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PipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN) (PETERPEN)

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ClinicalTrials.gov Identifier: NCT03671967
Recruitment Status : Recruiting
First Posted : September 14, 2018
Last Update Posted : October 22, 2020
Sponsor:
Collaborators:
Rabin Medical Center
University of Modena and Reggio Emilia
Tel Aviv Medical Center
Meir Medical Center
Soroka University Medical Center
The Chaim Sheba Medical Center
McGill University Health Centre/Research Institute of the McGill University Health Centre
Jewish General Hospital
Information provided by (Responsible Party):
Roni Oren MD, Rambam Health Care Campus

Tracking Information
First Submitted Date  ICMJE September 12, 2018
First Posted Date  ICMJE September 14, 2018
Last Update Posted Date October 22, 2020
Actual Study Start Date  ICMJE May 1, 2019
Estimated Primary Completion Date January 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 12, 2018)
  • All-cause mortality [ Time Frame: 30 days from randomization ]
  • Treatment failure [ Time Frame: 7 days from randomization ]
    death OR fever > 38°C in the last 48 hours OR lack of resolution of symptoms attributed to the focus of infection OR Sequential Failure Organ Assessment (SOFA) score increasing OR positive blood cultures by the time point assessed
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 13, 2019)
  • All-cause mortality [ Time Frame: 14 and 90 days from randomization ]
  • Treatment failure [ Time Frame: 14 days and 30 days from randomization ]
    death OR fever > 38°C in the last 48 hours OR lack of resolution of symptoms attributed to the focus of infection OR Sequential Failure Organ Assessment (SOFA) score increasing OR positive blood cultures by the time point assessed
  • Microbiological failure [ Time Frame: 7 days and 14 days from randomization ]
    Repeat positive blood cultures with index pathogen on day 4 or later from randomization
  • Recurrent positive blood cultures (relapse) [ Time Frame: 30 days and 90 days from randomization ]
    recurrent positive blood cultures with the index pathogen after prior sterilization of blood cultures or after end of treatment
  • Clostridium difficile associated diarrhea [ Time Frame: 90 days from randomization ]
  • Clinically or microbiologically documented infection other than Gram-negative bacteremia [ Time Frame: 90 days from randomization ]
  • Number of hospital re-admissions [ Time Frame: 90 days from randomization ]
  • Development of resistance [ Time Frame: 90 days from randomization ]
    clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
  • Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital [ Time Frame: 90 days from randomization ]
    detected by weekly rectal surveillance of carriage while in-hospital
  • Total in-hospital days [ Time Frame: 30 days and 90 days from randomization ]
  • Total antibiotic days [ Time Frame: 30 days and 90 days from randomization ]
  • Adverse events [ Time Frame: 30 days from randomization ]
    diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria
Original Secondary Outcome Measures  ICMJE
 (submitted: September 12, 2018)
  • All-cause mortality [ Time Frame: 14 and 90 days from randomization ]
  • Treatment failure [ Time Frame: 14 days and 30 days from randomization ]
    death OR fever > 38°C in the last 48 hours OR lack of resolution of symptoms attributed to the focus of infection OR Sequential Failure Organ Assessment (SOFA) score increasing OR positive blood cultures by the time point assessed
  • Microbiological failure [ Time Frame: 7 days and 14 days from randomization ]
    Repeat positive blood cultures with index pathogen on day 4 or later from randomization
  • Relapse [ Time Frame: 30 days and 90 days from randomization ]
    recurrent positive blood cultures with the same microorganism/s after prior sterilization of blood cultures or after end of treatment
  • Clostridium difficile associated diarrhea [ Time Frame: 90 days from randomization ]
  • Clinically or microbiologically documented infection other than Gram-negative bacteremia [ Time Frame: 90 days from randomization ]
  • Number of hospital re-admissions [ Time Frame: 90 days from randomization ]
  • Development of resistance [ Time Frame: 90 days from randomization ]
    clinical isolates resistant to piperacillin/tazobactam and meropenem and any carbapenem-resistant bacteria
  • Carriage of carbapenemase-producing Enterobacteriaceae (CPE) and non-CPE carbapenem-resistant Enterobacteriaceae in-hospital [ Time Frame: 90 days from randomization ]
    detected by weekly rectal surveillance of carriage while in-hospital
  • Total in-hospital days [ Time Frame: 30 days and 90 days from randomization ]
  • Total antibiotic days [ Time Frame: 30 days and 90 days from randomization ]
  • Adverse events [ Time Frame: 30 days from randomization ]
    diarrhea, liver function test abnormalities, antibiotic rash or other immediate-type allergy, acute kidney injury defined according to RIFLE criteria
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE PipEracillin Tazobactam Versus mERoPENem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae (PETERPEN)
Official Title  ICMJE Piperacillin Tazobactam Versus Meropenem for Treatment of Bloodstream Infections Caused by Cephalosporin-resistant Enterobacteriaceae- a Non-inferiority Randomized Controlled Trial
Brief Summary Data regarding optimal treatment for extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae blood-stream infection are lacking. Observational studies show conflicting results when comparing treatment with combination beta-lactam-beta-lactamase inhibitor and carbapenems. The investigators aim to evaluate the effect of definitive treatment with meropenem vs. piperacillin-tazobactam on the outcome of patients with bacteremia due to cephalosporin-non-susceptible Enterobacteriaceae. The investigators hypothesize that piperacillin-tazobactam is non-inferior to meropenem.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
open-label randomized controlled trial
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Beta Lactam Resistant Bacterial Infection
  • Enterobacteriaceae Infections
  • Bacteremia
Intervention  ICMJE
  • Drug: Piperacillin/tazobactam
    4.5 grams QID
  • Drug: Meropenem
    1 gram TID
Study Arms  ICMJE
  • Experimental: piperacillin tazobactam
    Intervention: Drug: Piperacillin/tazobactam
  • Active Comparator: meropenem
    Intervention: Drug: Meropenem
Publications * Bitterman R, Koppel F, Mussini C, Geffen Y, Chowers M, Rahav G, Nesher L, Ben-Ami R, Turjeman A, Huberman Samuel M, Cheng MP, Lee TC, Leibovici L, Yahav D, Paul M. Piperacillin-tazobactam versus meropenem for treatment of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacteriaceae: a study protocol for a non-inferiority open-label randomised controlled trial (PeterPen). BMJ Open. 2021 Feb 8;11(2):e040210. doi: 10.1136/bmjopen-2020-040210.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 12, 2018)
1084
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2024
Estimated Primary Completion Date January 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Adults (age ≥ 18 years)
  2. New onset BSI due to E. coli or Klebsiella spp. in one or more blood cultures associated with evidence of infection.
  3. The microorganism will have to be non-susceptible to third generation cephalosporins (ceftriaxone and ceftazidime) and susceptible to both PTZ and meropenem (see microbiological methods).
  4. Both community and hospital-acquired bacteremias will be included.
  5. We will permit the inclusion of bacteremias due to E. coli or Klebsiella spp. with concomitant growth in blood of skin commensals considered as contaminants.

