Skin and Subcutaneous Tissue Bacterial Infections
Conditions
Keywords
ABSSSI, Tedizolid Phosphate, TR-701, Acute Bacterial Skin and Skin Structure Infections
Brief summary
This is a randomized, double-blind, double-dummy, multicenter, global Phase 3 study of IV to oral TR-701 FA 200 mg once daily for 6 days versus IV to oral Zyvox® (linezolid) 600 mg every 12 hours for 10 days for the treatment of ABSSSI in adults. Patients are to start treatment with at least 2 IV doses and may receive IV therapy for the entire treatment duration. Approximately 100 to 140 sites globally will participate in this study. Patients with an ABSSSI caused by suspected or documented gram positive pathogen(s) at baseline will be randomized 1:1 to study treatment.
Detailed description
The primary objective is to determine the noninferiority (NI) in the early clinical response rate of intravenous (IV) to oral 6 day TR-701 free acid (FA) compared with that of IV to oral 10-day linezolid treatment at 48-72 hours after the first infusion of study drug in the intent-to-treat (ITT) analysis set in patients with acute bacterial skin and skin structure infections (ABSSSI).
Interventions
DRUGTR-701 FA
* TR-701 FA 200 mg once daily in 250 mL sterile saline for injection as a 60 minute IV infusion * TR-701 FA Tablets, 200 mg, orally once daily
DRUGLinezolid
* Linezolid 600 mg IV Injection twice daily in 300 mL sterile saline for injection as a 60 minute IV infusion * Linezolid Tablets, 600 mg, orally every 12 hours
Sponsors
Trius Therapeutics 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
* Patients requiring IV antibiotic therapy and with systemic signs of infection diagnosed with ABSSSI. * Diagnosed with Cellulitis/ erysipelas, major cutaneous abscess, or wound infections
Exclusion criteria
* Uncomplicated skin infections * Severe sepsis or septic shock * ABSSSI solely due to gram-negative pathogens
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Early Clinical Response Rate | 48-72 hours | Responder: No increase in lesion surface area from baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Response at the End of Therapy Visit in the Clinically Evaluable at End of Therapy Analysis Set | End of Therapy Day 11 | Responder: No increase in lesion surface area from baseline. |
| Investigator's Assessment of Clinical Success at the Post Treatment Evaluation Visit | Post-Treatment Evaluation (7-14 days after the End of Therapy) | Clinical success defined as resolution/near resolution of disease specific signs and symptoms, absence/near resolution of baseline systemic signs of infection, and no further antibiotic therapy required for treatment of primary ABSSSI lesion. |
| Investigator's Assessment of Clinical Success of the Post Therapy Evaluation Visit in Clinically Evaluable-Post Treatment Evaluation Analysis Set. | Post-Treatment Evaluation (7-14 days after the End of Therapy) | Clinical success defined as resolution/near resolution of disease specific signs and symptoms, absence/near resolution of baseline systemic signs of infection, no new signs, symptoms or complications attributable to the ABSSSI and no further antibiotic therapy required for treatment of primary ABSSSI lesion. |
| Clinical Response at the End of Therapy Visit | Day 11 | Responder: No increase in lesion surface area from baseline. |
| Investigator's Assessment of Clinical Response at the Day-7 Visit | Day 7 | Clinical improvement defined as improvement in overall clinical status. |
| Change From Baseline in Patient-reported Pain, by Study Visit | Multiple | 0=no pain, 10=worst pain Only 1 visit per participant for Day 4-6, only 1 visit for Day 7-9, and only 1 visit for Day 10-13. |
| Investigator's Assessment of Clinical Response at the 48-72 Hour Visit | 48-72 Hours | Clinical improvement defined as improvement in overall clinical status. |
Countries
Argentina, Australia, Brazil, Germany, Mexico, New Zealand, Poland, Russia, South Africa, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Tedizolid Phosphate IV to oral tedizolid phosphate 200 mg once daily for six days followed by four days of placebo. | 332 |
| Linezolid IV to oral linezolid 600 mg twice daily for 10 days. | 334 |
| Total | 666 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Lost to Follow-up | 11 | 14 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Randomized but didn't receive study drug | 1 | 7 |
| Overall Study | Withdrawal by Subject | 6 | 5 |
Baseline characteristics
| Characteristic | Tedizolid Phosphate | Linezolid | Total |
|---|---|---|---|
| Age, Continuous | 45.6 years STANDARD_DEVIATION 15.79 | 45.6 years STANDARD_DEVIATION 15.57 | 45.6 years STANDARD_DEVIATION 15.67 |
| Sex: Female, Male Female | 107 Participants | 120 Participants | 227 Participants |
| Sex: Female, Male Male | 225 Participants | 214 Participants | 439 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 84 / 331 | 90 / 327 |
| serious Total, serious adverse events | 7 / 331 | 9 / 327 |
Outcome results
Primary
The Early Clinical Response Rate
Responder: No increase in lesion surface area from baseline.
Time frame: 48-72 hours
Population: The Intent to Treat analysis set includes data from all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | The Early Clinical Response Rate | 283 participants |
| Linezolid | The Early Clinical Response Rate | 276 participants |
95% CI: [-3, 8.2]
Secondary
Change From Baseline in Patient-reported Pain, by Study Visit
0=no pain, 10=worst pain Only 1 visit per participant for Day 4-6, only 1 visit for Day 7-9, and only 1 visit for Day 10-13.
