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

• ClinicalTrials.gov Identifier: NCT01732250
• Recruitment Status: Completed
• First Posted: November 22, 2012
• Last Update Posted: April 12, 2017
• Sponsor: Mical Paul
• 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

• 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

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 :

1. 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 :

1. 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).

2. Clinical success with modification [ Time Frame: 14 days ]
   Clinical success, but with modification to the antibiotic treatment not permitted by protocol
3. Time to defervescence [ Time Frame: 28 days ]
   defined as time to reach a temperature of <38°C with no recurrence for 3 days
4. Time to weaning [ Time Frame: 28 days ]
   Time to weaning from mechanical ventilation in VAP for patients weaned alive
5. Time to hospital discharge [ Time Frame: 28 days ]
   Time to hospital discharge for patient discharged alive
6. 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
7. Superinfections [ Time Frame: 28 days ]
   Defined as a new clinically or microbiologically-documented infections by CDC criteria within 28 days
8. 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
9. CDAD [ Time Frame: 28 days ]
   Clostridium-difficile-associated diarrhea, defined by diarrhea with a positive C. difficile toxin test

Eligibility Criteria

• 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

Locations

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

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

More Information

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

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.

• Responsible Party: Mical Paul, MD, Rabin Medical Center
• ClinicalTrials.gov Identifier: NCT01732250
• Other Study ID Numbers: 0276-12-RMC
• First Posted: November 22, 2012
• 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:

Bacterial Infections; Gram-Negative Bacterial Infections; Infections; Bacterial Infections and Mycoses; Meropenem; Colistin; Anti-Bacterial Agents; Anti-Infective Agents