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

NCT02019420 | Completed Phase 3 Results DMC FDA Drug

• 4 other identifiers: 1986-002TR701-1322013-004154-22MK-1986-002
• Study Type: interventional
• Target: 726
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Pneumonia

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (11)

• Number of Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population

  Up to 28 days

• Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population

  7-14 days after end of therapy - TOC

• Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population

  7-14 days after end of therapy - TOC

• Number of Methicillin-Susceptible Staphylococcus Aureus (MSSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population

  Up to 28 days

• Number of Methicillin-Resistant Staphylococcus Aureus (MRSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population

  Up to 28 days

Study Arms (2)

Tedizolid phosphate IV

EXPERIMENTAL

Ventilated HABP/VABP participants receive tedizolid phosphate 200 mg IV once daily for 7 days, or for 14 days for concurrent bacteremia.

Drug: Tedizolid phosphate

Linezolid IV

ACTIVE COMPARATOR

Ventilated HABP/VABP participants receive linezolid 600 mg IV every 12 hours for 10 days, or for 14 days for concurrent bacteremia.

Drug: Linezolid

Interventions

Tedizolid phosphate DRUG

Tedizolid phosphate IV 200 mg once daily

Also known as: SIVEXTRO®, TR-701 FA, MK-1986

Tedizolid phosphate IV

Linezolid DRUG

Linezolid IV 600 mg twice daily

Also known as: ZYVOX®

Linezolid IV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Requires IV antibiotic therapy with diagnosis of ventilated nosocomial pneumonia
• Gram-positive bacteria on respiratory Gram stain

You may not qualify if:

• Pneumonia of community, viral, fungal or parasitic etiology
• Structural lung abnormalities
• Immunosuppression
• Previous antibiotics for \> 24 hours
• Expected survival of \< 72 hours

Sponsors & Collaborators

• Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): lead

Related Publications (15)

• 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.

  PMID: 16600048 BACKGROUND

• 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.

  PMID: 15699079 BACKGROUND

• 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.

  PMID: 14625336 BACKGROUND

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

  PMID: 3390511 BACKGROUND

• 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.

  PMID: 16652315 BACKGROUND

• 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.

  PMID: 19759040 BACKGROUND

• 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.

  PMID: 18989656 BACKGROUND

• 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.

  PMID: 21911576 BACKGROUND

• 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.

  PMID: 21555763 BACKGROUND

• 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.

  PMID: 21217178 BACKGROUND

• 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.

  PMID: 21163725 BACKGROUND

• 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.

  PMID: 22354302 BACKGROUND

• 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.

  PMID: 22247123 BACKGROUND

• Mikamo H, Nagashima M, Kusachi S, Fujimi S, Oshima N, De Anda C, Takase A. Efficacy and safety of tedizolid for the treatment of ventilated gram-positive hospital-acquired or ventilator-associated bacterial pneumonia in Japanese patients: Results from a subgroup analysis of a phase 3, randomized, double-blind study comparing tedizolid and linezolid. J Infect Chemother. 2022 Sep;28(9):1235-1241. doi: 10.1016/j.jiac.2022.04.027. Epub 2022 Jun 16.

  PMID: 35718656 DERIVED

• Wunderink RG, Roquilly A, Croce M, Rodriguez Gonzalez D, Fujimi S, Butterton JR, Broyde N, Popejoy MW, Kim JY, De Anda C. A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia. Clin Infect Dis. 2021 Aug 2;73(3):e710-e718. doi: 10.1093/cid/ciab032.

  PMID: 33720350 DERIVED

MeSH Terms

Conditions

Pneumonia

Interventions

tedizolid phosphate; Linezolid

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Oxazolidinones; Oxazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 18, 2013
• First Posted: December 24, 2013
• Study Start: January 6, 2014
• Primary Completion: June 22, 2018
• Study Completion: June 22, 2018
• Last Updated: June 27, 2019
• Results First Posted: June 27, 2019

Record last verified: 2019-06

Data Sharing

• IPD Sharing: Will share