Pneumonia
Conditions
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).
Interventions
Tedizolid phosphate IV 200 mg once daily
DRUGLinezolid
Linezolid IV 600 mg twice daily
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population | Up to 28 days | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | Up to 28 days | 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. |
| Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | 7-14 days after end of therapy - TOC | 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. |
| Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | 7-14 days after end of therapy - TOC | 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. |
| 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 | 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. |
| 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 | 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. |
| Number of Participants With ≥1 Adverse Events (AEs) | Up to 32 days | 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. |
| Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiologically-Evaluable 1 (ME-1) Population | 1-3 days after completing study therapy (Days 8-10 or Days 15-17) | 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). |
| Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (mITT) Population | 7-14 days after end of therapy - TOC | 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). |
| Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiologically-Evaluable 2 (ME-2) Population | 7-14 days after end of therapy - TOC | 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). |
| Number of Participants Discontinuing Study Therapy Due to an Adverse Event (AE) | Up to 14 days | 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. |
| Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population | 1-3 days after completing study therapy (Days 8-10 or Days 15-17) | 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). |
Participant flow
Recruitment details
Ventilated participants with presumed gram-positive hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP) were enrolled at study sites located in 34 countries.
Participants by arm
| Arm | Count |
|---|---|
| Tedizolid Ventilated HABP/VABP participants received tedizolid phosphate 200 mg IV once daily for 7 days, or for 14 days for concurrent bacteremia. | 366 |
| Linezolid Ventilated HABP/VABP participants received linezolid 600 mg IV every 12 hours for 10 days, or for 14 days for concurrent bacteremia. | 360 |
| Total | 726 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | At request of sponsor or investigator | 0 | 1 |
| Overall Study | Death | 104 | 99 |
| Overall Study | Did not receive study drug | 2 | 2 |
| Overall Study | Transferred to other care facility | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Linezolid | Total | Tedizolid |
|---|---|---|---|
| Age, Continuous | 58.7 Years STANDARD_DEVIATION 17.44 | 58.4 Years STANDARD_DEVIATION 17.93 | 58.1 Years STANDARD_DEVIATION 18.41 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 61 Participants | 126 Participants | 65 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 289 Participants | 579 Participants | 290 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 10 Participants | 21 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 70 Participants | 138 Participants | 68 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 14 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 19 Participants | 42 Participants | 23 Participants |
| Race (NIH/OMB) White | 258 Participants | 527 Participants | 269 Participants |
| Sex: Female, Male Female | 106 Participants | 223 Participants | 117 Participants |
| Sex: Female, Male Male | 254 Participants | 503 Participants | 249 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 101 / 357 | 103 / 361 |
| other Total, other adverse events | 176 / 357 | 175 / 361 |
| serious Total, serious adverse events | 129 / 357 | 149 / 361 |
Outcome results
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.
Time frame: Up to 28 days
Population: The ITT set is all randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population | 103 Participants |
| Linezolid | Number of Participants With All-Cause Mortality in the Intent-to-Treat (ITT) Population | 95 Participants |
95% CI: [-8.2, 4.7]
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.
Time frame: 7-14 days after end of therapy - TOC
Population: The CE set is all randomized and treated participants who had assessment data available and did not have confounding events.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tedizolid | Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | Clinical Success | 143 Participants |
| Tedizolid | Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | Clinical Failure | 124 Participants |
| Tedizolid | Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | Indeterminate | 0 Participants |
| Linezolid | Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | Clinical Success | 146 Participants |
| Linezolid | Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | Clinical Failure | 97 Participants |
| Linezolid | Clinical Response at Test of Cure (TOC) Visit in the Clinically-Evaluable (CE) Population | Indeterminate | 0 Participants |
95% CI: [-15.1, 2.1]
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.
Time frame: 7-14 days after end of therapy - TOC
Population: The ITT set includes all randomized participants.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tedizolid | Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | Clinical Success | 206 Participants |
| Tedizolid | Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | Clinical Failure | 144 Participants |
| Tedizolid | Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | Indeterminate | 16 Participants |
| Linezolid | Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | Clinical Success | 230 Participants |
| Linezolid | Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | Clinical Failure | 110 Participants |
| Linezolid | Clinical Response at Test of Cure (TOC) Visit in the Intent-to-Treat (ITT) Population | Indeterminate | 20 Participants |
95% CI: [-14.7, -0.5]
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.
