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Clinical Trials to Reduce the Risk of Antimicrobial Resistance

Primary Purpose

Bacterial Pneumonia

Status
Terminated
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
IV meropenem
I.V. Meropenem
Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h
Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.
tobramycin nebulization
Sponsored by
University of Florida
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Bacterial Pneumonia focused on measuring gram negative pathogens, Pseudomonas aeruginosa, Acinetobacter, HCAP, VABP, HABP

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Written informed consent by the subject/subject's LAR.

Hospitalized males or females ≥ 18 yrs with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP.

Onset or exacerbation of pneumonia at least 48 hours after admission to any patient health care facility or onset of pneumonia in a nursing home or rehabilitation facility with subsequent transfer to an acute care facility

Women of childbearing potential if their pregnancy test is negative

Subjects who have received previous antibacterial therapy within 14 days of pre-treatment bronchoscopy entry may be entered only if the subject has not responded clinically.). While less than 24 hours of pre-treatment antibiotics is preferential, recovery of >104 CFU/ml in the quantitative Bronchoscopic BAL will be seen as primary evidence that the prior therapy was not efficacious and enrollment will be allowed.)

Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP:

Within 48 hours before starting empiric therapy a subject's chest radiograph should show the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of pneumonia

Within 36 hours before the start of empiric study therapy, a quantitative culture of Bronchoscopic BAL fluid must be obtained.

Patients with VABP should have a Clinical Pulmonary Infection Score of >/= 5.

Exclusion Criteria:

Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or equal to 16µg/ml) or a prior meropenem therapy failure.

Subjects with contra-indications to ANY study medication, in particular with known or suspected allergy or hypersensitivity.

Women who are pregnant or lactating.

Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled into the study at the discretion of the site investigator.

Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia.

Subjects with primary lung cancer or another malignancy metastatic to the lungs.

Subjects who were previously enrolled in this study.

Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study.

Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study drug.

Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count <200 cells/µl, neutropenia (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis.

Subjects with little chance of survival for the duration of study therapy.

Subjects with an APACHE II score >35.

Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs.

Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment.

Subjects who have undergone bone marrow transplantation.

Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.

Sites / Locations

  • InClin, Inc.
  • UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine
  • Emory University
  • Northwestern University
  • JMI Laboratories
  • Washington University in St. Louis School of Medicine
  • Weill Cornell Medical Center of Cornell University
  • Cleveland Clinic Lerner College of Medicine
  • Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere
  • Hannover Clinical Trial Center GmbH
  • Hospital Vall d'Hebron

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

IV meropenem; parenteral aminoglycoside

I.V. Meropenem

Arm Description

Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.

Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.

Outcomes

Primary Outcome Measures

Number of Participants With Suppression and Emergence of Resistance
The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.

Secondary Outcome Measures

Clinical Response
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Clinical Response in Subjects Who Received Prior Antibiotics
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Overall Microbiologic Response
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Pretreatment Pathogen Response
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Suppression of the Emergence of Resistance in Other Gram-negative Pathogens
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Occurrence of Repeat Negative Cultures
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Mortality
Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
Mortality
Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)

Full Information

First Posted
March 22, 2012
Last Updated
September 1, 2017
Sponsor
University of Florida
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1. Study Identification

Unique Protocol Identification Number
NCT01570192
Brief Title
Clinical Trials to Reduce the Risk of Antimicrobial Resistance
Official Title
Impact of Aggressive Empiric Antibiotic Therapy and Duration of Therapy on the Emergence of Antimicrobial Resistance During the Treatment of Hospitalized Subjects With Pneumonia Requiring Mechanical Ventilation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2017
Overall Recruitment Status
Terminated
Why Stopped
NIAID terminated the study due to low subject enrollment
Study Start Date
September 2010 (undefined)
Primary Completion Date
April 2015 (Actual)
Study Completion Date
April 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Florida

