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.
연구 개요
상태
연구 유형
등록 (추정된)
단계
- 3단계
연락처 및 위치
연구 연락처
- 이름: Alexandre BLEIBTREU, MD
- 전화번호: + 33 1 84 02 76 92
- 이메일: alexandre.bleibtreu@aphp.fr
연구 장소
-
-
-
Amiens, 프랑스, 80054
- CHU Amiens
-
연락하다:
- Stéphanie MALAQUIN, MD
-
Angers, 프랑스, 49933
- CHU Angers
-
연락하다:
- Pierre ASFAR, MD
-
Bobigny, 프랑스, 93000
- Hopital Avicenne
-
연락하다:
- Sophie NAGLE, MD
-
Clermont-Ferrand, 프랑스, 63003
- CHU clermont-ferrand
-
연락하다:
- Renaud GUERIN, MD
-
Colombes, 프랑스, 92700
- Hôpital Louis Mourier
-
연락하다:
- Baptiste GABORIEU, MD
-
Créteil, 프랑스, 94000
- Hopital Henri Mondor
-
연락하다:
- Pierre BAY, MD
-
Le Kremlin-Bicêtre, 프랑스, 94270
- Hôpital Bicêtre
-
연락하다:
- Nadia ANGUEL, MD
-
Nice, 프랑스, 06200
- CHU NICE
-
연락하다:
- Mathieu JOZWIAK, MD
-
Orléans, 프랑스, 45000
- Chu Orleans
-
연락하다:
- François BARBIER, MD
-
Paris, 프랑스, 75013
- Hôpital Pitié-Salpêtrière
-
연락하다:
- Alexandre BLEIBTREU, MD
-
-
참여기준
자격 기준
공부할 수 있는 나이
- 성인
- 고령자
건강한 자원 봉사자를 받아들입니다
설명
Inclusion Criteria:
- Patients ≥ 18 years old
- Intubated and mechanically ventilated for at least 48 hours
- Mechanical ventilation expected to continue for at least 3 days
- Clinical diagnosis of VAP
- 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)
- 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.
- Patient with childbearing potential* should have reliable contraception for the all duration of the study
- Affiliation to social security (AME excluded)
Exclusion Criteria:
- Severe hypoxemia as defined by PaO2/FiO2 < 100 mmHg, except if the patient is on ECMO (extracorporeal membrane oxygenation)
- Impossibility to set a tidal volume of 6 ml/kg of ideal body weight during nebulization without risk of barotrauma
- Patients with cystic fibrosis, lung cancer, lung resection, known bronchial obstruction, or active tuberculosis
- Patient not expecting to survive 48 hours after randomization
- 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.
- Contraindication to nebulization
- 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
- Pregnancy or breastfeeding
- Patients under guardianship or curatorship
공부 계획
연구는 어떻게 설계됩니까?
디자인 세부사항
- 주 목적: 치료
- 할당: 무작위
- 중재 모델: 병렬 할당
- 마스킹: 삼루타
무기와 개입
참가자 그룹 / 팔 |
개입 / 치료 |
|---|---|
|
실험적: 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.
|
Five administrations of phages daily from D1 to D5
|
|
위약 비교기: 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.
|
Five administrations of saline solution daily from D1 to D5
|
연구는 무엇을 측정합니까?
주요 결과 측정
결과 측정 |
측정값 설명 |
기간 |
|---|---|---|
|
Proportion of patients alive and cured at D28 and without any recurrence of Pa-VAP between the initial episode and D28.
기간: Day 28
|
Cure is defined as :
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
|
2차 결과 측정
결과 측정 |
기간 |
|---|---|
|
Resolution of ventilator-associated pneumonia symptoms
기간: Day 7 +/- 3 days
|
Day 7 +/- 3 days
|
|
Incidence of new ventilator-associated pneumonia
기간: Day 7 +/- 3 days and day 14
|
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
기간: Day 14
|
Day 14
|
|
Incidence of Pseudomonas aeruginosa detection in respiratory samples
기간: Day 3, Day 5, Day 7, Day 10, Day 14 and Day 28
|
Day 3, Day 5, Day 7, Day 10, Day 14 and Day 28
|
|
Number of days alive
기간: Day 28
|
Day 28
|
|
Number of day without invasive mechanical ventilation
기간: Day 28
|
Day 28
|
|
Number of day without antibiotics
기간: Day 28
|
Day 28
|
|
Anti-phage antibody presence and titers,
기간: Day 1, 7, 10, 14 and 28
|
Day 1, 7, 10, 14 and 28
|
|
Phage neutralization titers
기간: Day 1, 7, 10, 14 and 28
|
Day 1, 7, 10, 14 and 28
|
|
Mortality rate
기간: Day 28 and Day 60
|
Day 28 and Day 60
|
|
Prevalence of ESBL-producing and carbapenem-resistant Gram-negative bacteria in fecal and tracheal aspirate samples
기간: Day 28
|
Day 28
|
공동 작업자 및 조사자
연구 기록 날짜
연구 주요 날짜
연구 시작 (추정된)
기본 완료 (추정된)
연구 완료 (추정된)
연구 등록 날짜
최초 제출
QC 기준을 충족하는 최초 제출
처음 게시됨 (실제)
연구 기록 업데이트
마지막 업데이트 게시됨 (실제)
QC 기준을 충족하는 마지막 업데이트 제출
마지막으로 확인됨
추가 정보
이 연구와 관련된 용어
추가 관련 MeSH 약관
기타 연구 ID 번호
- APHP222819
- 2024-514008-15 (EudraCT 번호)
개별 참가자 데이터(IPD) 계획
개별 참가자 데이터(IPD)를 공유할 계획입니까?
IPD 계획 설명
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 공유 기간
IPD 공유 액세스 기준
IPD 공유 지원 정보 유형
- 연구_프로토콜
- 수액
- ICF
약물 및 장치 정보, 연구 문서
미국 FDA 규제 의약품 연구
미국 FDA 규제 기기 제품 연구
이 정보는 변경 없이 clinicaltrials.gov 웹사이트에서 직접 가져온 것입니다. 귀하의 연구 세부 정보를 변경, 제거 또는 업데이트하도록 요청하는 경우 register@clinicaltrials.gov. 문의하십시오. 변경 사항이 clinicaltrials.gov에 구현되는 즉시 저희 웹사이트에도 자동으로 업데이트됩니다. .