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Trial details imported from ClinicalTrials.gov
For full trial details, please see the original record at
https://clinicaltrials.gov/ct2/show/NCT02019420
Registration number
NCT02019420
Ethics application status
Date submitted
18/12/2013
Date registered
24/12/2013
Date last updated
27/06/2019
Titles & IDs
Public title
Tedizolid Phosphate (TR-701 FA, MK-1986) vs Linezolid for the Treatment of Nosocomial Pneumonia (MK-1986-002)
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Scientific title
A Phase 3 Randomized Double-blind Study Comparing TR-701 FA and Linezolid in Ventilated Gram-positive Nosocomial Pneumonia
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Secondary ID [1]
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TR701-132
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Secondary ID [2]
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1986-002
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Pneumonia
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Condition category
Condition code
Respiratory
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Other respiratory disorders / diseases
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Infection
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Other infectious diseases
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Infection
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Studies of infection and infectious agents
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
Treatment: Drugs - Tedizolid phosphate
Treatment: Drugs - Linezolid
Experimental: Tedizolid phosphate IV - Ventilated HABP/VABP participants receive tedizolid phosphate 200 mg IV once daily for 7 days, or for 14 days for concurrent bacteremia.
Active Comparator: Linezolid IV - Ventilated HABP/VABP participants receive linezolid 600 mg IV every 12 hours for 10 days, or for 14 days for concurrent bacteremia.
Treatment: Drugs: Tedizolid phosphate
Tedizolid phosphate IV 200 mg once daily
Treatment: Drugs: Linezolid
Linezolid IV 600 mg twice daily
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Intervention code [1]
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Treatment: Drugs
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Comparator / control treatment
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Control group
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Outcomes
Primary outcome [1]
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Number of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population
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Assessment method [1]
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The numbers of participants with all-cause mortality within 28 days after randomization was determined in the ITT population. Any participants who were lost to follow-up and not known to be alive or deceased by Day 28 were imputed as deceased.
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Timepoint [1]
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Up to 28 days
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Secondary outcome [1]
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Number of Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population
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Assessment method [1]
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The numbers of participants with all-cause mortality within 28 days after randomization was determined in the mITT population. Any participants who were lost to follow-up and not known to be alive or deceased by Day 28 were imputed as deceased.
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Timepoint [1]
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Up to 28 days
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Secondary outcome [2]
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Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population
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Assessment method [2]
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The clinical response in the ITT population at the TOC visit (derived from the Investigator's assessment at the EOT and TOC visits) was determined by the investigator to be either: clinical success, clinical failure, or indeterminate. Clinical success was declared when most or all clinical signs were completely resolved, with no new signs of infection, no additional antibiotic therapy was required, and the participant was alive. Indeterminate was declared when the investigator could not determine success or failure. Clinical failure was declared with progression, relapse, or recurrence of new symptoms of infection, or a persistence or insufficient improvement in signs and symptoms of VNP.
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Timepoint [2]
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7-14 days after end of therapy - TOC
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Secondary outcome [3]
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Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population
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Assessment method [3]
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The clinical response in the CE population at the TOC visit (derived from the Investigator's assessment at the EOT and TOC visits) was determined by the investigator to be either: clinical success, clinical failure, or indeterminate. Clinical success was declared when most or all clinical signs were completely resolved, with no new signs of infection, no additional antibiotic therapy was required, and the participant was alive. Indeterminate was declared when the investigator could not determine success or failure. Clinical failure was declared with progression, relapse, or recurrence of new symptoms of infection, or a persistence or insufficient improvement in signs and symptoms of VNP.
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Timepoint [3]
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7-14 days after end of therapy - TOC
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Secondary outcome [4]
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Number of Methicillin-Susceptible Staphylococcus Aureus (MSSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population
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Assessment method [4]
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The number of MSSA-infected participants with all-cause mortality within 28 days after randomization was determined in the mITT population. Participants who had confirmed MSSA culture results from respiratory tract or pleural fluid specimens obtained within 36 hours of study Day 1 were included. Any participants who were lost to follow-up and not known to be alive or deceased by Day 28 were imputed as deceased.
