Clinical trial NCT05696093: Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit
Official title: Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit. Multicentric Non-inferiority Randomised Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ventilator Associated Pneumonia
Keywords: intensive care unit
de-escalation
cotrimoxazole
Ventilator Associated Pneumonia
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2023-01-25
Enrollment: 628
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP.
Primary purpose: TREATMENT

Brief summary: Efficacy of cotrimoxazole as a de-escalation treatment for adult patients Ventilator-Associated Pneumonia in intensive care unit Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP

Detailed description: Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP. Selection of patients will be done by physicians in ICU. All clinically suspected VAP will be confirmed with a lung sample (preferably bronchoalveolar lavage or protected distal specimen, otherwise endotracheal aspiration). Patients with a microbiologically confirmed VAP due to an Enterobacteriaceae susceptible to cotrimoxazole and at least one antibiotic of the empiric antibiotic therapy (based on international recommendations) will be included. After written informed consent, they will be randomized (1:1), using a computer-generated randomization scheme of various-sized blocks, stratified by presence of septic shock at VAP diagnosis and by presence of COVID-19 pneumonia on ICU admission, through a centralized 24 hours internet service (CleanWEB™) to cotrimoxazole, or best standard of care (either a beta-lactam or a fluoroquinolone), after randomization for a total duration of 7 days (including empiric initial appropriate treatment). Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patients. Because antibiotic therapy will be variable in the control group, single or double blind is not appropriate. Daily follow-up until death or ICU discharge or day 28 will be performed (vital status, antibiotic therapy, new infection, Clostridium-difficile infection). Clinical (arterial blood gas, temperature, haematology, tracheal secretions) and radiological cure (chest X-ray) will be assessed at Day 7. Systematic MDR bacteria screening will be performed weekly and at ICU discharge. Vital status will be assessed at day 90. Alive patients leaving ICU before 90 days will be contacted by phone (if discharge at home) or by interview at hospital (if transferred in a different ward). Assessment of the clinical and radiological cure by an independent committee (1 specialist in infectious disease and 1 intensivist), blinded of the randomization arm (PROBE methodology).

Eligibility criteria: Inclusion Criteria:

* Adult patients hospitalized in an ICU
* Under mechanical ventilation for at least five days
* Microbiologically confirmed VAP preferably on a distal lung sample (bronchoalveolar lavage or protected distal specimen) otherwise endotracheal aspiration
* Enterobacteriaceae susceptible to cotrimoxazole, and for polymicrobial VAP, all bacteria susceptible to cotrimoxazole
* 5) Treated for at least 24 hours by an appropriate empiric antibiotic therapy (at least one effective antibiotic from the initiation of treatment for this VAP episode), and for polymicrobial VAP, all bacteria susceptible to empiric antibiotic therapy
* Stability of haemodynamic (stability or decrease in catecholamine dose) and respiratory (stability or improvement of FIO2) parameters

Exclusion Criteria:

* Haemodynamic instability (increasing dose of a catecholamine in the last 24 hours)
* Contra-indication to cotrimoxazole:

  * allergy,
  * advanced liver insufficiency,
  * renal dysfunction with clearance \<15 mL/min/1.73 m² without hemodialysis
  * G6PD deficiency
  * history of hypersensitivity to one of the components (in particular, hypersensitivity to sulphonamides
  * known macrocytic anemia defined by VGM \>
  * treatment with methotrexate
* Infection requiring prolonged antibiotic-therapy (pleural empyema, lung abscess, necrotizing pneumonia, etc...)
* Cystic fibrosis
* Immunosuppression (neutropenia, HIV with CD4 lymphocytes below 200/mm3, immunosuppressive therapy or corticosteroid therapy \>0.5 mg/kg/j before ICU admission)
* Cardiac arrest without awakening
* Moribund state (patient likely to die within 24h)
* Limitation of life support (comfort care applied only) at the time of screening
* Enrolment to another interventional study on VAP care/management
* Pregnancy or breastfeeding
* Subject deprived of freedom, subject under a legal protective measure
* No affiliation to any health insurance system
* Refusal to participate to the study (patient or legal representative or family member or close relative if present)
* Patients previously included in the study