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The primary objective of this study is to demonstrate a low rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp during the treatment of hospitalized patients with pneumonia requiring mechanical ventilation treated with PD optimized meropenem administered as a prolonged infusion in combination with a parenteral aminoglycoside plus tobramycin by inhalation (Group 1) compared to therapy with meropenem alone (Group 2 - control arm).
Detailed Description
The goal of this clinical study is to demonstrate that the application of pharmacodynamic dosing principles to the antibiotic treatment of hospitalized subjects with culture-documented pneumonia (including HABP, VABP and HCAP) requiring mechanical ventilation can inhibit the emergence of antibiotic-resistant organisms during treatment and therefore may improve the rate of a satisfactory clinical response. Antibiotic resistance is defined as an increase in meropenem or aminoglycoside MIC by two tube dilutions (fourfold) from baseline. In animal models of infection, the pharmacodynamic driver for bactericidal effect by β lactam antibiotics such as meropenem is the proportion of the dosing interval during which plasma drug levels are maintained above the MIC of the causative pathogen. The hypothesis of this study is that prolongation of time above MIC by increasing total meropenem dose and the duration of infusion will counter-select for the emergence of antimicrobial resistance during the treatment of hospitalized subjects with pneumonia (i.e. HABP, VABP and HCAP) caused by P.aeruginosa, Acinetobacter species (spp), or other pathogens with intermediate susceptibility to meropenem, and that the addition of parenteral aminoglycosides (amikacin, tobramycin or gentamicin) and nebulized aminoglycoside (tobramycin) given along optimal pharmacodynamic principles will further reduce the likelihood of resistance emergence, particularly among the non-fermenting Gram-negative bacilli, such as Pseudomonas aeruginosa and Acinetobacter spp. The observed incidence of resistance emergence to meropenem will be compared across therapeutic regimens.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Bacterial Pneumonia
Keywords
gram negative pathogens, Pseudomonas aeruginosa, Acinetobacter, HCAP, VABP, HABP

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Masking Description
This is an open-label study with 1:1 randomization between two active treatment groups.
Allocation
Randomized
Enrollment
43 (Actual)

