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Clinical Trials to Reduce the Risk of Antimicrobial Resistance

This study has been terminated.
(NIAID terminated the study due to low subject enrollment)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01570192
First Posted: April 4, 2012
Last Update Posted: April 20, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
University of Florida
Results First Submitted: December 22, 2016  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition: Bacterial Pneumonia
Interventions: Drug: IV meropenem
Drug: I.V. Meropenem
Drug: 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
Drug: Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.
Device: tobramycin nebulization

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
We had 8 clinical sites: recruitment into the study began September 2010 and ended April 10, 2015.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Enrolled participants were excluded from the trial before assignment to groups because participants had no qualifying organisms; this includes participants with no growth on screening BAL, those with < 104 CFU/mL on BAL, and those with only Gram-positive bacteria cultured from the BAL.

Reporting Groups
  Description
IV Meropenem; Parenteral Aminoglycoside

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.

IV meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).

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: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)

Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.

tobramycin nebulization: tobramycin nebulization 600mg/day

I.V. Meropenem

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.

I.V. Meropenem: 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

Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.


Participant Flow:   Overall Study
    IV Meropenem; Parenteral Aminoglycoside   I.V. Meropenem
STARTED   13   30 
COMPLETED   6   17 
NOT COMPLETED   7   13 
no qualifying organism                6                12 
changed to palliative care                1                0 
Physician Decision                0                1 



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Number of patients enrolled in the study and who had a baseline BAL.

Reporting Groups
  Description
IV Meropenem; Parenteral Aminoglycoside

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.

IV meropenem: Subjects assigned to this group will receive IV meropenem (2 g infused over 3 hrs q 8 hr).

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: a parenteral aminoglycoside (tobramycin or gentamicin-5mg/kg IV Q24h or amikacin 20 mg/kg IV Q24h)

Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.

tobramycin nebulization: tobramycin nebulization 600mg/day

I.V. Meropenem

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.

I.V. Meropenem: 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

Linezolid or Vancomcin (per institutional guidelines) will be available for MRSA coverage.: Linezolid or vancomycin (per institutional guidelines) will be available for MRSA coverage.

Total Total of all reporting groups

Baseline Measures
   IV Meropenem; Parenteral Aminoglycoside   I.V. Meropenem   Total 
Overall Participants Analyzed 
[Units: Participants]
 13   30   43 
Age 
[Units: Participants]
Count of Participants
     
<=18 years      0   0.0%      0   0.0%      0   0.0% 
Between 18 and 65 years      6  46.2%      20  66.7%      26  60.5% 
>=65 years      7  53.8%      10  33.3%      17  39.5% 
Age 
[Units: Years]
Mean (Standard Deviation)
 61.2  (18.3)   58.4  (12.6)   59.2  (14.4) 
Sex: Female, Male 
[Units: Participants]
Count of Participants
     
Female      7  53.8%      13  43.3%      20  46.5% 
Male      6  46.2%      17  56.7%      23  53.5% 
Region of Enrollment 
[Units: Participants]
     
United States   11   18   29 
France   2   11   13 
Spain   0   1   1 
Baseline acute physiology and chronic health evaluation II (APACHE II) score [1] 
[Units: Units on a scale]
Mean (Standard Deviation)
 22.6  (4.6)   21.0  (6.2)   21.5  (5.8) 
[1] A severity of disease classification system applied within 24 hours of patient admission to an ICU. The point score is calculated from a patient's age and physiological measurements. The range of score is between 0-71. Physiological measurements and all ages fit into that range. Note: the higher the score, the higher the probability of death.


  Outcome Measures

1.  Primary:   Number of Participants With Suppression and Emergence of Resistance   [ Time Frame: up to 28 days after enrollment ]

2.  Secondary:   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) ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

3.  Secondary:   A Pharmacodynamic Relationship Between Meropenem Exposure in Plasma and Extracellular Lung Fluid (ELF)   [ Time Frame: Patients will participate up to 45 days ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

4.  Secondary:   28 Day All-cause Mortality Between the Treatment Groups.   [ Time Frame: Late-Follow-Up (LFU, 30 (±2) days Post Therapy) ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

5.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

6.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

7.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

8.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

9.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  

10.  Secondary:   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 ]
Results not yet reported.   Anticipated Reporting Date:   07/2017  


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information
  Hide More Information

Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.


