Skin Diseases, Infectious, Skin Diseases, Bacterial
Conditions
Brief summary
The purpose of the study is to compare the safety of intravenous (IV) and/or oral 6-day 200 mg tedizolid phosphate with 10-day comparator in participants 12 to \<18 years with cSSTI.
Detailed description
A randomized, single-blind, multicenter, Phase 3 study of IV and/or oral tedizolid phosphate 200 mg once per day for 6 days compared with IV and/or oral comparator for 10 days for the treatment of cSSTI, also known as acute bacterial skin and skin structure infections, in participants 12 to \<18 years. cSSTI includes major cutaneous abscess, cellulitis/erysipelas, and wound infection.
Interventions
DRUGTedizolid Phophate
Tedizolid Phophate 200 mg, IV and/or oral for 6 days
DRUGAntibiotic comparator
Antibiotic comparator drug, IV and/or orally for 10 days. Antibiotic comparator included the following: Vancomycin, Linezolid, Clindamycin, Flucloxacillin, Cefazolin, Cephalexin.
DRUGAztreonam
In countries and/or sites where aztreonam is available, adjunctive aztreonam (IV) may be initiated on Day 1 or during the first 3 days of treatment if the participant is determined or suspected to have an infection with gram-negative aerobic pathogens.
DRUGMetronidazole
Metronidazole (IV or oral) may be initiated on Day 1 or during the first 3 days of treatment if the participant is determined or suspected to have an infection with anaerobic pathogens.
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
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Males or females 12 years to \<18 years * Adequate venous access for IV administration of study drug for at least 24 hours (for participants receiving IV medication) and collection of protocol-specified blood samples * Local symptoms must have started within 7 days before Study Day -1 * cSSTI meeting at least 1 of the clinical syndrome definitions. * Suspected or documented Gram-positive infection from baseline Gram stain or culture. * Parent/legally authorized representative (LAR) able to give informed consent and willing and able to comply with all required study procedures. Assent is also required of children who in the Investigator's judgment are capable of understanding the nature of the study
Exclusion criteria
* Uncomplicated minor skin and skin structure infections such as pustules, folliculitis, furuncles, minor abscesses (small volume of suppuration not surrounded by cellulitis/erysipelas), impetiginous lesions, superficial or limited cellulitis/erysipelas, and minor wound associated foreign body reactions (eg, stitch abscesses) * Known bacteremia, severe sepsis or septic shock * Recent history of opportunistic infections where the underlying cause of these infections is still active (eg, leukemia, transplant, acquired immunodeficiency syndrome) * Hypersensitivity to tedizolid phosphate or any component in the formulation * Hypersensitivity to all of the comparator drugs; hypersensitivity to a comparator drug does not preclude participation if an alternative comparator can be used * For participants with wound infections: history of hypersensitivity to ceftazidime, aztreonam, or any component of the aztreonam formulation, if aztreonam adjunctive therapy is required; history of hypersensitivity to metronidazole or any component of the formulation, if metronidazole adjunctive therapy is required * Needs oral administration of methotrexate, topotecan, irinotecan or rosuvastatin, during administration of oral study drug. * Uses monoamine oxidase inhibitors, tricyclic antidepressants, buspirone, selective serotonin reuptake inhibitors and serotonin 5 hydroxytryptamine receptor agonists (triptans) within 14 days prior to study drug administration
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events on Tedizolid Phosphate and Comparator Drugs | Up to 40 days (including 30-day follow-up) | An adverse event (AE) refers to a treatment-emergent adverse event (TE-AE). A TE-AE is any AE that newly appeared, increased in frequency, or worsened in severity following initiation of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Investigator's Assessment Indicating Clinical Success at TOC Visit (Clinically Evaluable-Test of Cure [CE-TOC] Analysis Set) | TOC Visit: 18-25 days after first drug infusion | Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2)absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. |
| Number of Participants With Early Clinical Responses Measured by Lesion Reduction | 48-72 hr after first drug infusion | Early clinical response is defined as ≥20% reduction from baseline lesion area (defined as length multiplied by the width of the erythema, edema, and/or induration \[EEI\]) at the 48-72 hour (hr) visit. |
| Number of Participants With Investigator's Assessment Indicating Clinical Success at End of Therapy (EOT) Visit (Intent to Treat Analysis Set) | EOT Visit: up to 13 days after first drug infusion | Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2)absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. |
| Number of Participants With Investigator's Assessment Indicating Clinical Success at EOT Visit (Clinically Evaluable-End of Therapy [CE-EOT] Analysis Set) | EOT Visit: up to 13 days after first drug infusion | Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2) absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. |
| Number of Participants With Investigator's Assessment Indicating Clinical Success at Test of Cure (TOC) Visit (Intent to Treat Analysis Set) | TOC Visit: 18-25 days after first drug infusion | Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2)absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve Time 0 to 24 Hours (AUC0-24h) of Tedizolid | Day 1 at 5-80 min and 4-12 hrs post-infusion or 2 samples collected between 4-12 hrs after oral dose, at least 60 min apart; at 48-72 hrs: within 60 min prior to administration and 4-12 hrs after administration; and anytime between Day 7 and 9 | AUC0-24h is a measure of the total tedizolid exposure in the plasma from the dose to 24 hours after last dose. AUC0-24h was estimated based on population pharmacokinetic analysis of observed pharmacokinetic data. Blood samples were collected for pharmacokinetic analysis at specific time points. |
| Peak Plasma Concentration (Cmax) of Tedizolid | Day 1 at 5-80 minutes (min) and 4-12 hrs post-infusion or 2 samples collected between 4-12 hrs after oral dose, at least 60 min apart; at 48-72 hrs: within 60 min prior to administration and 4-12 hrs after administration; and anytime between Day 7 and 9 | The Cmax of tedizolid in plasma after the last dose was estimated based on population pharmacokinetic analysis of observed pharmacokinetic data. Blood samples were collected for pharmacokinetic analysis at specific time points. |
| Change From Baseline in Lesion Size | Baseline and TOC visit (18 to 25 days after infusion) | Lesion size is the area in cm\^2 of erythema, edema or induration. A negative number corresponds to a decrease in lesion size. |
Participant flow
Pre-assignment details
All participants who were enrolled and provided informed consent/ascent were randomized to one of two treatment groups.
