Tedizolid Phosphate (TR-701 FA, MK-1986) vs Linezolid for the Treatment of Nosocomial Pneumonia (MK-1986-002)

Pneumonia Clinical Trial

Official title:

A Phase 3 Randomized Double-blind Study Comparing TR-701 FA and Linezolid in Ventilated Gram-positive Nosocomial Pneumonia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02019420
• Other study ID #: 1986-002
• Secondary ID: TR701-1322013-00
• Status: Completed
• Phase: Phase 3
• Start date: January 6, 2014
• Est. completion date: June 22, 2018

Study information

• Verified date: June 2019
• Source: Cubist Pharmaceuticals LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 726
• Est. completion date: June 22, 2018
• Est. primary completion date: June 22, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Requires IV antibiotic therapy with diagnosis of ventilated nosocomial pneumonia

• Gram-positive bacteria on respiratory Gram stain

Exclusion Criteria:

• Pneumonia of community, viral, fungal or parasitic etiology

• Structural lung abnormalities

• Immunosuppression

• Previous antibiotics for > 24 hours

• Expected survival of < 72 hours

Related Conditions & MeSH terms

• Healthcare-Associated Pneumonia
• Pneumonia

Intervention

Drug:
• Tedizolid phosphate
Tedizolid phosphate IV 200 mg once daily
• Linezolid
Linezolid IV 600 mg twice daily

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Cubist Pharmaceuticals LLC

References & Publications (13)

Alp E, Voss A. Ventilator associated pneumonia and infection control. Ann Clin Microbiol Antimicrob. 2006 Apr 6;5:7. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Lan KK, Wittes J. The B-value: a tool for monitoring data. Biometrics. 1988 Jun;44(2):579-85. — View Citation

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. Epub 2006 Apr 27. Review. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population	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.	Up to 28 days
Secondary	Number of Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population	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.	Up to 28 days
Secondary	Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population	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.	7-14 days after end of therapy - TOC
Secondary	Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population	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.	7-14 days after end of therapy - TOC
Secondary	Number of Methicillin-Susceptible Staphylococcus Aureus (MSSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population	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.	Up to 28 days
Secondary	Number of Methicillin-Resistant Staphylococcus Aureus (MRSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population	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.	Up to 28 days
Secondary	Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population	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).	1-3 days after completing study therapy (Days 8-10 or Days 15-17)
Secondary	Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiologically-Evaluable 1 (ME-1) Population	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).	1-3 days after completing study therapy (Days 8-10 or Days 15-17)
Secondary	Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (mITT) Population	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).	7-14 days after end of therapy - TOC
Secondary	Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiologically-Evaluable 2 (ME-2) Population	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).	7-14 days after end of therapy - TOC
Secondary	Number of Participants With =1 Adverse Events (AEs)	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.	Up to 32 days
Secondary	Number of Participants Discontinuing Study Therapy Due to an Adverse Event (AE)	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.	Up to 14 days