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Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem

Primary Purpose

Gram-Negative Bacterial Infections

Status
Completed
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Colistin
Meropenem
Sponsored by
Mical Paul
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Gram-Negative Bacterial Infections focused on measuring Gram-Negative Bacterial Infections, Resistant Bacteria, Drug Resistance, Bacterial, Colistin

Eligibility Criteria

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

Inclusion Criteria:

  • Adult inpatients
  • Clinically significant, microbiological-documented infection caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria and identified according to CDC criteria- blood stream infections, hospital acquired pneumonia, ventilator associated pneumonia, and urinary tract infections
  • Patient recruitment will occur only after microbiological documentation and susceptibility testing. Patients will be included within 96 hours of the time the index culture was taken (typically within 48 hours of isolate identification), regardless of the antibiotic treatment administered during this time period.

Exclusion Criteria:

  • Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection
  • Pregnant women
  • Epilepsy or prior seizures
  • Known allergy to colistin or a carbapenem

Sites / Locations

  • Atikkon Hospital
  • Laikon Hosptial
  • Rambam Health Care Center
  • Rabin Medical Center
  • Tel-Aviv Sourasky Medical Center
  • Monaldi Hospital, University of Naples S.U.N.
  • Agostino Gemelli Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Colistin and Meropenem

Colistin

Arm Description

IV meropenem, 2 gram q8h, adjusted for renal function IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function

IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function

Outcomes

Primary Outcome Measures

Clinical success
defined as a composite of all of the following, all measured at 14 days: Patient alive Systolic blood pressure >90 mmHg without need for vasopressor support Stable or improved SOFA score, define as: for baseline SOFA ≥ 3: a decrease of at least 30%; for baseline SOFA <3: stable or decreased SOFA score For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile

Secondary Outcome Measures

Secondary outcomes and adverse events
14 and 28-day all-cause mortality. If patients are discharged or death occurs before end of follow-up (day 28), we will end data collection at that date. We will attempt to determine survival status at day 28 for all patients (central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and Italy).
Clinical success with modification
Clinical success, but with modification to the antibiotic treatment not permitted by protocol
Time to defervescence
defined as time to reach a temperature of <38°C with no recurrence for 3 days
Time to weaning
Time to weaning from mechanical ventilation in VAP for patients weaned alive
Time to hospital discharge
Time to hospital discharge for patient discharged alive
Microbiological failure
Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in a clinical sample (blood or other) 7 days or more after start of treatment or its identification in respiratory samples. For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day 7, regardless of clinical response For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless of clinical response For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if the patient is febrile at that time
Superinfections
Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days
New resistant infection
Colonization or infection by newly-acquired (other species than the initial infection) carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be assessed by rectal surveillance
CDAD
Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test

Full Information

First Posted
November 19, 2012
Last Updated
April 10, 2017
Sponsor
Mical Paul
Collaborators
European Commission
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1. Study Identification

Unique Protocol Identification Number
NCT01732250
Brief Title
Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem
Official Title
Multicenter Open-label RCT to Compare Colistin Alone vs. Colistin Plus Meropenem
Study Type
Interventional

2. Study Status

Record Verification Date
April 2017
Overall Recruitment Status
Completed
Study Start Date
March 2013 (Actual)
Primary Completion Date
January 31, 2017 (Actual)
Study Completion Date
February 28, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Mical Paul
Collaborators
European Commission

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to determine whether the addition of meropenem to colistin is better than colistin alone in the treatment of clinically significant infections caused by multi-drug resistant bacteria

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Gram-Negative Bacterial Infections
Keywords
Gram-Negative Bacterial Infections, Resistant Bacteria, Drug Resistance, Bacterial, Colistin