Exclusion Criteria:

  1. More than 72 hr. elapsed since initial blood culture taken, regardless of the time covering antibiotics were started (up to 72 hrs.).
  2. Polymicrobial bacteremia. Polymicrobial bacteremia will be defined as either growth of two or more different species of microorganisms in the same blood culture, or growth of different species in two or more separate blood cultures within the same episode.
  3. Patients with prior bacteremia or infection that have not completed antimicrobial therapy for the previous infectious episode.
  4. Patients with septic shock at the time of enrollment and randomization, defined as at least 2 measurements of systolic blood pressure < 90 mmHg and/or use of vasopressors (dopamine>15μg/kg/min, adrenalin>0.1μg/kg/min, noradrenalin>0.1μg/kg/min, vasopressin any dose) in the 12 hours prior to randomization. In the absence of the use of vasopressors, a systolic blood pressure <90 would need to represent a deviation for the patient's known normal blood pressure.
  5. BSI due to specific infections known at the time of randomization:

    1. Endocarditis / endovascular infections
    2. Osteomyelitis (not resected)
    3. Central nervous system infections
  6. Allergy to any of the study drugs confirmed by history taken by the investigator
  7. Previous enrollment in this trial
  8. Concurrent participation in another interventional clinical trial
  9. Imminent death (researcher's assessment of expected death within 48 hrs. of recruitment)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Roni Bitterman, MD 972-4-7772991 ro_oren@rambam.health.gov.il
Contact: Mical Paul, MD 972-4-7772991 m_paul@rambam.health.gov.il
Listed Location Countries  ICMJE Israel
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03671967
Other Study ID Numbers  ICMJE MOH_2018-12-25_004857
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: De-identified individual patient data collected during the trial will be made available for an unlimited time period following publication of trial results. Data will be available for researchers who provide a methodologically sound proposal and contingent on both the researchers' and our ethics committee approval and the signing of a data sharing agreement.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Supporting Materials: Analytic Code
Time Frame: following publication and for unlimited time
Access Criteria: proposals should be sent to the principal investigator at ro_oren@rambam.health.gov.il
Responsible Party Roni Oren MD, Rambam Health Care Campus
Study Sponsor  ICMJE Rambam Health Care Campus
Collaborators  ICMJE
  • Rabin Medical Center
  • University of Modena and Reggio Emilia
  • Tel Aviv Medical Center
  • Meir Medical Center
  • Soroka University Medical Center
  • The Chaim Sheba Medical Center
  • McGill University Health Centre/Research Institute of the McGill University Health Centre
  • Jewish General Hospital
Investigators  ICMJE
Principal Investigator: Roni Bitterman, MD Rambam Health Care Campus
Study Director: Mical Paul, MD Rambam Health Care Campus
Study Director: Leonard Leibovici, MD Rabin Medical Center
Study Director: Cristina Mussini, MD University of Modena and Reggio Emilia
PRS Account Rambam Health Care Campus
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP