Trial record 1 of 1 for:    NCT01570192
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Clinical Trials to Reduce the Risk of Antimicrobial Resistance

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2014 by University of Florida
Sponsor:
Information provided by (Responsible Party):
University of Florida
ClinicalTrials.gov Identifier:
NCT01570192
First received: March 22, 2012
Last updated: March 7, 2014
Last verified: March 2014
  Purpose

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).


Condition Intervention Phase
Bacterial Pneumonia
Drug: IV meropenem; parenteral aminoglycoside
Drug: I.V. Meropenem
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by University of Florida:

Primary Outcome Measures:
  • Rate of emergence of antibiotic resistance in P. aeruginosa and Acinetobacter spp [ Time Frame: Day 5 or Early Extubation ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Efficacy(clinical outcome) and safety (numbers of SAEs) of PD optimized/combination therapy (Group 1) of meropenem (2g infused over 3 hours Q8h) plus aminoglycoside parenterally [ Time Frame: Test-of-Cure Visit (TOC, 7-14 days post therapy) and Late-Follow-Up (LFU 14 days after test of cure or up to 42 ± 3 days after study drug initiation) ] [ Designated as safety issue: No ]
    The efficacy and safety of PD optimized/combination therapy (Group 1) of meropenem (2g infused over 3 hours Q8h) plus aminoglycoside parenterally (tobramycin/or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kgIV Q 24h) plus tobramycin nebulization in the treatment of hospitalized subjects with pneumonia requiring mechanical ventilation caused by P. aeruginosa, Acinetobacter spp, (or other Gram-negative pathogens) when compared to the Group 2 (control arm) of monotherapy meropenem

  • A pharmacodynamic relationship between meropenem exposure in plasma and extracellular lung fluid (ELF) [ Time Frame: Patients will participate up to 45 days ] [ Designated as safety issue: No ]
  • 28 day all-cause mortality between the treatment groups. [ Time Frame: Late-Follow-Up (LFU, 30 (±2) days Post Therapy) ] [ Designated as safety issue: No ]
  • Microbiological response at EOT, TOC and LFU between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
  • Rates of pathogen response to those seen in the control arm. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
  • Rates of resistance of other Gram-negative bacteria (non-Pseudomonas or Acinetobacter spp) between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
  • The proportion of subjects whose repeat cultures are negative (e.g. rates of clearance of bacterial infection) at Day 5 between treatment groups and among fermentor and non-fermentor pathogens. [ Time Frame: Day 5/EE ] [ Designated as safety issue: No ]
  • Clinical outcome in proportion of subjects who received prior antibiotics vs. those with no prior antibiotics [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]
  • Health care resource utilization (length of ICU stay, antibiotic usage, length of hospitalization, and duration of ventilation) between treatment groups. [ Time Frame: End-of-Treatment (EOT last day of study drug, up to 14 days) Test-of-Cure Test-of-Cure Visit (TOC, 7-14 days post therapy)and Late-Follow-Up (LFU - 14 days after TOC or up to 42 ± 3 days after study drug initiation ] [ Designated as safety issue: No ]

Estimated Enrollment: 480
Study Start Date: January 2013
Estimated Study Completion Date: September 2016
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization
Drug: IV meropenem; parenteral aminoglycoside
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr) plus a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h) plus tobramycin nebulization
Other Names:
  • Merrem I.V.
  • Tobramycin for Injection USP
  • Tobramycin Inhalation Solution USP
  • Gentamicin Sulfate, Injection Solution Concentrate
  • Amikacin Sulfate Injection USP
Active Comparator: I.V. Meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Drug: I.V. Meropenem
Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).
Other Name: Merrem I.V.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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 24 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.

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01570192

Contacts
Contact: George L. Drusano, M.D. 407-313-7060 gdrusano@ufl.edu
Contact: Evelyn J. Ellis-Grosse, Ph.D. 484-597-0232 evelyn@e2gconsulting.com

