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

Primary Purpose

Ventilator Associated Pneumonia

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
cotrimoxazole
standard antibiotic therapy
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ventilator Associated Pneumonia focused on measuring intensive care unit, de-escalation, cotrimoxazole, Ventilator Associated Pneumonia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Experimental

    Active Comparator

    Arm Label

    cotrimoxazole

    standard antibiotic therapy

    Arm Description

    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.

    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.

    Outcomes

    Primary Outcome Measures

    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

    Secondary Outcome Measures

    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
    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
    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)
    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
    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
    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
    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)
    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
    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
    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
    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

    Full Information

    First Posted
    November 21, 2022
    Last Updated
    August 4, 2023
    Sponsor
    Assistance Publique - Hôpitaux de Paris
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05696093
    Brief Title
    Efficacy of Cotrimoxazole as a De-escalation Treatment of Ventilator-Associated Pneumonia in Intensive Care Unit
    Acronym
    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
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 1, 2023 (Anticipated)
    Primary Completion Date
    October 31, 2026 (Anticipated)
    Study Completion Date
    December 31, 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Assistance Publique - Hôpitaux de Paris

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    No
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    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).

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Ventilator Associated Pneumonia
    Keywords
    intensive care unit, de-escalation, cotrimoxazole, Ventilator Associated Pneumonia

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Model Description
    Multicentre randomized non-inferiority trial comparing cotrimoxazole to standard antibiotic therapy for enterobacterial VAP.
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    628 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    cotrimoxazole
    Arm Type
    Experimental
    Arm Description
    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.
    Arm Title
    standard antibiotic therapy
    Arm Type
    Active Comparator
    Arm Description
    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.
    Intervention Type
    Drug
    Intervention Name(s)
    cotrimoxazole
    Intervention Description
    Use of cotrimoxazole therapy for enterobacterial VAP
    Intervention Type
    Drug
    Intervention Name(s)
    standard antibiotic therapy
    Intervention Description
    Use of standard antibiotic therapy for enterobacterial VAP
    Primary Outcome Measure Information:
    Title
    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
    Description
    Vital status at day 28
    Time Frame
    28 days after inclusion
    Secondary Outcome Measure Information:
    Title
    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
    Description
    Vital status at day 90
    Time Frame
    90 days after inclusion
    Title
    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
    Description
    number of MV-free-days through day 28
    Time Frame
    28 days after inclusion
    Title
    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
    Description
    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)
    Time Frame
    days 7 and 10 after inclusion
    Title
    To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of VAP recurrence
    Description
    new episode of VAP with the same Enterobacteriaceae
    Time Frame
    28 days after inclusion
    Title
    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
    Description
    ICU length of stay
    Time Frame
    28 days after inclusion
    Title
    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
    Description
    hospital length of stay
    Time Frame
    28 days after inclusion
    Title
    To assess the safety of cotrimoxazole compared to best standard of care at day 28 in terms of allergy to antibiotics
    Description
    safety (rate of allergy due to antimicrobial drug)
    Time Frame
    28 days after inclusion
    Title
    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
    Description
    Vital status at day 28
    Time Frame
    28 days after inclusion
    Title
    To demonstrate that cotrimoxazole is superior to best standard of care for the treatment of VAP in ICU in terms of overall antibiotic consumption
    Description
    antibiotic-free days at day 28
    Time Frame
    day 28 after inclusion
    Title
    To assess the ecological impact of the treatment in terms of acquisition of MDR bacteria in ICU
    Description
    evolution of rate of MDR bacterial colonization on systematic screening at enrolment until ICU discharge
    Time Frame
    28 days after inclsuion
    Title
    To assess the ecological impact of the treatment in terms of rate of Clostridioides difficile infection
    Description
    diagnostic of Clostridioides difficile infection between inclusion and day 28
    Time Frame
    28 days after inclusion

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    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 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
    Central Contact Person:
    First Name & Middle Initial & Last Name or Official Title & Degree
    Damien Roux, MD-PhD
    Phone
    01.47.60.63.29
    Email
    damien.roux@aphp.fr
    First Name & Middle Initial & Last Name or Official Title & Degree
    Aline DECHANET
    Phone
    01.40.25.78.30
    Email
    aline.dechanet@aphp.fr

    12. IPD Sharing Statement

    Plan to Share IPD
    No

    Learn more about this trial

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

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