8. Arms, Groups, and Interventions

Arm Title
IV meropenem; parenteral aminoglycoside
Arm Type
Experimental
Arm Description
Subjects assigned to this group will receive: IV meropenem (2 g infused over 3 hrs q 8 hr); a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) tobramycin nebulization Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat potential Gram-positive pathogens.
Arm Title
I.V. Meropenem
Arm Type
Active Comparator
Arm Description
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage to treat Gram-positive pathogens. **NOTE: Empiric MRSA coverage is allowed in both arms. This therapy is advised for any subjects with known or suspected MRSA entering the study. Once microbiologic results are available, this coverage may be discontinued at the investigator's discretion.
Intervention Type
Drug
Intervention Name(s)
IV meropenem
Other Intervention Name(s)
Merrem I.V.
Intervention Description
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Intervention Type
Drug
Intervention Name(s)
I.V. Meropenem
Other Intervention Name(s)
Merrem I.V.
Intervention Description
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr). Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage
Intervention Type
Drug
Intervention Name(s)
Parenteral aminoglycoside; tobramycin for injection USP OR gentamicin sulfate injection solution concentrate 5mg.kg IV q24h; amikacin sulfate injection USP 20 mg/kg IV q24h
Intervention Description
a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)
Intervention Type
Drug
Intervention Name(s)
Linezolid or Vancomycin (per institutional guidelines) will be available for MRSA coverage.
Intervention Description
Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.
Intervention Type
Device
Intervention Name(s)
tobramycin nebulization
Intervention Description
tobramycin nebulization 600mg/day
Primary Outcome Measure Information:
Title
Number of Participants With Suppression and Emergence of Resistance
Description
The emergence of resistance is defined as a change of meropenem MIC or aminoglycoside MIC by two tube dilutions (fourfold) from baseline when assessed at the second BAL procedure on day 5/early extubation. Patients are evaluable for this endpoint IF they had baseline BAL and Day 5/early extubation and if they had positive cultures on baseline and Day/EE.
Time Frame
up to 28 days after enrollment
Secondary Outcome Measure Information:
Title
Clinical Response
Description
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time Frame
End of treatment - up to 28 days after enrollment
Title
Clinical Response in Subjects Who Received Prior Antibiotics
Description
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time Frame
End of treatment - up to 28 days after enrollment
Title
Overall Microbiologic Response
Description
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time Frame
End of treatment - up to 28 days after enrollment
Title
Pretreatment Pathogen Response
Description
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time Frame
End of treatment - up to 28 days after enrollment
Title
Suppression of the Emergence of Resistance in Other Gram-negative Pathogens
Description
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time Frame
Day 5/Early Extubation
Title
Occurrence of Repeat Negative Cultures
Description
Percentage of patients with successful responses by efficacy endpoint, treatment group and population (n/N)
Time Frame
Day 5/Early Extubation
Title
Mortality
Description
Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
Time Frame
14 days
Title
Mortality
Description
Percentage of patients who died by efficacy endpoint, treatment group and population (n/N)
Time Frame
28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion criteria: Written informed consent by the subject/subject's LAR. Hospitalized males or females ≥ 18 yrs with respiratory failure requiring mechanical ventilation and clinical suspicion of HABP, HCAP or VABP. Onset or exacerbation of pneumonia at least 48 hours after admission to any patient health care facility or onset of pneumonia in a nursing home or rehabilitation facility with subsequent transfer to an acute care facility Women of childbearing potential if their pregnancy test is negative Subjects who have received previous antibacterial therapy within 14 days of pre-treatment bronchoscopy entry may be entered only if the subject has not responded clinically.). While less than 24 hours of pre-treatment antibiotics is preferential, recovery of >104 CFU/ml in the quantitative Bronchoscopic BAL will be seen as primary evidence that the prior therapy was not efficacious and enrollment will be allowed.) Patients should have clinical findings that support a diagnosis of HABP/VABP/HCAP: Within 48 hours before starting empiric therapy a subject's chest radiograph should show the presence of a NEW or progressive infiltrate, cavitation, or effusion suggestive of pneumonia Within 36 hours before the start of empiric study therapy, a quantitative culture of Bronchoscopic BAL fluid must be obtained. Patients with VABP should have a Clinical Pulmonary Infection Score of >/= 5. Exclusion Criteria: Subjects with pneumonia caused by pathogens resistant to meropenem (MIC greater than or equal to 16µg/ml) or a prior meropenem therapy failure. Subjects with contra-indications to ANY study medication, in particular with known or suspected allergy or hypersensitivity. Women who are pregnant or lactating. Subjects taking anticonvulsant medications for a known seizure disorder.Patients with a history of seizures, AND who are stabilized on anti-seizure medication, may be enrolled into the study at the discretion of the site investigator. Subjects with known or suspected community acquired bacterial pneumonia (CABP) or viral pneumonia; or Subjects with acute exacerbation of chronic bronchitis without evidence of pneumonia. Subjects with primary lung cancer or another malignancy metastatic to the lungs. Subjects who were previously enrolled in this study. Subjects who have had an investigational drug or have used an investigational device within 30 days prior to entering the study. Subjects with another focus of infection requiring concurrent antibiotics that would interfere with evaluation of the response to study drug. Subjects with cystic fibrosis, AIDS with a CD4 lymphocyte count <200 cells/µl, neutropenia (absolute neutrophil count <500 cells/ml), known or suspected active tuberculosis. Subjects with little chance of survival for the duration of study therapy. Subjects with an APACHE II score >35. Subjects with underlying condition(s) which would make it difficult to interpret response to the study drugs. Subjects with hypotension or acidosis despite attempts at fluid resuscitation. Subjects requiring ongoing treatment with vasopressors will be eligible for the study if their hypotension is controlled and acidosis has resolved. Subjects with intractable septic shock are not eligible for enrollment. Subjects who have undergone bone marrow transplantation. Subjects with profound hypoxia as defined by a PaO2/FiO2 ratio <100.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
George L Drusano, MD
Organizational Affiliation
University of Florida
Official's Role
Principal Investigator
Facility Information:
Facility Name
InClin, Inc.
City
San Mateo
State/Province
California
ZIP/Postal Code
94403
Country
United States
Facility Name
UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine
City
Gainesville
State/Province
Florida
ZIP/Postal Code
32610
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
ZIP/Postal Code
30322-4250
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States
Facility Name
JMI Laboratories
City
North Liberty
State/Province
Iowa
ZIP/Postal Code
52317
Country
United States
Facility Name
Washington University in St. Louis School of Medicine
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Facility Name
Weill Cornell Medical Center of Cornell University
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Cleveland Clinic Lerner College of Medicine
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere
City
Paris
ZIP/Postal Code
Cedex 13
Country
France
Facility Name
Hannover Clinical Trial Center GmbH
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Hospital Vall d'Hebron
City
Barcelona
ZIP/Postal Code
08035
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
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