Nebulized Amikacine for Ventilator associated gram negative Pneumonia in ECMO veno-arterial patients: A randomized Pilot Study (NAVAP-ECMO)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Assistance Publique Hopitaux De Paris

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Bacterial Infections and Mycoses [C01]

Decision date (initial)

2024-06-27

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To show that the administration of inhaled amikacin for 5 days in addition to the usual antibiotic therapy in adult patients with documented Gram-negative Bacillus-positive pulmonary arterial disease undergoing VA-ECMO improves the bacterial eradication rate at D5 compared with the usual antibiotic therapy alone.

Secondary objectives 6

1. To compare the clinical cure rate at D5 between the inhaled amikacin group with standard antibiotic therapy and the standard antibiotic therapy group alone
2. To compare the rate of persistence of pneumonia at D5 between the inhaled amikacin group with standard antibiotic therapy and the standard antibiotic therapy group alone
3. To compare the evolution of the clinical pulmonary infection score (CPIS) between randomisation and D5 between the inhaled amikacin group with standard antibiotic therapy and the standard antibiotic therapy group alone
4. To compare the evolution of the lung aeration assessment score by lung ultrasound at randomization and D5 between the inhaled amikacin group with standard antibiotic therapy and the standard antibiotic therapy group alone
5. To compare adverse events and serious adverse events between the inhaled amikacin group with standard antibiotic therapy and the standard antibiotic therapy group alone
6. To measure plasma and alveolar concentrations of piperacillin-tazobactam at equilibrium after 2 days of treatment in patients undergoing ECMO-VA

Conditions and MedDRA coding

gram-negative bacillus pneumonia acquired during mechanical ventilation in patients receiving Extracorporeal Membrane veno-arterial oxygenation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. Age ≥ 18 years old
2. Circulatory assistance by ECMO veno-arterial for at least 24 hours prior to documentation of pneumonia
3. Invasive mechanical ventilation
4. Diagnostic suspicion of pneumonia based on suggestive criteria (presence of at least 2 of the following criteria): fever >38. 5°C, hyperleukocytosis >11 × 109 l-1 or leukopenia <4 × 109 l-1, purulent tracheobronchial secretions, altered oxygenation with the need to increase FiO2 on the ECMO or ventilator for the same SaO2 or PaO2 target, new or persistent pulmonary infiltrate(s) on chest X-ray in bed, or an image suggestive of pneumonia on a chest CT scan, or consolidation of an appearance suggestive of an infectious origin on lung ultrasound
5. Microbiological confirmation of gram-negative ventilator-associated pneumonia by quantitative culture on bronchoalveolar lavage (BAL, significance threshold > 104 CFU/ml) or protected distal sampling (PDP, significance threshold > 103 CFU/ml)
6. Probabilistic antibiotic therapy with piperacillin - tazobactam
7. Informed consent obtained from the patient or his/her trusted support person if unable to consent at the time of inclusion, or inclusion procedure in an emergency situation
8. Patient affiliated to a social security scheme (excluding AME)

Exclusion criteria 12

1. Known allergy to amikacin or another aminoglycoside
2. Contraindications to the administration of amikacin
3. Contraindications to nebulisation
4. Intravenous antibiotic therapy started more than 72 hours before administration of the first dose of study treatment
5. Probabilistic venous antibiotic therapy other than piperacillin-tazobactam
6. Administration of inhaled antibiotics in the 7 days prior to inclusion
7. Positive pregnancy test for women of childbearing potential
8. Presence of HIV infection with CD4 count <200 cells/mm3 or fungal lung infection or pulmonary abscess or empyema
9. Presence of renal insufficiency with creatinine clearance < 15 ml/min, with the exception of patients receiving continuous renal purification or daily haemodialysis sessions as part of their intensive care treatment
10. Patient moribund or with a high probability of death within 48 hours
11. Patient under legal protection (curatorship, guardianship or safeguard of justice)
12. Participating in another interventional clinical trial or within the exclusion period at the end of a previous study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Bacterial eradication rate, defined as absence of germs on direct examination and negative culture of a tracheal aspirate taken on day 5 (D5) after randomisation and at least 12 hours after the last administration of inhaled amikacin

Secondary endpoints 7

1. Clinical cure rate, defined as the disappearance of clinical signs suggestive of pneumonia, biological inflammatory syndrome, and correction of haematosis disorders, at D5
2. Pneumonia persistence rate defined as the presence of the pathogen identified at a significant level on culture of tracheal aspirate at D5
3. Difference between CPIS score at D5 and CPIS score at randomization
4. Difference between ultrasound lung ventilation score at D5 and lung ventilation score at randomization
5. Quantifying and analysing adverse events
6. Pharmacokinetic analysis of plasma concentrations of piperacillin-tazobactam
7. Measurement of the ratio of penetration into alveolar fluid (AUC alveolar fluid/AUC plasma) of piperacillin-tazobactam in patients undergoing VA-ECMO after 2 days of intravenous antibiotic therapy

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Assistance Publique Hopitaux De Paris

Sponsor organisation

Assistance Publique Hopitaux De Paris

Address

Porte 23, 1 Avenue Claude Vellefaux 1 Avenue Claude Vellefaux

City

Paris Cedex 10

Postcode

75475

Country

France

Scientific contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr Pauline DUREAU

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr Pauline DUREAU

Locations

1 EU/EEA country · 2 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 12 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications