Back to resultsCefiderocol and Ampicillin-sulbactam vs. Colistin +/- Meropenem for Carbapenem Resistant A. Baumannii (CASCADE)
Primary Purpose
Carbapenem Resistant Bacterial Infection, Acinetobacter Bacteremia, Acinetobacter Pneumonia
Status
Not yet recruiting
Phase
Phase 4
Locations
Study Type
Interventional
Intervention
Cefiderocol
Ampicillin-sulbactam
Colistin
Meropenem
Sponsored by
About this trial
This is an interventional treatment trial for Carbapenem Resistant Bacterial Infection
Eligibility Criteria
Inclusion Criteria: Adults >18 years with bacteremia or hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP) (Table 3) caused by carbapenem-resistant A. baumannii (CRAB) (meropenem and/ or imipenem minimal inhibitory concentration (MIC) >8 μg/mL) susceptible to cefiderocol (disc zone diameter >=17 mm, corresponding to an MIC <2 μg/mL). We will include CRAB regardless of colistin, ampicillin-sulbactam, minocycline, tigecycline, trimethoprim/sulfamethoxazole and/or aminoglycoside susceptibility of the isolate. Attribution of the HAP/ VAP to CRAB will be allowed with isolation of CRAB from any respiratory sample within 7 days prior to the clinical diagnosis of pneumonia. Exclusion Criteria: More than 72 hours of therapy with in-vitro coverage against the CRAB within 96 hours of enrolment Polymicrobial carbapenem-susceptible infections: growth of other pathogens susceptible to carbapenems, or another beta-lactam, deemed clinically-significant by the treating physicians in blood or sputum (with HAP/ VAP). We will allow recruitment of patients with other carbapenem-resistant Gram-negative bacteria CRAB susceptible any beta-lactam other than cefiderocol Coronavirus 2019 (COVID-19) co-infection Immediate-type hypersensitivity to penicillin Pregnant women Previous participation in the trial Lack of informed consent, considering the procedures acceptable to ethics committees per locale, including deferred consent Infection requiring treatment for over 14 days, at the discretion of the investigators Life expectancy less than 24 hours or expected futility of antibiotic treatment
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Cefiderocol + ampicillin-sulbactam
Colistin or colistin + meropenem
Arm Description
Cefiderocol 2 gram intravenous (IV) q8 hours and ampicillin-sulbactam 3 gram IV q6 hours for patients with normal creatinine clearance, both administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies.
Colistin 9 million units (MIU) intravenous (IV) loading dose followed by 4.5 MIU for patients with normal creatinine clearance +/- meropenem 2 gram IV administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies.
Outcomes
Primary Outcome Measures
All cause mortality
Death from any cause
Secondary Outcome Measures
All cause mortality
Death from any cause
Clinical failure
Composite of:
Death
Systolic blood pressure ≤90 mmHg or need for vasopressor support
Worsening sequential organ failure assessment score (SOFA) score, define as:
for baseline SOFA ≥ 3: stable or increased
for baseline SOFA <3: any increase
For patients with hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP), partial pressure of oxygen in arterial blood (PaO2)/ fraction of inspired oxygen (FiO2) ratio worsened
For patients with bacteremia, growth of the initial isolate in blood cultures after ≥ 5 days since study treatment start
Microbiological failure
Isolation of the initial isolate (phenotypically identical) in blood cultures 5 days or more after start of treatment or in respiratory samples 7 days or more.
Resistance development to cefiderocol
Development of carbapenemase-producing Enterobacterales (CPE), non-CPE carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant A. baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) resistance to cefiderocol in clinical and surveillance cultures collected as defined in the study's protocol
Hospital stay
Among 28-day survivors
Decline in functional capacity
Functional capacity will be assessed in four categories: independent; requires some assistance; requires assistance for activities of daily living (ADL); and bedridden. Decline in functional capacity will be defined as any 1-category worsening.
Adverse event - Clostridiodes difficile infection
Diarrhea with a positive C. difficile toxin test
Adverse event - renal failure
Renal failure due to any reason using the RIFLE ( risk, injury, failure, loss, End stage kidney disease) criteria (classifying patients to None, Risk, Injury, Failure, Loss and ESRD) at day 14 and day 28 and defined as worsening by two RIFLE categories (e.g. from Risk to Failure, etc.)
Adverse event - Acute liver injury
Increase in aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3-fold or increased bilirubin >2 above upper limits of normal (ULN) or baseline value if higher than ULN.
Full Information
NCT ID
NCT05922124
First Posted
May 31, 2023
Last Updated
July 5, 2023
Sponsor
Rambam Health Care Campus
Collaborators
Monaldi Hospital, Rutgers Robert Wood Johnson Medical School, Pisa University Hospital, Assaf-Harofeh Medical Center, Sheba Medical Center
1. Study Identification
Unique Protocol Identification Number
NCT05922124
Brief Title
Cefiderocol and Ampicillin-sulbactam vs. Colistin +/- Meropenem for Carbapenem Resistant A. Baumannii
Acronym
CASCADE
Official Title
Cefiderocol and Ampicillin-sulbactam vs. Colistin or Colistin-meropenem for Carbapenem Resistant Acinetobacter Baumannii Bacteremia or Hospital-acquired Pneumonia: Controlled Clinical Study With Historical Controls (CASCADE)
Study Type
Interventional
2. Study Status
Record Verification Date
July 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
September 2023 (Anticipated)
Primary Completion Date
January 2025 (Anticipated)
Study Completion Date
February 2025 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Rambam Health Care Campus
Collaborators
Monaldi Hospital, Rutgers Robert Wood Johnson Medical School, Pisa University Hospital, Assaf-Harofeh Medical Center, Sheba Medical Center
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
No
5. Study Description
Brief Summary
Patients with bloodstream infections, hospital acquired pneumonia or ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB) treated with cefiderocol combined with ampicillin sulbactam will be compared to patients treated treated with colistin alone or colistin combined with meropenem.
Detailed Description
This will be a prospective controlled clinical study with historical controls.
In the prospective CASCADE study consecutive consenting patients with bloodstream infections, hospital acquired pneumonia or ventilator-associated pneumonia will be treated with cefiderocol combined with ampicillin sulbactam in 3 hospitals in Israel and 2 hospitals in Italy, all endemic for CRAB. We plan to recruit 150 patients into this prospective studies.
The CASCADE cohort will be compared to patients treated for the same types of infection in two recently completed randomized controlled trials (AIDA and OVERCOME). These trials compared between treatment with colistin vs. treatment with colistin-meropenem combination therapy, both finding no difference between treatment groups among patients with carbapenem-resistant Acinetobacter baumannii (CRAB) pneumonia. Thus, patients in CASCADE will be compared to all patients with CRAB bloodstream infections, hospital acquired pneumonia or ventilator-associated pneumonia in these randomized controlled trials.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Carbapenem Resistant Bacterial Infection, Acinetobacter Bacteremia, Acinetobacter Pneumonia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Controlled clinical study with historical controls
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
734 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Cefiderocol + ampicillin-sulbactam
Arm Type
Experimental
Arm Description
Cefiderocol 2 gram intravenous (IV) q8 hours and ampicillin-sulbactam 3 gram IV q6 hours for patients with normal creatinine clearance, both administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies.
Arm Title
Colistin or colistin + meropenem
Arm Type
Active Comparator
Arm Description
Colistin 9 million units (MIU) intravenous (IV) loading dose followed by 4.5 MIU for patients with normal creatinine clearance +/- meropenem 2 gram IV administered as extended infusion of 3 hours. Dosing adjusted according to reduced and augmented renal clearance and to renal replacement therapies.
Intervention Type
Drug
Intervention Name(s)
Cefiderocol
Other Intervention Name(s)
Fetroja
Intervention Description
Test drug regimen
Intervention Type
Drug
Intervention Name(s)
Ampicillin-sulbactam
Other Intervention Name(s)
Unasyn
Intervention Description
Synergistic combination
Intervention Type
Drug
Intervention Name(s)
Colistin
Intervention Description
Historical comparator
Intervention Type
Drug
Intervention Name(s)
Meropenem
Intervention Description
Historical comparator synergistic combination
Primary Outcome Measure Information:
Title
All cause mortality
Description
Death from any cause
Time Frame
28 days
Secondary Outcome Measure Information:
Title
All cause mortality
Description
Death from any cause
Time Frame
14 days
Title
Clinical failure
Description
Composite of:
Death
Systolic blood pressure ≤90 mmHg or need for vasopressor support
Worsening sequential organ failure assessment score (SOFA) score, define as:
for baseline SOFA ≥ 3: stable or increased
for baseline SOFA <3: any increase
For patients with hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP), partial pressure of oxygen in arterial blood (PaO2)/ fraction of inspired oxygen (FiO2) ratio worsened
For patients with bacteremia, growth of the initial isolate in blood cultures after ≥ 5 days since study treatment start
Time Frame
Day 10-14
Title
Microbiological failure
Description
Isolation of the initial isolate (phenotypically identical) in blood cultures 5 days or more after start of treatment or in respiratory samples 7 days or more.
Time Frame
Day 5-7
Title
Resistance development to cefiderocol
Description
Development of carbapenemase-producing Enterobacterales (CPE), non-CPE carbapenem-resistant Enterobacterales (CRE), carbapenem-resistant A. baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) resistance to cefiderocol in clinical and surveillance cultures collected as defined in the study's protocol
Time Frame
28 days
Title
Hospital stay
Description
Among 28-day survivors
Time Frame
28 days
Title
Decline in functional capacity
Description
Functional capacity will be assessed in four categories: independent; requires some assistance; requires assistance for activities of daily living (ADL); and bedridden. Decline in functional capacity will be defined as any 1-category worsening.
