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.
調査の概要
研究の種類
入学 (推定)
段階
- フェーズ 3
連絡先と場所
研究連絡先
- 名前：Alexandre BLEIBTREU, MD
- 電話番号：+ 33 1 84 02 76 92
- メール：alexandre.bleibtreu@aphp.fr
研究場所
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Amiens、フランス、80054
- CHU Amiens
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コンタクト：
- Stéphanie MALAQUIN, MD
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Angers、フランス、49933
- CHU Angers
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コンタクト：
- Pierre ASFAR, MD
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Bobigny、フランス、93000
- Hopital Avicenne
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コンタクト：
- Sophie NAGLE, MD
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Clermont-Ferrand、フランス、63003
- CHU clermont-ferrand
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コンタクト：
- Renaud GUERIN, MD
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Colombes、フランス、92700
- Hôpital Louis Mourier
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コンタクト：
- Baptiste GABORIEU, MD
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Créteil、フランス、94000
- Hopital Henri Mondor
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コンタクト：
- Pierre BAY, MD
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Le Kremlin-Bicêtre、フランス、94270
- Hôpital Bicêtre
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コンタクト：
- Nadia ANGUEL, MD
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Nice、フランス、06200
- CHU NICE
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コンタクト：
- Mathieu JOZWIAK, MD
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Orléans、フランス、45000
- Chu Orleans
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コンタクト：
- François BARBIER, MD
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Paris、フランス、75013
- Hôpital Pitié-Salpêtrière
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コンタクト：
- Alexandre BLEIBTREU, MD
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
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
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：トリプル
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：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
|
|
プラセボコンパレーター：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
|
この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
Proportion of patients alive and cured at D28 and without any recurrence of Pa-VAP between the initial episode and D28.
時間枠：Day 28
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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
|
二次結果の測定
結果測定 |
時間枠 |
|---|---|
|
Resolution of ventilator-associated pneumonia symptoms
時間枠：Day 7 +/- 3 days
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Day 7 +/- 3 days
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Incidence of new ventilator-associated pneumonia
時間枠：Day 7 +/- 3 days and day 14
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Day 7 +/- 3 days and day 14
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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
時間枠：Day 14
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Day 14
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Incidence of Pseudomonas aeruginosa detection in respiratory samples
時間枠：Day 3, Day 5, Day 7, Day 10, Day 14 and Day 28
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Day 3, Day 5, Day 7, Day 10, Day 14 and Day 28
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Number of days alive
時間枠：Day 28
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Day 28
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Number of day without invasive mechanical ventilation
時間枠：Day 28
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Day 28
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Number of day without antibiotics
時間枠：Day 28
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Day 28
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Anti-phage antibody presence and titers,
時間枠：Day 1, 7, 10, 14 and 28
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Day 1, 7, 10, 14 and 28
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Phage neutralization titers
時間枠：Day 1, 7, 10, 14 and 28
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Day 1, 7, 10, 14 and 28
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Mortality rate
時間枠：Day 28 and Day 60
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Day 28 and Day 60
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Prevalence of ESBL-producing and carbapenem-resistant Gram-negative bacteria in fecal and tracheal aspirate samples
時間枠：Day 28
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Day 28
|
協力者と研究者
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
追加の関連 MeSH 用語
その他の研究ID番号
- APHP222819
- 2024-514008-15 (EudraCT番号)
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
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 共有時間枠
IPD 共有アクセス基準
IPD 共有サポート情報タイプ
- STUDY_PROTOCOL
- SAP
- ICF
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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