Study of Daptomycin in Subjects Undergoing Surgery for Osteomyelitis Associated With an Infected Prosthetic Caused by Staphylococci

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Randomized Study Investigating the Safety, Efficacy and Pharmacokinetics of Daptomycin 6 mg/kg and 8 mg/kg Versus Comparator in the Treatment of Subjects Undergoing Surgical Standard of Care for Osteomyelitis Associated With an Infected Prosthetic Hip or Knee Joint Caused by Staphylococci

Conditions
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Osteomyelitis

Intervention / Treatment
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* Drug: daptomycin
* Drug: daptomycin
* Drug: vancomycin
* Drug: teicoplanin
* Drug: nafcillin
* Drug: oxacillin
* Drug: flucloxacillin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Daptomycin 6 mg/kg<br>Daptomycin (6 mg/kg every 24 hours [q24h]) as a 30 minute intravenous (IV) infusion for 6 weeks (± one week). | Drug: daptomycin<br>* 6 mg/kg<br>* Other names: Cubicin;|
| Experimental: Daptomycin 8 mg/kg<br>Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (± one week). | Drug: daptomycin<br>* 8 mg/kg<br>* Other names: Cubicin;|
| Active Comparator: Comparator<br>Vancomycin was administered at 1 gram every 12 hours (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). | Drug: vancomycin<br>* 1 gram<br>* Other names: Vancocin;Drug: teicoplanin<br>* 6 mg/kg; used only at UK sites<br>* Other names: Targocid;Drug: nafcillin<br>* 1-2 gram<br>* Other names: Unipen;Drug: oxacillin<br>* 1-2 gram<br>* Other names: Bactocill;Drug: flucloxacillin<br>* 1-2 mg<br>* Other names: Fluclox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the 3rd day of therapy to 1 week post last dose (approximately week 7) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From the 1st day of therapy to maximum of 23 weeks post last dose (up to maximum of week 30) | 
| 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. | Approximately 6 weeks post last dose (approximately week 12) | 
| Microbiological Response | Sponsor's assessment of subject-level microbiological response at the test-of-cure visit for the modified Intent-to-Treat (mITT) population. | Approximately 6 weeks post last dose (approximately week 12) | 
| 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. | Day 4 (steady state) | 
| 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. | Day 4 (steady state) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osteomyelitis, Prosthetic Hip, Prosthetic Knee, MRSA, Osteomyelitis Associated with an Infected Prosthetic Hip or Knee Joint, Staphylococci