered at a significant level from lung sample (≥10^4/ml for BAL or ≥10^5/ml for tracheal aspirate or ≥ 10^3 CFU/mL for plugged telescopic catheter).	Day 28

Secondary Outcome Measures

Outcome Measure	Time Frame
Resolution of ventilator-associated pneumonia symptoms	Day 7 +/- 3 days
Incidence of new ventilator-associated pneumonia	Day 7 +/- 3 days and day 14
Clinical improvement, defined by a modified Clinical pulmonary infection score <4 (range 0-12, with higher score indicating worse outcome) and no new Pseudomonas aeruginosa ventilator-associated pneumonia episode	Day 14
Incidence of Pseudomonas aeruginosa detection in respiratory samples	Day 3, Day 5, Day 7, Day 10, Day 14 and Day 28
Number of days alive	Day 28
Number of day without invasive mechanical ventilation	Day 28
Number of day without antibiotics	Day 28
Anti-phage antibody presence and titers,	Day 1, 7, 10, 14 and 28
Phage neutralization titers	Day 1, 7, 10, 14 and 28
Mortality rate	Day 28 and Day 60
Prevalence of ESBL-producing and carbapenem-resistant Gram-negative bacteria in fecal and tracheal aspirate samples	Day 28

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): November 3, 2026
• Primary Completion (Estimated): December 3, 2029
• Study Completion (Estimated): January 3, 2030

Study Registration Dates

• First Submitted: July 23, 2026
• First Submitted That Met QC Criteria: August 31, 2026
• First Posted (Actual): September 4, 2026

Study Record Updates

• Last Update Posted (Actual): September 4, 2026
• Last Update Submitted That Met QC Criteria: August 31, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: Nebulized Bacteriophages; Ventilator Associated Bacterial Pneumonia
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Negative Bacterial Infections; Pseudomonas Infections; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Saline Solution
• Other Study ID Numbers: APHP222819; 2024-514008-15 (EudraCT Number)

Plan for Individual participant data (IPD)

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

IPD Plan Description

The procedures carried out with the French data privacy authority (CNIL, Commission nationale de l'informatique et des libertés) do not provide for the transmission of the database, nor do the information and consent documents signed by the patients.

Consultation by the editorial board or interested researchers of individual participant data that underlie the results reported in the article after deidentification may nevertheless be considered, subject to prior determination of the terms and conditions of such consultation and in respect for compliance with the applicable regulations

• IPD Sharing Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• IPD Sharing Access Criteria: Researchers who provide a methodologically sound proposal
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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