Osteomyelitis
Conditions
Keywords
Osteomyelitis, Prosthetic Hip, Prosthetic Knee, MRSA, Osteomyelitis Associated with an Infected Prosthetic Hip or Knee Joint, Staphylococci
Brief summary
This is a research study designed to look at the efficacy and safety of daptomycin given at a dose of 6 mg/kg or 8 mg/kg in subjects being treated for prosthetic hip or knee infections caused by Staphylococci. These types of bacteria are among the most common types of bacteria causing infections of prosthetic joints.
Interventions
DRUGdaptomycin
6 mg/kg
DRUGvancomycin
1 gram
DRUGteicoplanin
6 mg/kg; used only at UK sites
DRUGnafcillin
1-2 gram
DRUGoxacillin
1-2 gram
DRUGflucloxacillin
1-2 mg
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
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Subject must be between the ages of 18 and 80, inclusive * Subject must have a diagnosis of prosthetic joint infection (PJI) in a hip or knee joint which has never previously been totally revised because of an infection and for which they are anticipated to undergo a two-stage replacement surgery * Subject must have a positive microbiological identifier of staphylococci. * If Subject is female of childbearing potential, must be willing to practice reliable birth control
Exclusion criteria
* Subject has permanent intravascular prosthetic material such as heart valves or pacemakers * Subject has a creatinine clearance (CLCR) \<30 mL/min as determined by the Cockcroft-Gault equation using actual body weight. * Subject has significant hepatic dysfunction * Subject has a fungal or mycobacterial PJI * Subject is known to be HIV-infected with CD4 count ≤ 200 cells/ mm3 * Subject has an abnormal creatine phosphokinase (CPK) (elevated CPK level ≥ 2x ULN) at baseline as measured by central laboratory * Subject is currently under treatment with chemotherapeutic agents excluding chronic maintenance therapy (e.g. tamoxifen to prevent relapse of primary breast cancer) * Subject is pregnant, nursing, or lactating. * Subject is receiving or is expected to receive chronic immunosuppressive therapy during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L) | From the 3rd day of therapy to 1 week post last dose (approximately week 7) | Number of subjects with CPK \>500 U/L between Day 3 and 7 days following the last dose of study medication (Day 7P) as measured by the central laboratory. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety - Notable Laboratory Abnormalities | From the 1st day of therapy to maximum of 23 weeks post last dose (up to maximum of week 30) | Summary of Notable Laboratory Abnormalities - description of the proportion of subjects within each treatment group that had clinical laboratory values outside the reference range. |
| Overall Clinical Outcome | Approximately 6 weeks post last dose (approximately week 12) | The sponsor determined overall clinical outcome based on blinded review of clinical, microbiological, and radiological response of the subject including, but not limited to, clinical signs and symptoms of PJI, microbiological assessments, radiographic findings, and surgical procedures performed. Subjects were a success if both clinical and microbiological responses were success. A subject who failed to respond clinically or microbiologically was a failure. If microbiological response was non-evaluable and/or clinical evaluation at TOC was not performed, the subject was non-evaluable. |
| Microbiological Response | Approximately 6 weeks post last dose (approximately week 12) | Sponsor's assessment of subject-level microbiological response at the test-of-cure visit for the modified Intent-to-Treat (mITT) population. |
| Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax) | Day 4 (steady state) | The pharmacokinetic (PK) parameters of daptomycin at steady state for the 6 mg/kg and 8 mg/kg dose groups. On treatment day 4, PK samples for daptomycin levels were to be obtained prior to start of daptomycin infusion (0 hr) and at 0.5 hr (end of infusion), 1-1.5 hr, 3-5 hr, 8-12 hr, and 24 hr after the start of daptomycin infusion. |
| Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss) | Day 4 (steady state) | The pharmacokinetic (PK) parameters of daptomycin at steady state for the 6 mg/kg and 8 mg/kg dose groups. On treatment day 4, PK samples for daptomycin levels were to be obtained prior to start of daptomycin infusion (0 hr) and at 0.5 hr (end of infusion), 1-1.5 hr, 3-5 hr, 8-12 hr, and 24 hr after the start of daptomycin infusion. |
Countries
Russia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Daptomycin 6 mg/kg Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week). | 25 |
| Daptomycin 8 mg/kg Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week). | 24 |
| Comparator Vancomycin was administered at 1 gm q12h as a 60-minute infusion and teicoplanin was administered 6 mg/kg q24h as a 30-minute infusion also for 6 weeks (±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (±1 week). | 25 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Completed Study Drug Treatment | Adverse Event | 2 | 4 | 4 |