Time frame: Up to 28 days
Population: The MRSA-infected mITT set is all randomized, treated participants who have MRSA confirmed by respiratory tract/pleural fluid culture results obtained within 72 hours before first study drug dose, and documented bacterial pathogen against which the investigational drug has antibacterial activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Methicillin-Resistant Staphylococcus Aureus (MRSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | 14 Participants |
| Linezolid | Number of Methicillin-Resistant Staphylococcus Aureus (MRSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | 20 Participants |
95% CI: [-12.8, 18.9]
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.
Time frame: Up to 28 days
Population: The MSSA-infected mITT set is all randomized, treated participants who have MSSA confirmed by respiratory tract/pleural fluid culture results obtained within 36 hours before first study drug dose, and documented bacterial pathogen against which the investigational drug has antibacterial activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Methicillin-Susceptible Staphylococcus Aureus (MSSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | 31 Participants |
| Linezolid | Number of Methicillin-Susceptible Staphylococcus Aureus (MSSA)-Infected Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | 32 Participants |
95% CI: [-12.5, 9.5]
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.
Time frame: Up to 14 days
Population: The safety set is all randomized participants who received any amount of study drug. A total of 4 participants were randomized to tedizolid but received linezolid.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants Discontinuing Study Therapy Due to an Adverse Event (AE) | 4 Participants |
| Linezolid | Number of Participants Discontinuing Study Therapy Due to an Adverse Event (AE) | 3 Participants |
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.
Time frame: Up to 32 days
Population: The safety set is all randomized participants who received any amount of study drug. A total of 4 participants were randomized to tedizolid but received linezolid.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With ≥1 Adverse Events (AEs) | 327 Participants |
| Linezolid | Number of Participants With ≥1 Adverse Events (AEs) | 325 Participants |
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).
Time frame: 1-3 days after completing study therapy (Days 8-10 or Days 15-17)
Population: The mITT set is all randomized, treated participants who have gram-positive pathogen(s) confirmed by respiratory tract/pleural fluid culture results obtained within 36 hours (or 72 hours if MRSA) before first study drug dose, and documented bacterial pathogen against which the investigational drug has antibacterial activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population | 123 Participants |
| Linezolid | Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiological Intent-to-Treat (mITT) Population | 166 Participants |
95% CI: [-21.7, -4.5]
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).
Time frame: 1-3 days after completing study therapy (Days 8-10 or Days 15-17)
Population: The ME-1 set is all mITT participants who did not receive an antibiotic (other than study drug) with activity against the baseline pathogen up to 28 days after randomization.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiologically-Evaluable 1 (ME-1) Population | 123 Participants |
| Linezolid | Number of Participants With a Favorable Response at End-of-Therapy (EOT) Visit in the Microbiologically-Evaluable 1 (ME-1) Population | 166 Participants |
95% CI: [-21.7, -4.5]
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).
Time frame: 7-14 days after end of therapy - TOC
Population: The mITT set is all randomized, treated participants who have gram-positive pathogen(s) confirmed by respiratory tract/pleural fluid culture results obtained within 36 hours (or 72 hours if MRSA) before first study drug dose, and documented bacterial pathogen against which the investigational drug has antibacterial activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (mITT) Population | 117 Participants |
| Linezolid | Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiological Intent-to-Treat (mITT) Population | 158 Participants |
95% CI: [-21.5, -3.5]
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).
Time frame: 7-14 days after end of therapy - TOC
Population: The ME-2 set is all mITT participants who did not receive an antibiotic (other than study drug) with activity against the baseline pathogen up to the TOC visit and is also in the clinically-evaluable (CE) set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiologically-Evaluable 2 (ME-2) Population | 65 Participants |
| Linezolid | Number of Participants With a Favorable Response at Test-of-Cure (TOC) Visit in the Microbiologically-Evaluable 2 (ME-2) Population | 74 Participants |
95% CI: [-26.2, -1.2]
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.
Time frame: Up to 28 days
Population: The mITT set is all randomized, treated participants who have gram-positive pathogen(s) confirmed by respiratory tract/pleural fluid culture results obtained within 36 hours (or 72 hours if methicillin-resistant S. aureus \[MRSA\]) before first study drug dose, and bacterial pathogen against which the investigational drug has antibacterial activity.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid | Number of Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | 46 Participants |
| Linezolid | Number of Participants With All-Cause Mortality in the Microbiological Intent-to-Treat (mITT) Population | 49 Participants |
95% CI: [-10.3, 7.1]