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Timepoint [4]
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Up to 28 days
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Secondary outcome [5]
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Number of Methicillin-Resistant Staphylococcus Aureus (MRSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population
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Assessment method [5]
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The number of MRSA-infected participants with all-cause mortality within 28 days after randomization was determined in the mITT population. Participants who had confirmed MRSA culture results from respiratory tract or pleural fluid specimens obtained within 72 hours of study Day 1 were included. Any participants who were lost to follow-up and not known to be alive or deceased by Day 28 were imputed as deceased.
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Timepoint [5]
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Up to 28 days
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Secondary outcome [6]
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Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population
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Assessment method [6]
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The number of patients in the mITT population with a favorable response at EOT was determined. Favorable response included eradication (absence of the baseline pathogen) and presumed eradication (no source specimen to culture in a participant assessed as a clinical cure by the investigator).
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Timepoint [6]
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1-3 days after completing study therapy (Days 8-10 or Days 15-17)
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Secondary outcome [7]
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Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiologically-Evaluable 1 (ME-1) Population
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Assessment method [7]
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The number of patients in the ME-1 population with a favorable response at EOT was determined. Favorable response included eradication (absence of the baseline pathogen) and presumed eradication (no source specimen to culture in a participant assessed as a clinical cure by the investigator).
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Timepoint [7]
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1-3 days after completing study therapy (Days 8-10 or Days 15-17)
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Secondary outcome [8]
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Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (mITT) Population
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Assessment method [8]
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The number of patients in the mITT population with a favorable response at TOC was determined. Favorable response included eradication (absence of the baseline pathogen) and presumed eradication (no source specimen to culture in a participant assessed as a clinical cure by the investigator).
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Timepoint [8]
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7-14 days after end of therapy - TOC
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Secondary outcome [9]
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Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiologically-Evaluable 2 (ME-2) Population
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Assessment method [9]
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The number of patients in the ME-2 population with a favorable response at TOC was determined. Favorable response included eradication (absence of the baseline pathogen) and presumed eradication (no source specimen to culture in a participant assessed as a clinical cure by the investigator).
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Timepoint [9]
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7-14 days after end of therapy - TOC
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Secondary outcome [10]
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Number of Participants With =1 Adverse Events (AEs)
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Assessment method [10]
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An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Safety analysis is based on actual treatment received instead of randomization.
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Timepoint [10]
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Up to 32 days
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Secondary outcome [11]
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Number of Participants Discontinuing Study Therapy Due to an Adverse Event (AE)
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Assessment method [11]
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An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Safety analysis was based on actual treatment received and not randomization.
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Timepoint [11]
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Up to 14 days
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Eligibility
Key inclusion criteria
- Requires IV antibiotic therapy with diagnosis of ventilated nosocomial pneumonia
- Gram-positive bacteria on respiratory Gram stain
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
- Pneumonia of community, viral, fungal or parasitic etiology
- Structural lung abnormalities
- Immunosuppression
- Previous antibiotics for > 24 hours
- Expected survival of < 72 hours
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Randomised controlled trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Blinded (masking used)
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Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
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Intervention assignment
Parallel
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Other design features
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Phase
Phase 3
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Type of endpoint/s
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Statistical methods / analysis
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Recruitment
Recruitment status
Completed
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Data analysis
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Reason for early stopping/withdrawal
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Other reasons
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Date of first participant enrolment
Anticipated
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Actual
6/01/2014
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Date of last participant enrolment
Anticipated
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Actual
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Date of last data collection
Anticipated
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Actual
22/06/2018
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Sample size
Target
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Accrual to date
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Final
726
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Recruitment in Australia
Recruitment state(s)
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Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
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Name
Cubist Pharmaceuticals LLC
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Address
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Country
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Ethics approval
Ethics application status
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Summary
Brief summary
This is a 1:1 ratio, randomized, double-blind, double-dummy, multicenter, global Phase 3
study of tedizolid phosphate (TR-701 FA) 200 mg intravenous (IV) once daily for 7 days versus
linezolid (Zyvox®, Zyvoxid®, etc) 600 mg IV every 12 hours for 10 days for the treatment of
ventilated participants with presumed gram-positive hospital-acquired bacterial pneumonia
(HABP) or ventilator-associated bacterial pneumonia (VABP), collectively referred to as
ventilated nosocomial pneumonia (VNP). Participants with concurrent gram-positive bacteremia
are to receive 14 days of active therapy in either treatment arm.