Time frame: Multiple
Population: The Intent to Treat analysis set includes data from all randomized participants.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tedizolid Phosphate | Change From Baseline in Patient-reported Pain, by Study Visit | Day 2 | -1.7 units on a scale | Standard Deviation 2.05 |
| Tedizolid Phosphate | Change From Baseline in Patient-reported Pain, by Study Visit | Day 4-6 | -3.1 units on a scale | Standard Deviation 2.67 |
| Tedizolid Phosphate | Change From Baseline in Patient-reported Pain, by Study Visit | Day 7-9 | -4.9 units on a scale | Standard Deviation 2.89 |
| Tedizolid Phosphate | Change From Baseline in Patient-reported Pain, by Study Visit | Day 10-13 | -5.4 units on a scale | Standard Deviation 2.8 |
| Linezolid | Change From Baseline in Patient-reported Pain, by Study Visit | Day 10-13 | -5.6 units on a scale | Standard Deviation 2.84 |
| Linezolid | Change From Baseline in Patient-reported Pain, by Study Visit | Day 2 | -2.1 units on a scale | Standard Deviation 2.29 |
| Linezolid | Change From Baseline in Patient-reported Pain, by Study Visit | Day 7-9 | -4.9 units on a scale | Standard Deviation 2.96 |
| Linezolid | Change From Baseline in Patient-reported Pain, by Study Visit | Day 4-6 | -3.3 units on a scale | Standard Deviation 2.56 |
Secondary
Clinical Response at the End of Therapy Visit
Responder: No increase in lesion surface area from baseline.
Time frame: Day 11
Population: The Intent to Treat analysis set includes data from all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | Clinical Response at the End of Therapy Visit | 289 participants |
| Linezolid | Clinical Response at the End of Therapy Visit | 294 participants |
95% CI: [-6.1, 4.1]
Secondary
Clinical Response at the End of Therapy Visit in the Clinically Evaluable at End of Therapy Analysis Set
Responder: No increase in lesion surface area from baseline.
Time frame: End of Therapy Day 11
Population: All randomized participants receiving minimal study therapy, completed EOT assessment, no concomitant systemic antibiotic therapy and no confounding events or factors.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | Clinical Response at the End of Therapy Visit in the Clinically Evaluable at End of Therapy Analysis Set | 272 participants |
| Linezolid | Clinical Response at the End of Therapy Visit in the Clinically Evaluable at End of Therapy Analysis Set | 280 participants |
95% CI: [-8.8, 0.3]
Secondary
Investigator's Assessment of Clinical Response at the 48-72 Hour Visit
Clinical improvement defined as improvement in overall clinical status.
Time frame: 48-72 Hours
Population: The Intent to Treat analysis set includes data from all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | Investigator's Assessment of Clinical Response at the 48-72 Hour Visit | 304 participants |
| Linezolid | Investigator's Assessment of Clinical Response at the 48-72 Hour Visit | 302 participants |
Comparison: A two-sided 95% CI was calculated for the observed differences in the clinical response rate based on the Investigator's assessment of clinical response at the 48-72 Hour Visit using the method of Miettinen and Nurminen without stratification.95% CI: [-3.3, 5.6]
Secondary
Investigator's Assessment of Clinical Response at the Day-7 Visit
Clinical improvement defined as improvement in overall clinical status.
Time frame: Day 7
Population: The Intent to Treat analysis set includes data from all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | Investigator's Assessment of Clinical Response at the Day-7 Visit | 309 participants |
| Linezolid | Investigator's Assessment of Clinical Response at the Day-7 Visit | 308 participants |
Comparison: A two-sided 95% CI was calculated for the observed differences in the clinical response rate based on the Investigator's assessment of clinical response at the Day 7 Visit using the method of Miettinen and Nurminen without stratification.95% CI: [-3.2, 4.9]
Secondary
Investigator's Assessment of Clinical Success at the Post Treatment Evaluation Visit
Clinical success defined as resolution/near resolution of disease specific signs and symptoms, absence/near resolution of baseline systemic signs of infection, and no further antibiotic therapy required for treatment of primary ABSSSI lesion.
Time frame: Post-Treatment Evaluation (7-14 days after the End of Therapy)
Population: The Intent to Treat analysis set includes data from all randomized participants.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | Investigator's Assessment of Clinical Success at the Post Treatment Evaluation Visit | 292 participants |
| Linezolid | Investigator's Assessment of Clinical Success at the Post Treatment Evaluation Visit | 293 participants |
95% CI: [-4.8, 5.3]
Secondary
Investigator's Assessment of Clinical Success of the Post Therapy Evaluation Visit in Clinically Evaluable-Post Treatment Evaluation Analysis Set.
Clinical success defined as resolution/near resolution of disease specific signs and symptoms, absence/near resolution of baseline systemic signs of infection, no new signs, symptoms or complications attributable to the ABSSSI and no further antibiotic therapy required for treatment of primary ABSSSI lesion.
Time frame: Post-Treatment Evaluation (7-14 days after the End of Therapy)
Population: All randomized participants receiving minimal study therapy, completed EOT and PTE Investigator's assessments, no concomitant systemic antibiotic therapy through PTE, and no confounding events or factors.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tedizolid Phosphate | Investigator's Assessment of Clinical Success of the Post Therapy Evaluation Visit in Clinically Evaluable-Post Treatment Evaluation Analysis Set. | 268 participants |
| Linezolid | Investigator's Assessment of Clinical Success of the Post Therapy Evaluation Visit in Clinically Evaluable-Post Treatment Evaluation Analysis Set. | 269 participants |
95% CI: [-7.7, 0.2]