Primary outcomes:
measure: To demonstrate that cotrimoxazole is non-inferior to best standard of care for the treatment of VAP in ICU in term of survival at day 28
timeFrame: 28 days after inclusion
Secondary outcomes:
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in term of mortality at day 90
timeFrame: 90 days after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in IC in terms of mechanical ventilation (MV)-free-days at day 28
timeFrame: 28 days after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of rate of cure between days 7 and 10
timeFrame: days 7 and 10 after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of VAP recurrence
timeFrame: 28 days after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of ICU length of stay
timeFrame: 28 days after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of hospital length of stay
timeFrame: 28 days after inclusion
measure: To assess the safety of cotrimoxazole compared to best standard of care at day 28 in terms of allergy to antibiotics
timeFrame: 28 days after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of mortality at day 28
timeFrame: 28 days after inclusion
measure: To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of overall antibiotic consumption
timeFrame: day 28 after inclusion
measure: To assess the ecological impact of the treatment in terms of acquisition of MDR bacteria in ICU
timeFrame: 28 days after inclsuion
measure: To assess the ecological impact of the treatment in terms of rate of Clostridioides difficile infection
timeFrame: 28 days after inclusion
Other outcomes:
Locations:
city: Amiens
country: France
facility: Médecine Intensive Réanimation - Centre Hospitalier Universitaire Amiens-Picardie
city: Angers
country: France
facility: Médecine Intensive Réanimation - Centre Hospitalier Universitaire Angers
city: Bobigny
country: France
facility: Réanimation Médico-chirurgicale - Hôpital Avicenne
city: Bordeaux
country: France
facility: Médecine Intensive Réanimation - CHU Bordeaux - Hôpital Pellegrin
city: Boulogne-Billancourt
country: France
facility: Réanimation Médico-chirurgicale - Hôpital Ambroise-Paré
city: Béthune
country: France
facility: Médecine Intensive Réanimation - Centre Hospitalier Béthune - Beuvry
city: Cholet
country: France
facility: Réanimation polyvalente et Unité de surveillance continue - Centre Hospitalier de Cholet
city: Clermont-Ferrand
country: France
facility: Réanimation Médicale - Centre Jean Perrin - Site Gabriel Montpied
city: Colombes
country: France
facility: Médecine Intensive Réanimation - Hôpital Louis Mourier
city: Corbeil-Essonnes
country: France
facility: Réanimation polyvalente et surveillance continus - Centre Hospitalier Sud Francilien
city: Dijon
country: France
facility: Médecine Intensive Réanimation - Hôpital François Mitterrand
city: La Roche-sur-Yon
country: France
facility: Médecine Intensive Réanimation - Centre Hospitalier Départemental Vendée
city: La Tronche
country: France
facility: Médecine Intensive Réanimation - Hôpital Michallon
city: Lille
country: France
facility: Réanimation Médicale - Hôpital Robert Salengro
city: Longjumeau
country: France
facility: Réanimation médicale - Centre Hospitalier de Longjumeau
city: Melun
country: France
facility: Réanimation et Surveillance continue - Centre Hospitalier de Melun
city: Nancy
country: France
facility: Médecine Intensive Réanimation - CHRU de Nancy - Hôpitaux de Brabois
city: Nantes
country: France
facility: Réanimation Médicale et Maladies Infectieuses - Hôpital Laennec
city: Paris
country: France
facility: Médecine Intensive et Réanimation - Hôpital de la Pitié Salpêtrière
city: Paris
country: France
facility: Réanimation Médicale - Hôpital de la Pitié Salpêtrière
city: Paris
country: France
facility: Réanimation Médicale - Hôpital Européen Georges Pompidou
city: Poissy
country: France
facility: Centre Hospitalier Intercommunal Saint-Germain-en-Laye
city: Pontoise
country: France
facility: Médecine Intensive Réanimation - Hôpital René Dubos
city: Provins
country: France
facility: Médecine Intensive Réanimation - Centre Hospitalier Léon Binet
city: Saint-Denis
country: France
facility: Médecin Intensive Réanimation - Hôpital Delafontaine
city: Saint-Priest-en-Jarez
country: France
facility: Réanimation Polyvalente - Centre Hospitalier Universitaire Nord Saint-Etienne
city: Strasbourg
country: France
facility: Médecine Intensive Réanimation - Nouvel Hôpital Civil
city: Toulon
country: France
facility: Réanimation Polyvalente - Hôpital Sainte Musse
city: Tours
country: France
facility: Médecine Intensive Réanimation - Hôpital Bretonneau
city: Épagny
country: France
facility: Réanimation Polyvalente - Centre Hospitalier Annecy Genevois
Study officials:
References: