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

Multicenter Open-label RCT to Compare Colistin Alone vs. Colistin Plus Meropenem

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

Study Overview

• Status: Completed
• Conditions: Gram-Negative Bacterial Infections
• Intervention / Treatment: Drug: Colistin; Drug: Meropenem

• Study Type: Interventional
• Enrollment (Actual): 406
• Phase: Phase 4

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	14 days

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Mical Paul
• Collaborators: European Commission
• Investigators: Study Chair: Johan Mouton, MD PhD, Radboud university medical center; Principal Investigator: Mical Paul, MD, Rambam Health Care Centre

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 1, 2013
• Primary Completion (ACTUAL): January 31, 2017
• Study Completion (ACTUAL): February 28, 2017

Study Registration Dates

• First Submitted: November 19, 2012
• First Submitted That Met QC Criteria: November 21, 2012
• First Posted (ESTIMATE): November 22, 2012

Study Record Updates

• Last Update Posted (ACTUAL): April 12, 2017
• Last Update Submitted That Met QC Criteria: April 10, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Gram-Negative Bacterial Infections; Drug Resistance, Bacterial; Colistin; Resistant Bacteria
• Additional Relevant MeSH Terms: Infections; Bacterial Infections and Mycoses; Bacterial Infections; Gram-Negative Bacterial Infections; Anti-Infective Agents; Anti-Bacterial Agents; Meropenem; Colistin
• Other Study ID Numbers: 0276-12-RMC