Results Point of Contact:  
Name/Title: Dr. George L. Drusano
Organization: University of Florida, Department of Medicine
phone: 407-313-7060
e-mail: gdrusano@ufl.edu


Publications:
Bauernfeind A, Jungwirth R. In Vitro Activity of SM 7338 and Imipenem. 28th ICAAC, Los Angeles, October 1988. Abstract 599
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.
Data on file. Drug Development Department, AstraZeneca Pharmaceuticals, Wilmington,DE 19897.
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, Sumita Y, Tada E, et al. SM 7338, A New Carbapenem Antibacterial: In Vitro Activity Against 1607 Clinical Strains of Gram-Positive and Gram-Negative Pathogens. 27th ICAAC, New York, October 1987, Abstract 753.
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.
Investigational Brochure, Drug Development Department, AstraZeneca Pharmaceuticals, Wilmington, Delaware 19897.
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.
Lancero MG, Young LS. In Vitro Studies with SM 7338; A Novel Carbapenem with Broad Bactericidal Activity. 28th ICAAC, Los Angeles, October 1988. Abstract 602.
Neu HG, Saha G, Chin NX. In Vitro Activity of SM 7338; A New Carbapenem, Compared with Other Antibacterials Against Multiply Resistant Bacteria. 28th ICAAC, Los Angeles, October 1988. Abstract 601.
Nord CE, Lindmark A, Persson I. Susceptibility of Anaerobic Bacteria to SM 7338. 28th ICAAC, Los Angeles, October 1988. Abstract 596.
Okuda T, Fukasawa M, Tanio T, et al. SM 7338, A New Carbapenem Antibacterial: In Vitro and In Vivo Antibacterial Activities. 27th ICAAC, New York, October 1987. Abstract 757.
Sanford Guide to Antimicrobial Therapy. Thirty-third Edition, 2003. Gilbert DN, Moellering RC, Sande MA.
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.
Strasbaugh LJ. Nosocomial repiratory infections. In: Mandell GL, Bennett JE, Dolin R, editors. Principles and practice of infectious disease. Philadelphia: Churchill Livingstone, 2000: 3021-3026.
Sumita Y, Fukasawa M, Okunda T. SM 7338, A New Carbapenem Antibacterial: Affinities for PBP's and Morphological Changes. 27th ICAAC, New York, October 1987. Abstract 756.
Sumita Y, Inoue M, Mitsuhashi S. In Vitro Antibacterial Activity of SM 7338. 28th ICAAC, Los Angeles, October 1988. Abstract 600.
Sunagawa M, Matsumura H, Inoue T, et al. SM 7338, A New Carbapenem Antibacterial: Structure-Activity Relations and Physiochemical Properties. 27th ICAAC, New York, October 1987. Abstract 752.
Vetter N. The Use of Meropenem ('Merrem'/'Meronen') in the Therapy of Hospital-acquired Lower Respiratory Infections: a Review of Clinical Experience. 18th International Congress of Chemotherapy, Stockholm, Sweden, 27 June-2 July, 1993. Abstract 70.
Wise R, Andrews JM, Ashby JP. The Bactericidal Activity of the Carbapenem, SM 7338, Alone and in Combination. 28th ICAAC, Los Angeles, October 1988. Abstract 605.
World Health Organization. Draft Global Strategy for the Containment of Antimicrobial Resistance. Available on the Internet at http://www.who.int/emc/amr.htm


Responsible Party: University of Florida
ClinicalTrials.gov Identifier: NCT01570192     History of Changes
Other Study ID Numbers: 10-0060
First Submitted: March 22, 2012
First Posted: April 4, 2012
Results First Submitted: December 22, 2016
Results First Posted: April 20, 2017
Last Update Posted: April 20, 2017



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