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

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ClinicalTrials.gov Identifier: NCT01732250

Recruitment Status : Completed

First Posted : November 22, 2012

Last Update Posted : April 12, 2017

Sponsor:

Collaborator:

European Commission

Information provided by (Responsible Party):

Mical Paul, Rabin Medical Center

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

Condition or disease	Intervention/treatment	Phase
Gram-Negative Bacterial Infections	Drug: Colistin Drug: Meropenem	Phase 4

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	406 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Multicenter Open-label RCT to Compare Colistin Alone vs. Colistin Plus Meropenem
Actual Study Start Date :	March 2013
Actual Primary Completion Date :	January 31, 2017
Actual Study Completion Date :	February 28, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bacterial Infections

Drug Information available for: Colistin Colistin sulfate Meropenem

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
Experimental: Colistin and Meropenem 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	Drug: Colistin IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days. Other Names: Colistimethate Sodium Coliracin Drug: Meropenem IV meropenem, 2 gram q8h, adjusted for renal function, for up to 10 days. Other Name: Meronem
Active Comparator: Colistin IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function	Drug: Colistin IV Colistin with loading dose of 9 mil IU units, Maintenance dose 4.5 mil IU q12h, adjusted for renal function, for 10 days. Other Names: Colistimethate Sodium Coliracin

Outcome Measures

Primary Outcome Measures :

Clinical success [ Time Frame: 14 days ]
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 [ Time Frame: 14 and 28 days ]
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 [ Time Frame: 14 days ]
Clinical success, but with modification to the antibiotic treatment not permitted by protocol
Time to defervescence [ Time Frame: 28 days ]
defined as time to reach a temperature of <38°C with no recurrence for 3 days
Time to weaning [ Time Frame: 28 days ]
Time to weaning from mechanical ventilation in VAP for patients weaned alive
Time to hospital discharge [ Time Frame: 28 days ]
Time to hospital discharge for patient discharged alive
Microbiological failure [ Time Frame: 28 days ]
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 [ Time Frame: 28 days ]
Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days
New resistant infection [ Time Frame: 28 days ]
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 [ Time Frame: 28 days ]
Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

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To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01732250

Locations

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Greece
Atikkon Hospital
Athens, Greece
Laikon Hosptial
Athens, Greece
Israel
Rambam Health Care Center
Haifa, Israel
Rabin Medical Center
Petach-Tikvah, Israel
Tel-Aviv Sourasky Medical Center
Tel-Aviv, Israel
Italy
Monaldi Hospital, University of Naples S.U.N.
Naples, Italy
Agostino Gemelli Hospital
Rome, Italy

Sponsors and Collaborators

Mical Paul

European Commission

Investigators

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Study Chair:	Johan Mouton, MD PhD	Radboud University
Principal Investigator:	Mical Paul, MD	Rambam Health Care Centre

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

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.

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Responsible Party:	Mical Paul, MD, Rabin Medical Center
ClinicalTrials.gov Identifier:	NCT01732250
Other Study ID Numbers:	0276-12-RMC
First Posted:	November 22, 2012 Key Record Dates
Last Update Posted:	April 12, 2017
Last Verified:	April 2017

Keywords provided by Mical Paul, Rabin Medical Center:


Gram-Negative Bacterial Infections Resistant Bacteria Drug Resistance, Bacterial Colistin

Additional relevant MeSH terms:

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Bacterial Infections Gram-Negative Bacterial Infections Meropenem	Colistin Anti-Bacterial Agents Anti-Infective Agents

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