Clinical trial NCT03159078: Polymyxin B Monotherapy vs Combination Therapy in Critically Ill Patients With Multi-drug Resistant Pathogens
Official title: Polymyxin B Monotherapy Versus Polymyxin B-Carbapenem Combination Therapy in Critically Ill Patients With Multi-drug Resistant Gram-negative Infection: A Prospective, Parallel-Group, Double-Blind, Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Trauma
Resistant Infection
Critical Illness
Keywords: Acinetobacter
Polymyxins
Imipenem
Pseudomona
Klebsiella
Lead sponsor: University of Puerto Rico
Sponsor class: OTHER
First posted: 2017-05-18
Enrollment: 40
Sex: ALL
Minimum age (years): 21
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: One arm with Polyxyxin B monotherapy and another arm with Polymyxin B plus carbapenem
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the safety and efficacy of polymyxin B as monotherapy versus a combined polymyxin B-carbapenem therapy against multidrug-resistant (MDR) gram negative infections. The investigators intend to evaluate if this synergistic drug regimen correlates with improved outcomes against gram-negative infections in critically ill patients including: better clinical resolution, reduced length of stay at hospital, reduced length of stay at the intensive care unit, and less recurrence of infection.

Detailed description: The "MUSEUM" trial is a single-center, prospective, parallel-group, double-blind, randomized, controlled study design. The trial will be conducted at the Intensive Care Unit of the Puerto Rico Trauma Hospital located in San Juan, Puerto Rico. Patients with clinical and microbiological evidence of an Multi-drug resistant infection related to Hospital-acquired pneumonia (HAP), Ventilator-associated pneumonia (VAP), Complicated Urinary tract infection (cUTI) or Bloodstream infection (BSI) will be considered candidates for the study. The pathogen should be resistant to all antibiotics except to polymyxin B. With a predicted survival rate of 67% (hazard ratio of 0.33), a significance of α = 0.05, power of 80%, and assuming a dropout rate of 15%, the estimated sample size is n = 40 patients (20 per group). In terms of safety, the most clinically relevant adverse effects are nephrotoxicity and neurotoxicity, which will be evaluated and adjudicated. The recurrence of infection will be defined as a new superinfection by the same or other species than the initial infection that is multidrug-resistant. Length of stay at the Hospital will be measured from the day of admission until the day of discharge. Length of stay in the ICU will be measured from the day of admission until the day of discharge from the unit. To our knowledge, this will be the first prospective, double blind, randomized, controlled clinical trial in representation of the critically ill trauma patients infected with Multi-drug resistant pathogens.

Eligibility criteria: Inclusion Criteria:

* 21 years or older admitted to the Intensive Care Unit of the Puerto Rico Trauma Hospital ° Consent form signed,
* Clinical and microbiological evidence of a MDR infection related to HAP, VAP, cUTI or BSI.
* The pathogen should be resistant to almost all antibiotics, AND/OR intermediate resistant to some of the antibiotics, AND/OR susceptible only to a class of antibiotic (i.e. aminoglycosides which are NOT recommended as monotherapy), AND/OR the clinician decision is to start the patient on polymyxin B due to severity of the infection.
* Patient with a diagnosis of MDR infection, who have not received antibiotics at all; OR if received would be \< 72 hours with polymyxin B or imipenem at/or after the diagnosis of MDR AND/OR at the time of randomization
* Have a life expectancy of \> 24 hours according to the attending physician's criteria.

Exclusion Criteria:

* Pregnant woman
* Prisoners
* Severe hepatic failure (defined by serum conjugated bilirubin \> 3 mg/dL)
* End-stage renal disease requiring hemodialysis
* Hypersensitivity to any study drug
* Septic shock at the moment of randomization
* Died within 48 hours of starting the study

Primary outcomes:
measure: Resolution of the evidence of clinical infection
timeFrame: 7-14 days, according to site of infection
Secondary outcomes:
measure: 30-day mortality
timeFrame: 30 days
measure: Recurrence of infection
timeFrame: 30 days
measure: Length of stay at Hospital
timeFrame: 30 days
measure: Length of stay at ICU.
timeFrame: 30 days
Other outcomes:
Locations:
city: San Juan
country: Puerto Rico
facility: Trauma Hospital
Study officials:
affiliation: School of Pharmacy, University of Puerto Rico
name: Juan M Maldonado Lozada, PharmD
role: PRINCIPAL_INVESTIGATOR
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