Participants by arm
| Arm | Count |
|---|---|
| Tedizolid Phosphate Tedizolid Phosphate IV and/or oral 200 mg once per day for 6 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | 91 |
| Antibiotic Comparator Drug IV and/or oral antibiotic comparator drug for 10 days. Participants with gram-negative wound infection may receive aztreonam (IV) and/or metronidazole (IV or oral). | 29 |
| Total | 120 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Gram-negative infection | 1 | 0 |
| Overall Study | Reason not specified | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Antibiotic Comparator Drug | Total | Tedizolid Phosphate |
|---|---|---|---|
| Age, Continuous | 14.4 Years STANDARD_DEVIATION 2 | 14.4 Years STANDARD_DEVIATION 1.7 | 14.4 Years STANDARD_DEVIATION 1.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 28 Participants | 114 Participants | 86 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 15 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 104 Participants | 80 Participants |
| Sex: Female, Male Female | 12 Participants | 45 Participants | 33 Participants |
| Sex: Female, Male Male | 17 Participants | 75 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 91 | 0 / 29 |
| other Total, other adverse events | 0 / 91 | 0 / 29 |
| serious Total, serious adverse events | 1 / 91 | 0 / 29 |
Outcome results
Primary
Number of Participants With Adverse Events on Tedizolid Phosphate and Comparator Drugs
An adverse event (AE) refers to a treatment-emergent adverse event (TE-AE). A TE-AE is any AE that newly appeared, increased in frequency, or worsened in severity following initiation of study drug.
Time frame: Up to 40 days (including 30-day follow-up)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid Phosphate | Number of Participants With Adverse Events on Tedizolid Phosphate and Comparator Drugs | 13 Participants |
| Antibiotic Comparator Drug | Number of Participants With Adverse Events on Tedizolid Phosphate and Comparator Drugs | 3 Participants |
Secondary
Number of Participants With Early Clinical Responses Measured by Lesion Reduction
Early clinical response is defined as ≥20% reduction from baseline lesion area (defined as length multiplied by the width of the erythema, edema, and/or induration \[EEI\]) at the 48-72 hour (hr) visit.
Time frame: 48-72 hr after first drug infusion
Population: All randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid Phosphate | Number of Participants With Early Clinical Responses Measured by Lesion Reduction | 84 Participants |
| Antibiotic Comparator Drug | Number of Participants With Early Clinical Responses Measured by Lesion Reduction | 28 Participants |
95% CI: [-12.9, 4.4]
Secondary
Number of Participants With Investigator's Assessment Indicating Clinical Success at End of Therapy (EOT) Visit (Intent to Treat Analysis Set)
Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2)absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion.
Time frame: EOT Visit: up to 13 days after first drug infusion
Population: All randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid Phosphate | Number of Participants With Investigator's Assessment Indicating Clinical Success at End of Therapy (EOT) Visit (Intent to Treat Analysis Set) | 88 Participants |
| Antibiotic Comparator Drug | Number of Participants With Investigator's Assessment Indicating Clinical Success at End of Therapy (EOT) Visit (Intent to Treat Analysis Set) | 28 Participants |
95% CI: [-7.4, 7.7]
Secondary
Number of Participants With Investigator's Assessment Indicating Clinical Success at EOT Visit (Clinically Evaluable-End of Therapy [CE-EOT] Analysis Set)
Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2) absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion.