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
406 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Colistin and Meropenem
Arm Type
Experimental
Arm Description
IV meropenem, 2 gram q8h, adjusted for renal function IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function
Arm Title
Colistin
Arm Type
Active Comparator
Arm Description
IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function
Intervention Type
Drug
Intervention Name(s)
Colistin
Other Intervention Name(s)
Colistimethate Sodium, Coliracin
Intervention Description
IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days.
Intervention Type
Drug
Intervention Name(s)
Meropenem
Other Intervention Name(s)
Meronem
Intervention Description
IV meropenem, 2 gram q8h, adjusted for renal function, for up to 10 days.
Primary Outcome Measure Information:
Title
Clinical success
Description
defined as a composite of all of the following, all measured at 14 days: Patient alive Systolic blood pressure >90 mmHg without need for vasopressor support Stable or improved SOFA score, define as: for baseline SOFA ≥ 3: a decrease of at least 30%; for baseline SOFA <3: stable or decreased SOFA score For patients with HAP/ VAP, PaO2/FiO2 ratio stable or improved For patients with bacteremia, no growth of the initial isolate in blood cultures taken on day 14 if patient still febrile
Time Frame
14 days
Secondary Outcome Measure Information:
Title
Secondary outcomes and adverse events
Description
14 and 28-day all-cause mortality. If patients are discharged or death occurs before end of follow-up (day 28), we will end data collection at that date. We will attempt to determine survival status at day 28 for all patients (central registry in Israel; re-admissions, rehabilitation centers, hospital transfers in Greece and Italy).
Time Frame
14 and 28 days
Title
Clinical success with modification
Description
Clinical success, but with modification to the antibiotic treatment not permitted by protocol
Time Frame
14 days
Title
Time to defervescence
Description
defined as time to reach a temperature of <38°C with no recurrence for 3 days
Time Frame
28 days
Title
Time to weaning
Description
Time to weaning from mechanical ventilation in VAP for patients weaned alive
Time Frame
28 days
Title
Time to hospital discharge
Description
Time to hospital discharge for patient discharged alive
Time Frame
28 days
Title
Microbiological failure
Description
Microbiological failure, defined as isolation of the initial isolate (phenotypically identical) in a clinical sample (blood or other) 7 days or more after start of treatment or its identification in respiratory samples. For all patients with VAP/ HAP sputum or tracheal aspirates will be obtained on day 7, regardless of clinical response For all patients with UTI, a repeat urine culture will be obtained on day 7, regardless of clinical response For patients with bacteremia, blood cultures will be repeated on day 7 and 14, only if the patient is febrile at that time
Time Frame
28 days
Title
Superinfections
Description
Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days
Time Frame
28 days
Title
New resistant infection
Description
Colonization or infection by newly-acquired (other species than the initial infection) carbapenem-resistant or colistin-resistant Gram-negative bacteria. Colonization will be assessed by rectal surveillance
Time Frame
28 days
Title
CDAD
Description
Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test
Time Frame
28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Adult inpatients Clinically significant, microbiological-documented infection caused by carbapenem-resistant and colistin-susceptible Gram-negative bacteria and identified according to CDC criteria- blood stream infections, hospital acquired pneumonia, ventilator associated pneumonia, and urinary tract infections Patient recruitment will occur only after microbiological documentation and susceptibility testing. Patients will be included within 96 hours of the time the index culture was taken (typically within 48 hours of isolate identification), regardless of the antibiotic treatment administered during this time period. Exclusion Criteria: Previous inclusion in the trial. Patients will be included in the RCT only once for the first identified episode of infection Pregnant women Epilepsy or prior seizures Known allergy to colistin or a carbapenem
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Johan Mouton, MD PhD
Organizational Affiliation
Radboud University Medical Center
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Mical Paul, MD
Organizational Affiliation
Rambam Health Care Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Atikkon Hospital
City
Athens
Country
Greece
Facility Name
Laikon Hosptial
City
Athens
Country
Greece
Facility Name
Rambam Health Care Center
City
Haifa
Country
Israel
Facility Name
Rabin Medical Center
City
Petach-Tikvah
Country
Israel
Facility Name
Tel-Aviv Sourasky Medical Center
City
Tel-Aviv
Country
Israel
Facility Name
Monaldi Hospital, University of Naples S.U.N.
City
Naples
Country
Italy
Facility Name
Agostino Gemelli Hospital
City
Rome
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
33789574
Citation
Daitch V, 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, Cavezza G, Adler A, Dickstein Y, Pavleas I, Zampino R, Bitterman R, Zayyad H, Koppel F, Zak-Doron Y, Levi I, Babich T, Turjeman A, Ben-Zvi H, Friberg LE, Mouton JW, Theuretzbacher U, Leibovici L. Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity. BMC Infect Dis. 2021 Mar 31;21(1):309. doi: 10.1186/s12879-021-05995-y.
Results Reference
derived
PubMed Identifier
30462182
Citation
Dickstein Y, Lellouche J, Ben Dalak Amar M, Schwartz D, Nutman A, Daitch V, Yahav D, Leibovici L, Skiada A, Antoniadou A, Daikos GL, Andini R, Zampino R, Durante-Mangoni E, Mouton JW, Friberg LE, Dishon Benattar Y, Bitterman R, Neuberger A, Carmeli Y, Paul M; AIDA Study Group. Treatment Outcomes of Colistin- and Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial. Clin Infect Dis. 2019 Aug 16;69(5):769-776. doi: 10.1093/cid/ciy988.
Results Reference
derived
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
derived
PubMed Identifier
27098822
Citation
Dickstein Y, Leibovici L, Yahav D, Eliakim-Raz N, Daikos GL, Skiada A, Antoniadou A, Carmeli Y, Nutman A, Levi I, Adler A, Durante-Mangoni E, Andini R, Cavezza G, Mouton JW, Wijma RA, Theuretzbacher U, Friberg LE, Kristoffersson AN, Zusman O, Koppel F, Dishon Benattar Y, Altunin S, Paul M; AIDA consortium. Multicentre open-label randomised controlled trial to compare colistin alone with colistin plus meropenem for the treatment of severe infections caused by carbapenem-resistant Gram-negative infections (AIDA): a study protocol. BMJ Open. 2016 Apr 20;6(4):e009956. doi: 10.1136/bmjopen-2015-009956.
Results Reference
derived

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Multicenter Open-label Randomized Controlled Trial (RCT) to Compare Colistin Alone Versus Colistin Plus Meropenem

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