Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit (COTRIVAP)

Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit. Multicentric Non-inferiority Randomised Controlled Trial

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

Study Overview

• Status: Recruiting
• Conditions: Ventilator Associated Pneumonia
• Intervention / Treatment: Drug: cotrimoxazole; Drug: standard antibiotic therapy

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).

• Study Type: Interventional
• Enrollment (Estimated): 628
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Damien Roux, MD-PhD; Phone Number: 01.47.60.63.29; Email: damien.roux@aphp.fr
• Study Contact Backup: Name: Aline DECHANET; Phone Number: 01.40.25.78.30; Email: aline.dechanet@aphp.fr

Study Locations

• France
  • Amiens, France, 80054
    • Active, not recruiting
    • Médecine Intensive Réanimation - Centre Hospitalier Universitaire Amiens-Picardie
  • Angers, France, 49100
    • Active, not recruiting
    • Médecine Intensive Réanimation - Centre Hospitalier Universitaire Angers
  • Bobigny, France, 93000
    • Not yet recruiting
    • Réanimation Médico-chirurgicale - Hôpital Avicenne
    • Contact: Stéphane GAUDRY; Phone Number: 01 48 95 55 55; Email: stephane.gaudry@aphp.fr
    • Principal Investigator: Stéphane GAUDRY
  • Bordeaux, France, 33000
    • Active, not recruiting
    • Médecine Intensive Réanimation - CHU Bordeaux - Hôpital Pellegrin
  • Boulogne-Billancourt, France, 92100
    • Active, not recruiting
    • Réanimation Médico-chirurgicale - Hôpital Ambroise-Paré
  • Béthune, France, 62660
    • Active, not recruiting
    • Médecine Intensive Réanimation - Centre Hospitalier Béthune - Beuvry
  • Cholet, France, 49300
    • Active, not recruiting
    • Réanimation polyvalente et Unité de surveillance continue - Centre Hospitalier de Cholet
  • Clermont-Ferrand, France, 63003
    • Active, not recruiting
    • Réanimation Médicale - Centre Jean Perrin - Site Gabriel Montpied
  • Colombes, France, 92700
    • Active, not recruiting
    • Médecine Intensive Réanimation - Hôpital Louis Mourier
  • Corbeil-Essonnes, France, 91100
    • Active, not recruiting
    • Réanimation polyvalente et surveillance continus - Centre Hospitalier Sud Francilien
  • Dijon, France, 21079
    • Active, not recruiting
    • Médecine Intensive Réanimation - Hôpital François Mitterrand
  • La Roche-sur-Yon, France, 85000
    • Active, not recruiting
    • Médecine Intensive Réanimation - Centre Hospitalier Départemental Vendée
  • La Tronche, France, 38700
    • Active, not recruiting
    • Médecine Intensive Réanimation - Hôpital Michallon
  • Lille, France, 59037
    • Not yet recruiting
    • Réanimation Médicale - Hôpital Robert Salengro
    • Principal Investigator: Saad NSEIR
    • Contact: Saad NSEIR; Phone Number: 03 20 44 40 84; Email: saad.nseir@chru-lille.fr
  • Longjumeau, France, 91160
    • Active, not recruiting
    • Réanimation médicale - Centre Hospitalier de Longjumeau
  • Melun, France, 77000
    • Active, not recruiting
    • Réanimation et Surveillance continue - Centre Hospitalier de Melun
  • Nancy, France, 54000
    • Active, not recruiting
    • Médecine Intensive Réanimation - CHRU de Nancy - Hôpitaux de Brabois
  • Nantes, France, 44093
    • Not yet recruiting
    • Réanimation Médicale et Maladies Infectieuses - Hôpital Laennec
    • Contact: Karim LAKHAL; Phone Number: 02 53 48 27 85; Email: karim.lakhal@chu-nantes.fr
    • Principal Investigator: Karim LAKHAL
  • Paris, France, 75013
    • Active, not recruiting
    • Médecine Intensive et Réanimation - Hôpital de la Pitié Salpêtrière
  • Paris, France, 75013
    • Recruiting
    • Réanimation Médicale - Hôpital de la Pitié Salpêtrière
    • Contact: Charles Edouard LUYT; Phone Number: 01 42 16 38 24; Email: charles-edouard.luyt@aphp.fr
    • Principal Investigator: Charles Edouard LUYT
  • Paris, France, 75015
    • Recruiting
    • Réanimation Médicale - Hôpital Européen Georges Pompidou
    • Contact: Jean-Luc DIEHL; Phone Number: 01 56 09 32 01; Email: jean-luc.diehl@aphp.fr
    • Principal Investigator: Jean-Luc DIEHL
  • Poissy, France, 78003
    • Not yet recruiting
    • Centre Hospitalier Intercommunal Saint-Germain-en-Laye
    • Contact: Jan HAYON; Email: jhayon@chi-poissy-st-germain.fr
    • Principal Investigator: Jan HAYON
  • Pontoise, France, 93500
    • Active, not recruiting
    • Médecine Intensive Réanimation - Hôpital René Dubos
  • Provins, France, 77160
    • Not yet recruiting
    • Médecine Intensive Réanimation - Centre Hospitalier Léon Binet
    • Contact: Mohamed FEJJAL; Phone Number: 01 64 60 47 42; Email: mfejjal@ch-provins.fr