Time frame: EOT Visit: up to 13 days after first drug infusion
Population: All randomized participants received a full dose of study treatment and completed EOT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid Phosphate | Number of Participants With Investigator's Assessment Indicating Clinical Success at EOT Visit (Clinically Evaluable-End of Therapy [CE-EOT] Analysis Set) | 87 Participants |
| Antibiotic Comparator Drug | Number of Participants With Investigator's Assessment Indicating Clinical Success at EOT Visit (Clinically Evaluable-End of Therapy [CE-EOT] Analysis Set) | 27 Participants |
95% CI: [0, 0]
Secondary
Number of Participants With Investigator's Assessment Indicating Clinical Success at Test of Cure (TOC) Visit (Intent to Treat Analysis Set)
Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2)absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion.
Time frame: TOC Visit: 18-25 days after first drug infusion
Population: All randomized participants.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid Phosphate | Number of Participants With Investigator's Assessment Indicating Clinical Success at Test of Cure (TOC) Visit (Intent to Treat Analysis Set) | 88 Participants |
| Antibiotic Comparator Drug | Number of Participants With Investigator's Assessment Indicating Clinical Success at Test of Cure (TOC) Visit (Intent to Treat Analysis Set) | 27 Participants |
95% CI: [-6.3, 13.5]
Secondary
Number of Participants With Investigator's Assessment Indicating Clinical Success at TOC Visit (Clinically Evaluable-Test of Cure [CE-TOC] Analysis Set)
Investigator's assessment of clinical success is defined as (1) resolution or near resolution of most disease-specific signs and symptoms, (2)absence or near resolution of regional or systemic signs of infection (lymphadenopathy, fever, \>10% immature neutrophils, abnormal white blood cell count), if present at baseline, and (3) no new signs, symptoms, or complications attributable to the infection under study so no further antibiotic therapy is required for the treatment of the primary lesion.
Time frame: TOC Visit: 18-25 days after first drug infusion
Population: All randomized participants who received a full dose of study treatment and completed TOC.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tedizolid Phosphate | Number of Participants With Investigator's Assessment Indicating Clinical Success at TOC Visit (Clinically Evaluable-Test of Cure [CE-TOC] Analysis Set) | 87 Participants |
| Antibiotic Comparator Drug | Number of Participants With Investigator's Assessment Indicating Clinical Success at TOC Visit (Clinically Evaluable-Test of Cure [CE-TOC] Analysis Set) | 26 Participants |
95% CI: [-3.4, 10.8]
Other Pre-specified
Area Under the Plasma Concentration Versus Time Curve Time 0 to 24 Hours (AUC0-24h) of Tedizolid
AUC0-24h is a measure of the total tedizolid exposure in the plasma from the dose to 24 hours after last dose. AUC0-24h was estimated based on population pharmacokinetic analysis of observed pharmacokinetic data. Blood samples were collected for pharmacokinetic analysis at specific time points.
Time frame: Day 1 at 5-80 min and 4-12 hrs post-infusion or 2 samples collected between 4-12 hrs after oral dose, at least 60 min apart; at 48-72 hrs: within 60 min prior to administration and 4-12 hrs after administration; and anytime between Day 7 and 9
Population: All randomized participants who received a dose of tedizolid phosphate. Pharmacokinetic analysis was not performed with participants receiving antibiotic comparator drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Tedizolid Phosphate | Area Under the Plasma Concentration Versus Time Curve Time 0 to 24 Hours (AUC0-24h) of Tedizolid | 28.6 µg*h/mL |
Other Pre-specified
Change From Baseline in Lesion Size
Lesion size is the area in cm\^2 of erythema, edema or induration. A negative number corresponds to a decrease in lesion size.
Time frame: Baseline and TOC visit (18 to 25 days after infusion)
Population: All randomized participants who received a full dose of study treatment, had a baseline value and a TOC visit value (Days 18 to 25).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tedizolid Phosphate | Change From Baseline in Lesion Size | Baseline | 135.44 cm^2 | Standard Deviation 158.66 |
| Tedizolid Phosphate | Change From Baseline in Lesion Size | Change at Day 25 | -134.27 cm^2 | Standard Deviation 161.18 |
| Antibiotic Comparator Drug | Change From Baseline in Lesion Size | Baseline | 83.22 cm^2 | Standard Deviation 48.55 |
| Antibiotic Comparator Drug | Change From Baseline in Lesion Size | Change at Day 25 | -82.51 cm^2 | Standard Deviation 49.94 |
Other Pre-specified
Peak Plasma Concentration (Cmax) of Tedizolid
The Cmax of tedizolid in plasma after the last dose was estimated based on population pharmacokinetic analysis of observed pharmacokinetic data. Blood samples were collected for pharmacokinetic analysis at specific time points.
Time frame: Day 1 at 5-80 minutes (min) and 4-12 hrs post-infusion or 2 samples collected between 4-12 hrs after oral dose, at least 60 min apart; at 48-72 hrs: within 60 min prior to administration and 4-12 hrs after administration; and anytime between Day 7 and 9
Population: All randomized participants who received a dose of tedizolid phosphate. Pharmacokinetic analysis was not performed with participants receiving antibiotic comparator drug.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Tedizolid Phosphate | Peak Plasma Concentration (Cmax) of Tedizolid | 3.13 µg/mL |