Locations
United States, California
InClin, Inc. Active, not recruiting
San Mateo, California, United States, 94403
United States, Florida
UFL Department of Medicine: Pulmonary, Critical Care and Sleep Medicine Recruiting
Gainesville, Florida, United States, 32610
Contact: Hassan Alnuaimat,, MD    352-273-8740    alnuah@medicine.ufl.edu   
Contact: Pamela Schreck, RN    352-294-5195    pamela.schreck@alphaone.ufl.edu   
Principal Investigator: Hassan Alnuaimat, MD         
United States, Georgia
Emory University Active, not recruiting
Atlanta, Georgia, United States, 30322-4250
United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Richard Wunderink, MD    312-695-1878    r-wunderink@northwestern.edu   
Contact: Helen Donnelly, RN    312-695-1881    h-donnelly@northwestern.edu   
Principal Investigator: Richard Wunderink, MD         
United States, Iowa
JMI Laboratories Active, not recruiting
North Liberty, Iowa, United States, 52317
United States, Missouri
Washington University in St. Louis School of Medicine Recruiting
St. Louis, Missouri, United States, 63130
Contact: Marin H Kollef, MD    314-454-8764    MKOLLEF@DOM.wustl.edu   
Contact: Lisa Mayfield, RN    314 286-1550    mayfieldl@wusm.wustl.edu   
Principal Investigator: Marin H Kollef, MD         
United States, New York
Weill Cornell Medical Center of Cornell University Not yet recruiting
New York, New York, United States, 10065
Contact: Thomas J Walsh, MD    301-693-1890    thw2003@med.cornell.edu   
Contact: Krisztina Skoba, RN    301-693-1890    krs2023@med.cornell.edu   
Principal Investigator: Thomas J Walsh, MD         
United States, Ohio
Cleveland Clinic Lerner College of Medicine Recruiting
Cleveland, Ohio, United States, 44195
Contact: Robert D Hite, MD    336-716-8898    hited@ccf.org   
Contact: Michelle Ferrari, RN    216-444-4000    FERRARM1@ccf.org   
Principal Investigator: Robert D Hite, MD         
France
Institut de Cardiologie, Groupe Hospitalier Pitie-Salpetriere Recruiting
Paris, France, Cedex 13
Contact: Jean Chastre, MD    011+33 142163822    jean.chastre@psl.ap-hop-paris.fr   
Contact: Alain Combes, MD    011+33 142163818    alain.combes@psl.aphp.fr   
Principal Investigator: Jean Chastre, MD         
Germany
Medizinische Hochschule Recruiting
Hannover, Germany, 30625
Contact: Tobias Welte, MD    +49 (511) 532-3530    Welte.Tobias@mh-hannover.de   
Contact: Rabea Gatzke, RN    +49 (511) 532-3530    Gatzke.Rabea@mh-hannover.de   
Principal Investigator: Tobias Welte, MD         
Hannover Clinical Trial Center GmbH Recruiting
Hannover, Germany, 30625
Contact: Heiko vonderLeyen, MD    49 511 53 33 33-0    vdleyen@clinical-trial-center.de   
Contact: Rabea Gatzke, RN    49 511-532-3454    Gatzke.Rabea@mh-hannover.de   
Spain
Hospital Vall d'Hebron Recruiting
Barcelona, Spain, 08035
Contact: Jordi Rello, MD    34 932746209    jrello@crips.es; jrello@vhebron.net   
Contact: Javier Fonts, RN    34 932746209    javier.fonts.vhir@gmail.com   
Principal Investigator: Jordi Rello, MD         
Sponsors and Collaborators
University of Florida
Investigators
Principal Investigator: George L Drusano, MD University of Florida
  More Information

Publications:
American Thoracic Society. Hospital-acquired Pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventative strategies. Am J Respir Crit Care Med 2005; 171:388-416.
Clarke AM, Zemcov SJV. SM 7338 (ICI 194,660), A New DHP-1 Stable Carbapenem; In Vitro Activity Against a Wide Range of Canadian Clinical Isolates. 28th ICAAC, Los Angeles, October 1988. Abstract 598.
Edwards JR, Wannop C. SM 7338, A New Carbapenem Antibacterial: In Vitro Activity Against Imipenem-Resistant Ps. aeruginosa. 27th ICAAC, New York October 1987, Abstract 754.
Edwards JR, Turner PJ, Withnell ES, et al. SM 7338, A New Carbapenem Antibacterial: In Vitro Activity Against Bacterial Strains of Clinical Origins. 27th ICAAC, New York, October 1987, Abstract 755.
Fukasawa M, Tada E, Nouda H, et al. Induction and Inhibition of b-Lactamases by SM 7338; A Novel Carbapenem Antibacterial. 28th ICAAC, Los Angeles, October 1988. Abstract 606.
Jones RN, Barry AL, et al. Antimicrobial Activity of SM 7338, A New DHP-1 Stable Carbapenem. 28th ICAAC, Los Angeles, October 1988. Abstract 597.
Kayser FH, Morenzoni G. Activity of SM 7338, A New Carbapenem Antibacterial Against Gram-Positive Bacteria. 28th ICAAC, Los Angeles, October 1988. Abstract 603.
Slaney L, Chubb H, Mohammed Z, et al. In Vitro Activity of SM 7338 Against Neisseria gonorrhoeae (Gc), Haemophilus ducreyi (Hd) and Haemophilus influenzae. 28th ICAAC, Los Angeles, October 1988. Abstract 604.

Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01570192     History of Changes
Other Study ID Numbers: 10-0060
Study First Received: March 22, 2012
Last Updated: March 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by University of Florida:
gram negative pathogens
Pseudomonas aeruginosa
Acinetobacter
HCAP
VABP
HABP

Additional relevant MeSH terms:
Pneumonia, Bacterial
Pneumonia
Bacterial Infections
Lung Diseases
Respiratory Tract Diseases
Respiratory Tract Infections
Amikacin
Tobramycin
Gentamicins
Meropenem
Anti-Infective Agents
Anti-Bacterial Agents
Therapeutic Uses
Pharmacologic Actions
Protein Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 29, 2014