The primary objective is to determine the noninferiority (NI) in all-cause mortality (ACM)
within 28 days after randomization of IV tedizolid phosphate compared with IV linezolid in
the Intent to Treat (ITT) Analysis Set (NI is declared when the lower bound of the 95% CI >
-10).
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Trial website
https://clinicaltrials.gov/ct2/show/NCT02019420
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Trial related presentations / publications
Alp E, Voss A. Ventilator associated pneumonia and infection control. Ann Clin Microbiol Antimicrob. 2006 Apr 6;5:7. doi: 10.1186/1476-0711-5-7.
American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med. 2005 Feb 15;171(4):388-416. doi: 10.1164/rccm.200405-644ST. No abstract available.
Chastre J, Wolff M, Fagon JY, Chevret S, Thomas F, Wermert D, Clementi E, Gonzalez J, Jusserand D, Asfar P, Perrin D, Fieux F, Aubas S; PneumA Trial Group. Comparison of 8 vs 15 days of antibiotic therapy for ventilator-associated pneumonia in adults: a randomized trial. JAMA. 2003 Nov 19;290(19):2588-98. doi: 10.1001/jama.290.19.2588.
Lan KK, Wittes J. The B-value: a tool for monitoring data. Biometrics. 1988 Jun;44(2):579-85.
Lawrence KR, Adra M, Gillman PK. Serotonin toxicity associated with the use of linezolid: a review of postmarketing data. Clin Infect Dis. 2006 Jun 1;42(11):1578-83. doi: 10.1086/503839. Epub 2006 Apr 27.
Lemaire S, Van Bambeke F, Appelbaum PC, Tulkens PM. Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. J Antimicrob Chemother. 2009 Nov;64(5):1035-43. doi: 10.1093/jac/dkp267. Epub 2009 Sep 16.
Torres A, Ewig S, Lode H, Carlet J; European HAP working group. Defining, treating and preventing hospital acquired pneumonia: European perspective. Intensive Care Med. 2009 Jan;35(1):9-29. doi: 10.1007/s00134-008-1336-9. Epub 2008 Nov 7.
Drusano GL, Liu W, Kulawy R, Louie A. Impact of granulocytes on the antimicrobial effect of tedizolid in a mouse thigh infection model. Antimicrob Agents Chemother. 2011 Nov;55(11):5300-5. doi: 10.1128/AAC.00502-11. Epub 2011 Sep 12.
Garonzik SM, Li J, Thamlikitkul V, Paterson DL, Shoham S, Jacob J, Silveira FP, Forrest A, Nation RL. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother. 2011 Jul;55(7):3284-94. doi: 10.1128/AAC.01733-10. Epub 2011 May 9.
Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, Kaplan SL, Karchmer AW, Levine DP, Murray BE, J Rybak M, Talan DA, Chambers HF. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary. Clin Infect Dis. 2011 Feb 1;52(3):285-92. doi: 10.1093/cid/cir034.
Pletz MW, Burkhardt O, Welte T. Nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia: linezolid or vancomycin? - Comparison of pharmacology and clinical efficacy. Eur J Med Res. 2010 Nov 30;15(12):507-13. doi: 10.1186/2047-783x-15-12-507.
Tessier PR, Keel RA, Hagihara M, Crandon JL, Nicolau DP. Comparative in vivo efficacies of epithelial lining fluid exposures of tedizolid, linezolid, and vancomycin for methicillin-resistant Staphylococcus aureus in a mouse pneumonia model. Antimicrob Agents Chemother. 2012 May;56(5):2342-6. doi: 10.1128/AAC.06427-11. Epub 2012 Feb 21.
Wunderink RG, Niederman MS, Kollef MH, Shorr AF, Kunkel MJ, Baruch A, McGee WT, Reisman A, Chastre J. Linezolid in methicillin-resistant Staphylococcus aureus nosocomial pneumonia: a randomized, controlled study. Clin Infect Dis. 2012 Mar 1;54(5):621-9. doi: 10.1093/cid/cir895. Epub 2012 Jan 12.
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Public notes
This record is viewable in the ANZCTR as it had previously listed Australia and/or New Zealand as a recruitment site, however these sites have since been removed
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Contacts
Principal investigator
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Medical Director
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Address
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Merck Sharp & Dohme LLC
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Contact person for public queries
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Contact person for scientific queries
Summary Results
For IPD and results data, please see
https://clinicaltrials.gov/ct2/show/NCT02019420
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