ASPIC - Antimicrobial Stewardship for Ventilator Associated Pneumonia in Intensive Care

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]

Trial duration

20 Sep 2022 → ongoing

Decision date (initial)

2024-09-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

DGOS - Ministry of Health

External identifiers

EU CT number

2024-513327-16-00

EudraCT number

2021-002197-78

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

The aim of this study is to investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in terms of all-cause mortality, treatment failure or occurrence of new episode of VAP

Secondary objectives 13

1. 1. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in term of all-cause mortality
2. 2. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in term of occurrence of treatment failure
3. 3. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would be non-inferior in term of occurrence of occurrence of new episode of VAP
4. 4. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would increase the number of antibiotic free-alive days, from initiation of VAP antibiotic therapy to day 28
5. 5. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after initiation of VAP antibiotic therapy the global DOOR (Desirability Of Outcome Ranking) score and RADAR (Response Adjusted for Duration of Antibiotic Risk analysis)11
6. 6. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the duration of invasive mechanical ventilation
7. 7. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the length of stay in intensive care unit
8. 8. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the rate of VAP recurrence
9. 9. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion the rate of complications of antibiotic therapy (antibiotic related side effects: gastro-intestinal symptoms (diarrhea, nausea, Clostridium difficile colitis), acute kidney injury, skin reactions and other drug-specific adverse12
10. 10. To investigate whether an antimicrobial stewardship for VAP based on daily assessment of clinical cure and antimicrobial discontinuation, if it is obtained, would reduce at day 28 after inclusion: 1) the rate of acquisition of carriage of MDR bacteria (carbapenem-resistant Enterobacteriaceae, resistant Staphylococcus aureus, extended-spectrum β-lactam-producing Enterobacteriaceae) 2) The rate of subsequent infection due to: carbapenem-resistant Enterobacteriaceae, resistant Staphylococcus aureus, extended-spectrum β-lactam-producing Enterobacteriaceae ticarcillin-resistant Pseudomonas aeruginosa, carbapenem-resistant Pseudomonas aeruginosa, Acinetobacter baumannii, or Stenotrophomonas maltophilia; high-concentration cephalosporinase-producing AmpC Enterobacteriaceae;
11. 11. To study if an antimicrobial stewardship based on daily clinical assessment of clinical cure of VAP versus standard management would improve survival at days 28 and 90 after inclusion.
12. 12. To study the adherence to the antimicrobial stewardship strategy (in order to identify factors associated to this adherence) in the intervention group only at day 28 after inclusion.
13. 13. To assess the medico-economic impact of antimicrobial stewardship applied to VAP at day 28 after inclusion.

Conditions and MedDRA coding

Intensive care

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Adult patient is ≥18
2. Diagnosis of microbiologically confirmed of first episode of VAP
3. - Initial appropriate antibiotic therapy (whether empirical or not)
4. Written informed consent from the patient or a legal representative if appropriate. If absence of a legal representative the patient may be included in emergency procedure
5. Definitive diagnosis of VAP (in agreement with international guidelines) is defined by association: - Patient under MV>48 hours at the time of the microbiological sampling - New pulmonary infiltrate of which an infectious origin is strongly suspected - worsening oxygenation - Have the following clinical criteria within the 24 hours prior to the first dose of antibiotic therapy  Purulent tracheal secretions  And at least 1 of the following : • Documented fever (body temperature >38,3°C) • Hypothermia (body temperature <35°C) • White blood cell (WBC) count >10,000 cells/mm3 or <4,000 cells/mm3 - microbiological criteria (positive quantitative culture of a lower respiratory tract (LRT): bronchoalveolar lavage fluid (BAL) (significant threshold ≥104 colony-forming units/mL) or plugged telescopic catheter (PTC) (significant threshold ≥ 103 colony-forming units/mL) or quantitative endotracheal aspirate (ETA) distal pulmonary secretion samples (significant threshold ≥105 colony-forming units/mL)

Exclusion criteria 12

1. - Patient under selective decontamination of the digestive tract
2. - Duration of antibiotic therapy prior to inclusion > 72h (for any reason) appropriate to the germs found in the bacterial documentation of the first episode of VAP
3. - Inclusion in another interventional study concerning empirical antimicrobial strategies
4. - Moribund (IGS II>80)
5. - Thoracic trauma with Abbreviated Injury Scale (AIS) thorax  3
6. - Severely immunocompromised patients (such as congenital immunodeficiency, neutropenia (<1leucocyte/ml or <0.5 neutrophil/ml) or acute hematologic malignancy or stem cell transplant, HIV infection with CD4 count below 200/mm3)
7. - Patients undergoing immunosuppressive therapy or long term corticotherapy > 0.5 mg/kg
8. - VAP due to: Pseudomonas aeruginosa, Carbapenem-resistant Acinetobacter spp, Carbapenem-resistant EnterobacteriaceaeBacterial VAP occurring in the context of co-infection of COVID-19 or other viral pneumonia (confirmed by RT-PCR)
9. - Patients with empyema, necrotizing and abscessed pneumonia
10. - Patients requiring extracorporeal oxygen therapy (ECMO), either veno-venous or veno-arterial
11. - Pregnant women
12. - No health insurance coverage

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint is a composite endpoint with non-inferiority criteria including: 1. all-cause mortality (ACM) measured at day 28 after initiation of antibiotic therapy OR 2. Treatment failure defined by signs of pneumonia within 72 hours after the end antibiotic therapy at the test of cure visit OR 3. New episode of microbiologically confirmed VAP from 72 hours after the end antibiotic treatment to day 28 after initiation of VAP antibiotic treatment

Secondary endpoints 13

1. 1) Rate of all-cause mortality
2. 2) Rate of treatment failure
3. 3) Rate of new episode of VAP
4. 4) Number of antibiotic free alive-days from initiation of VAP antibiotic therapy to day 28
5. 5) Global score constructed with the DOOR and RADAR. Overall clinical outcome at day 28, from most to least desirable are: 1. Survival, clinical cure 2. Survival, new pulmonary infection 3. Death
6. 6) Duration of invasive MV, at day 28 after inclusion, defined as total of days under MV
7. 7) Length of ICU stay at day 28 after inclusion, defined by the number of days between inclusion and ICU discharge or in-ICU death.
8. 8) Rate of VAP recurrence by the intensivist at day 28
9. 9) Rate of antibiotic related side effects
10. 10) Rate of acquisition of MDR bacteria at day 28 defined as the identification of a MDR bacteria carriage not present at admission
11. 11) Rate of death at days 28 and 90 at day 28
12. 12) Rate of non-interruption of antibiotic therapy despite a positive clinical cure in the intervention group only at day 28 after inclusion.
13. 13) Total cumulative costs of antibiotics at day 28 and incremental cost effectiveness ratio

Investigational products

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

Test 1

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. Arnaud FOUCRIER

Public contact point

Organisation

Assistance Publique Hopitaux De Paris

Contact name

Dr. Arnaud FOUCRIER

Locations

1 EU/EEA country · 29 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 13 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