    • Principal Investigator: Mohamed FEJJAL
  • Saint-Denis, France, 93200
    • Not yet recruiting
    • Médecin Intensive Réanimation - Hôpital Delafontaine
    • Contact: Daniel DA SILVA; Phone Number: 01 42 35 61 40; Email: daniel.silva@ch-stdenis.fr
    • Principal Investigator: Daniel DA SILVA
  • Saint-Priest-en-Jarez, France, 42270
    • Active, not recruiting
    • Réanimation Polyvalente - Centre Hospitalier Universitaire Nord Saint-Etienne
  • Strasbourg, France, 67091
    • Active, not recruiting
    • Médecine Intensive Réanimation - Nouvel Hôpital Civil
  • Toulon, France, 83056
    • Active, not recruiting
    • Réanimation Polyvalente - Hôpital Sainte Musse
  • Tours, France, 37000
    • Active, not recruiting
    • Médecine Intensive Réanimation - Hôpital Bretonneau
  • Épagny, France, 74370
    • Not yet recruiting
    • Réanimation Polyvalente - Centre Hospitalier Annecy Genevois
    • Contact: Noémie ZUCMAN; Email: nzucman@ch-annecygenevois.fr
    • Principal Investigator: Noémie ZUCMAN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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
• 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)
• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: cotrimoxazole; Use of cotrimoxazole for enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.	Drug: cotrimoxazole; Use of cotrimoxazole therapy for enterobacterial VAP
Active Comparator: standard antibiotic therapy; Use of standard antibiotic therapy enterobacterial VAP. Posology and modalities of antibiotic administration will be optimized based on most recent recommendations for ICU patient. They will receive the treatment for 28 days or until death or until ICU discharge if its before 28days.	Drug: standard antibiotic therapy; Use of standard antibiotic therapy for enterobacterial VAP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Vital status at day 28	28 days after inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Vital status at day 90	90 days after inclusion
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	number of MV-free-days through day 28	28 days after inclusion
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	Clinical, biological and radiological cure evaluated 7 to 10 days after VAP diagnosis, defined as the combination of resolution of signs and symptoms present at enrolment, biological improvement, and improvement or lack of progression of radiological signs, as adjudicated by an independent committee (PROBE methodology)	days 7 and 10 after inclusion
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of VAP recurrence	new episode of VAP with the same Enterobacteriaceae	28 days after inclusion
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	ICU length of stay	28 days after inclusion
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	hospital length of stay	28 days after inclusion
To assess the safety of cotrimoxazole compared to best standard of care at day 28 in terms of allergy to antibiotics	safety (rate of allergy due to antimicrobial drug)	28 days after inclusion
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	Vital status at day 28	28 days after inclusion
To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of overall antibiotic consumption	antibiotic-free days at day 28	day 28 after inclusion
To assess the ecological impact of the treatment in terms of acquisition of MDR bacteria in ICU	evolution of rate of MDR bacterial colonization on systematic screening at enrolment until ICU discharge	28 days after inclsuion
To assess the ecological impact of the treatment in terms of rate of Clostridioides difficile infection	diagnostic of Clostridioides difficile infection between inclusion and day 28	28 days after inclusion

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: November 21, 2022
• First Submitted That Met QC Criteria: January 23, 2023
• First Posted (Actual): January 25, 2023

Study Record Updates

• Last Update Posted (Actual): March 29, 2024
• Last Update Submitted That Met QC Criteria: March 28, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: intensive care unit; Ventilator Associated Pneumonia; cotrimoxazole; de-escalation
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Disease Attributes; Cross Infection; Iatrogenic Disease; Healthcare-Associated Pneumonia; Pneumonia; Pneumonia, Ventilator-Associated; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antimalarials; Anti-Infective Agents, Urinary; Anti-Bacterial Agents; Trimethoprim, Sulfamethoxazole Drug Combination
• Other Study ID Numbers: APHP220799

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No