Time Frame
28 days
Title
Adverse event - Clostridiodes difficile infection
Description
Diarrhea with a positive C. difficile toxin test
Time Frame
28 days
Title
Adverse event - renal failure
Description
Renal failure due to any reason using the RIFLE ( risk, injury, failure, loss, End stage kidney disease) criteria (classifying patients to None, Risk, Injury, Failure, Loss and ESRD) at day 14 and day 28 and defined as worsening by two RIFLE categories (e.g. from Risk to Failure, etc.)
Time Frame
28 days
Title
Adverse event - Acute liver injury
Description
Increase in aspartate aminotransferase (AST) or alanine transaminase (ALT) > 3-fold or increased bilirubin >2 above upper limits of normal (ULN) or baseline value if higher than ULN.
Time Frame
28 days
Other Pre-specified Outcome Measures:
Title
Desirability of Outcome Ranking (DOOR)
Description
Defined DOOR outcome analysis: Alive no event; Alive 1 event; Alive 2 events; Alive 3 events; Dead. The DOOR events will be: (1) Clinical failure as defined above (2) Hospital stay >14 days from enrolment (3) Adverse events: renal failure, Clostridiodes difficile infection or acute liver injury
Time Frame
28 days
10. Eligibility
Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Adults >18 years with bacteremia or hospital-acquired pneumonia (HAP)/ ventilator-associated pneumonia (VAP) (Table 3) caused by carbapenem-resistant A. baumannii (CRAB) (meropenem and/ or imipenem minimal inhibitory concentration (MIC) >8 μg/mL) susceptible to cefiderocol (disc zone diameter >=17 mm, corresponding to an MIC <2 μg/mL). We will include CRAB regardless of colistin, ampicillin-sulbactam, minocycline, tigecycline, trimethoprim/sulfamethoxazole and/or aminoglycoside susceptibility of the isolate. Attribution of the HAP/ VAP to CRAB will be allowed with isolation of CRAB from any respiratory sample within 7 days prior to the clinical diagnosis of pneumonia.
Exclusion Criteria:
More than 72 hours of therapy with in-vitro coverage against the CRAB within 96 hours of enrolment
Polymicrobial carbapenem-susceptible infections: growth of other pathogens susceptible to carbapenems, or another beta-lactam, deemed clinically-significant by the treating physicians in blood or sputum (with HAP/ VAP). We will allow recruitment of patients with other carbapenem-resistant Gram-negative bacteria
CRAB susceptible any beta-lactam other than cefiderocol
Coronavirus 2019 (COVID-19) co-infection
Immediate-type hypersensitivity to penicillin
Pregnant women
Previous participation in the trial
Lack of informed consent, considering the procedures acceptable to ethics committees per locale, including deferred consent
Infection requiring treatment for over 14 days, at the discretion of the investigators
Life expectancy less than 24 hours or expected futility of antibiotic treatment
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mical Paul
Phone
0502062140
Email
paulm@technion.ac.il
First Name & Middle Initial & Last Name or Official Title & Degree
Marco Falcone
Email
marco.falcone@unipi.it
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marco Falcone
Organizational Affiliation
Pisa University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dafna Yahav
Organizational Affiliation
Sheba Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Mical Paul
Organizational Affiliation
Rambam Health Care Campus
Official's Role
Principal Investigator
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
Protocol will be published. At the end of the study the database will be made available from the lead author.
IPD Sharing Time Frame
As soon as published
IPD Sharing Access Criteria
Justification to lead author
Citations:
PubMed Identifier
37538951
Citation
Kaye KS, Marchaim D, Thamlikitkul V, Carmeli Y, Chiu CH, Daikos G, Dhar S, Durante-Mangoni E, Gikas A, Kotanidou A, Paul M, Roilides E, Rybak M, Samarkos M, Sims M, Tancheva D, Tsiodras S, Kett D, Patel G, Calfee D, Leibovici L, Power L, Munoz-Price S, Stevenson K, Susick L, Latack K, Daniel J, Chiou C, Divine GW, Ghazyaran V, Pogue JM. Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms. NEJM Evid. 2023 Jan;2(1):10.1056/evidoa2200131. doi: 10.1056/evidoa2200131. Epub 2022 Dec 6.
Results Reference
background
PubMed Identifier
29456043
Citation
Paul M, Daikos GL, Durante-Mangoni E, Yahav D, Carmeli Y, Benattar YD, Skiada A, Andini R, Eliakim-Raz N, Nutman A, Zusman O, Antoniadou A, Pafundi PC, Adler A, Dickstein Y, Pavleas I, Zampino R, Daitch V, Bitterman R, Zayyad H, Koppel F, Levi I, Babich T, Friberg LE, Mouton JW, Theuretzbacher U, Leibovici L. Colistin alone versus colistin plus meropenem for treatment of severe infections caused by carbapenem-resistant Gram-negative bacteria: an open-label, randomised controlled trial. Lancet Infect Dis. 2018 Apr;18(4):391-400. doi: 10.1016/S1473-3099(18)30099-9. Epub 2018 Feb 16.
Results Reference
result
Learn more about this trial
Cefiderocol and Ampicillin-sulbactam vs. Colistin +/- Meropenem for Carbapenem Resistant A. Baumannii
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