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

Ventilator Associated Pneumonia Clinical Trial

— COTRIVAP  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05696093
• Other study ID #: APHP220799
• Status: Recruiting
• Phase: Phase 3
• Start date: October 19, 2023
• Est. completion date: December 31, 2026

Study information

• Verified date: March 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Damien Roux, MD-PhD
• Phone: 01.47.60.63.29
• Email: damien.roux[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 628
• Est. completion date: December 31, 2026
• Est. primary completion date: October 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Pneumonia
• Pneumonia, Ventilator-Associated
• Ventilator Associated Pneumonia

Intervention

Drug:
• cotrimoxazole
Use of cotrimoxazole therapy for enterobacterial VAP
• standard antibiotic therapy
Use of standard antibiotic therapy for enterobacterial VAP

Locations

Country	Name	City	State
France	Médecine Intensive Réanimation - Centre Hospitalier Universitaire Amiens-Picardie	Amiens
France	Médecine Intensive Réanimation - Centre Hospitalier Universitaire Angers	Angers
France	Médecine Intensive Réanimation - Centre Hospitalier Béthune - Beuvry	Béthune
France	Réanimation Médico-chirurgicale - Hôpital Avicenne	Bobigny
France	Médecine Intensive Réanimation - CHU Bordeaux - Hôpital Pellegrin	Bordeaux
France	Réanimation Médico-chirurgicale - Hôpital Ambroise-Paré	Boulogne-Billancourt
France	Réanimation polyvalente et Unité de surveillance continue - Centre Hospitalier de Cholet	Cholet
France	Réanimation Médicale - Centre Jean Perrin - Site Gabriel Montpied	Clermont-Ferrand
France	Médecine Intensive Réanimation - Hôpital Louis Mourier	Colombes
France	Réanimation polyvalente et surveillance continus - Centre Hospitalier Sud Francilien	Corbeil-Essonnes
France	Médecine Intensive Réanimation - Hôpital François Mitterrand	Dijon
France	Réanimation Polyvalente - Centre Hospitalier Annecy Genevois	Épagny
France	Médecine Intensive Réanimation - Centre Hospitalier Départemental Vendée	La Roche-sur-Yon
France	Médecine Intensive Réanimation - Hôpital Michallon	La Tronche
France	Réanimation Médicale - Hôpital Robert Salengro	Lille
France	Réanimation médicale - Centre Hospitalier de Longjumeau	Longjumeau
France	Réanimation et Surveillance continue - Centre Hospitalier de Melun	Melun
France	Médecine Intensive Réanimation - CHRU de Nancy - Hôpitaux de Brabois	Nancy
France	Réanimation Médicale et Maladies Infectieuses - Hôpital Laennec	Nantes
France	Médecine Intensive et Réanimation - Hôpital de la Pitié Salpêtrière	Paris
France	Réanimation Médicale - Hôpital de la Pitié Salpêtrière	Paris
France	Réanimation Médicale - Hôpital Européen Georges Pompidou	Paris
France	Centre Hospitalier Intercommunal Saint-Germain-en-Laye	Poissy
France	Médecine Intensive Réanimation - Hôpital René Dubos	Pontoise
France	Médecine Intensive Réanimation - Centre Hospitalier Léon Binet	Provins
France	Médecin Intensive Réanimation - Hôpital Delafontaine	Saint-Denis
France	Réanimation Polyvalente - Centre Hospitalier Universitaire Nord Saint-Etienne	Saint-Priest-en-Jarez
France	Médecine Intensive Réanimation - Nouvel Hôpital Civil	Strasbourg
France	Réanimation Polyvalente - Hôpital Sainte Musse	Toulon
France	Médecine Intensive Réanimation - Hôpital Bretonneau	Tours

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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