| Completed Study Drug Treatment | Protocol Violation | 0 | 1 | 1 |
| Completed Study Drug Treatment | Randomized Not Treated | 0 | 0 | 1 |
| Completed Study Drug Treatment | Withdrawal by Subject | 0 | 1 | 1 |
| Completed Test of Cure (TOC) Visit | Adverse Event | 0 | 1 | 1 |
| Completed Test of Cure (TOC) Visit | Lack of Efficacy | 2 | 0 | 0 |
| Completed Test of Cure (TOC) Visit | Microbiologic failure | 0 | 1 | 0 |
| Completed Test of Cure (TOC) Visit | Protocol Violation | 0 | 0 | 1 |
| Completed Test of Cure (TOC) Visit | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Daptomycin 6 mg/kg | Daptomycin 8 mg/kg | Comparator | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 10 Participants | 10 Participants | 35 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 14 Participants | 15 Participants | 39 Participants |
| Sex: Female, Male Female | 14 Participants | 10 Participants | 11 Participants | 35 Participants |
| Sex: Female, Male Male | 11 Participants | 14 Participants | 14 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 25 | 18 / 24 | 22 / 25 |
| serious Total, serious adverse events | 8 / 25 | 4 / 24 | 8 / 25 |
Outcome results
Primary
Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L)
Number of subjects with CPK \>500 U/L between Day 3 and 7 days following the last dose of study medication (Day 7P) as measured by the central laboratory.
Time frame: From the 3rd day of therapy to 1 week post last dose (approximately week 7)
Population: Safety Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin 6 mg/kg | Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L) | 4 Participants |
| Daptomycin 8 mg/kg | Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L) | 5 Participants |
| Comparator | Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L) | 2 Participants |
Secondary
Microbiological Response
Sponsor's assessment of subject-level microbiological response at the test-of-cure visit for the modified Intent-to-Treat (mITT) population.
Time frame: Approximately 6 weeks post last dose (approximately week 12)
Population: Modified Intent to Treat Population. Six treated patients in the ITT population were not included in the mITT population, as they did not have confirmed baseline staphylococcal infection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin 6 mg/kg | Microbiological Response | Non-evaluable | 4 Participants |
| Daptomycin 6 mg/kg | Microbiological Response | Failure | 8 Participants |
| Daptomycin 6 mg/kg | Microbiological Response | Success | 12 Participants |
| Daptomycin 8 mg/kg | Microbiological Response | Non-evaluable | 8 Participants |
| Daptomycin 8 mg/kg | Microbiological Response | Success | 12 Participants |
| Daptomycin 8 mg/kg | Microbiological Response | Failure | 3 Participants |
| Comparator | Microbiological Response | Non-evaluable | 7 Participants |
| Comparator | Microbiological Response | Success | 8 Participants |
| Comparator | Microbiological Response | Failure | 6 Participants |
Secondary
Overall Clinical Outcome
The sponsor determined overall clinical outcome based on blinded review of clinical, microbiological, and radiological response of the subject including, but not limited to, clinical signs and symptoms of PJI, microbiological assessments, radiographic findings, and surgical procedures performed. Subjects were a success if both clinical and microbiological responses were success. A subject who failed to respond clinically or microbiologically was a failure. If microbiological response was non-evaluable and/or clinical evaluation at TOC was not performed, the subject was non-evaluable.
Time frame: Approximately 6 weeks post last dose (approximately week 12)
Population: Modified Intent-to-Treat Population. Six treated patients in the ITT population were not included in the mITT population, as they did not have confirmed baseline staphylococcal infection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin 6 mg/kg | Overall Clinical Outcome | Nonevaluable | 1 Participants |
| Daptomycin 6 mg/kg | Overall Clinical Outcome | Success | 13 Participants |
| Daptomycin 6 mg/kg | Overall Clinical Outcome | Failure | 10 Participants |
| Daptomycin 8 mg/kg | Overall Clinical Outcome | Failure | 8 Participants |
| Daptomycin 8 mg/kg | Overall Clinical Outcome | Success | 13 Participants |
| Daptomycin 8 mg/kg | Overall Clinical Outcome | Nonevaluable | 2 Participants |
| Comparator | Overall Clinical Outcome | Failure | 11 Participants |
| Comparator | Overall Clinical Outcome | Success | 8 Participants |
| Comparator | Overall Clinical Outcome | Nonevaluable | 2 Participants |
Secondary
Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss)
The pharmacokinetic (PK) parameters of daptomycin at steady state for the 6 mg/kg and 8 mg/kg dose groups. On treatment day 4, PK samples for daptomycin levels were to be obtained prior to start of daptomycin infusion (0 hr) and at 0.5 hr (end of infusion), 1-1.5 hr, 3-5 hr, 8-12 hr, and 24 hr after the start of daptomycin infusion.
Time frame: Day 4 (steady state)
Population: Pharmacokinetic evaluable population. Pharmacokinetics not analyzed for the comparator group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daptomycin 6 mg/kg | Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss) | 499 µg•hr/mL |
| Daptomycin 8 mg/kg | Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss) | 821 µg•hr/mL |
Secondary
Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax)
The pharmacokinetic (PK) parameters of daptomycin at steady state for the 6 mg/kg and 8 mg/kg dose groups. On treatment day 4, PK samples for daptomycin levels were to be obtained prior to start of daptomycin infusion (0 hr) and at 0.5 hr (end of infusion), 1-1.5 hr, 3-5 hr, 8-12 hr, and 24 hr after the start of daptomycin infusion.
Time frame: Day 4 (steady state)
Population: Pharmacokinetic evaluable population. Pharmacokinetics not analyzed for the comparator group.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Daptomycin 6 mg/kg | Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax) | 59.1 µg/mL |
| Daptomycin 8 mg/kg | Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax) | 92.3 µg/mL |
Secondary
Safety - Notable Laboratory Abnormalities
Summary of Notable Laboratory Abnormalities - description of the proportion of subjects within each treatment group that had clinical laboratory values outside the reference range.
Time frame: From the 1st day of therapy to maximum of 23 weeks post last dose (up to maximum of week 30)
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Hematocrit (<30%, >60%) | 12 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Hemoglobin (<9,>19 g/dL) | 10 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Red Blood Cell (Female <2.5,>6.0; Male <3.0, >6.5) | 2 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | White Blood Cell (<2, >20 x 10^9/L) | 1 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Platelets (<40, >450 x 10^9/L) | 13 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Albumin (<3, >6 g/dL) | 7 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Alkaline Phosphatase (>1350 U/L) | 0 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Alanine aminotransferase (>235 U/L) | 0 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Aspartate aminotransferase (>185 U/L) | 1 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Total bilirubin (>2.2 mg/dL) | 0 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Blood Urea Nitrogen (>50 mg/dL) | 2 Participants |
| Daptomycin 6 mg/kg | Safety - Notable Laboratory Abnormalities | Creatinine (Female >2.0; Male>2.8 mg/dL) | 1 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Creatinine (Female >2.0; Male>2.8 mg/dL) | 0 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Hematocrit (<30%, >60%) | 10 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Alkaline Phosphatase (>1350 U/L) | 0 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Aspartate aminotransferase (>185 U/L) | 0 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Hemoglobin (<9,>19 g/dL) | 10 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Albumin (<3, >6 g/dL) | 4 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Blood Urea Nitrogen (>50 mg/dL) | 0 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Red Blood Cell (Female <2.5,>6.0; Male <3.0, >6.5) | 4 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Alanine aminotransferase (>235 U/L) | 0 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Platelets (<40, >450 x 10^9/L) | 13 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | White Blood Cell (<2, >20 x 10^9/L) | 0 Participants |
| Daptomycin 8 mg/kg | Safety - Notable Laboratory Abnormalities | Total bilirubin (>2.2 mg/dL) | 0 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | White Blood Cell (<2, >20 x 10^9/L) | 0 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Platelets (<40, >450 x 10^9/L) | 10 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Total bilirubin (>2.2 mg/dL) | 0 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Albumin (<3, >6 g/dL) | 4 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Alkaline Phosphatase (>1350 U/L) | 0 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Alanine aminotransferase (>235 U/L) | 0 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Blood Urea Nitrogen (>50 mg/dL) | 1 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Hematocrit (<30%, >60%) | 15 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Hemoglobin (<9,>19 g/dL) | 12 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Aspartate aminotransferase (>185 U/L) | 0 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Red Blood Cell (Female <2.5,>6.0; Male <3.0, >6.5) | 3 Participants |
| Comparator | Safety - Notable Laboratory Abnormalities | Creatinine (Female >2.0; Male>2.8 mg/dL) | 2 Participants |