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

Phase 3CompletedNCT02019420

Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)726 enrolled

Overview

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).

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

726

Conditions

Pneumonia

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

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.

Time frame: Up to 28 days

Secondary Outcomes

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.

Time frame: Up to 28 days

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.

Time frame: 7-14 days after end of therapy - TOC

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.

Time frame: 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

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.

Time frame: 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

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.

Time frame: Up to 28 days

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).

Time frame: 1-3 days after completing study therapy (Days 8-10 or Days 15-17)

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).

Time frame: 1-3 days after completing study therapy (Days 8-10 or Days 15-17)

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).

Time frame: 7-14 days after end of therapy - TOC

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).

Time frame: 7-14 days after end of therapy - TOC

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.

Time frame: Up to 32 days

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.

Time frame: Up to 14 days