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

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

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.

Study Overview

• Status: Completed
• Conditions: Osteomyelitis
• Intervention / Treatment: Drug: daptomycin; Drug: daptomycin; Drug: vancomycin; Drug: teicoplanin; Drug: nafcillin; Drug: oxacillin; Drug: flucloxacillin

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 2

Contacts and Locations

Study Locations

• Russian Federation
  • Kurgan, Russian Federation, 640014
    • Federal National Institution of Science "Russian Ilizarov Scientific Center" "Restorative Traumatology and Orthopedics" of Rosmedtechnology
  • Moscow, Russian Federation, 117292
    • National Healthcare Institution of Moscow "City Clinical Hospital #64"
  • Novosibirsk, Russian Federation, 630091
    • Federal Healthcare Institute "Novosibirsk Scientific Research Institute of Traumatology and Orthopedy Rosmeditechnology"
  • Saint Petersburg, Russian Federation, 195067
    • National Educational Institution of Higher Professional Education "Saint Petersburg State Medical Academy n.a. Mechnikov of Roszdrav"
  • Saint Petersburg, Russian Federation, 197046
    • Russian Research Institute of Traumatology and Orthopedy
  • Samara, Russian Federation, 443095
    • National Healthcare Institution "Samara Regional Clinical Hospital n.a. Kalinin"
• United Kingdom
  • Oxfordshire
    • Headington, Oxford, Oxfordshire, United Kingdom, OX37LD
      • Nuffield Orthopaedics Centre, Bone Infection Unit
  • Scotland
    • Edinburgh, Scotland, United Kingdom, EH164SA
      • The Royal Infirmary of Edinburgh at Little France
    • Glasgow, Scotland, United Kingdom, G120YN
      • Brownlee Centre - Gartnavel General Hospital
• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72205-7199
      • UAMS College of Medicine
  • Colorado
    • Englewood, Colorado, United States, 80133
      • South Denver Infectious Disease Associates, PC
  • District of Columbia
    • Washington, District of Columbia, United States, 20016
      • Kane and Davis Associates
  • Florida
    • Tampa, Florida, United States, 33606
      • Infectious Disease Association of Tampa Bay
  • Idaho
    • Idaho Falls, Idaho, United States, 83404
      • Idaho Falls Infectious Diseases, PLLC
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush St. Luke's Medical Center
    • Springfield, Illinois, United States, 62794
      • Southern Illinois University School of Medicine
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Nevada
    • Reno, Nevada, United States, 89502
      • Sierra Infectious Disease
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth-Hitchcock Medical Center
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Ohio
    • Akron, Ohio, United States, 44304
      • Summa Health Systems
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Lima, Ohio, United States, 45801
      • Regional Infectious Diseases-Infusion Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Lehigh Valley Hospital Trauma and Critical Care Research
    • Philadelphia, Pennsylvania, United States, 19107
      • Rothman Institute
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Clinic, Ltd

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Cubist Pharmaceuticals LLC
• Investigators: Study Director: Alistair Wheeler, MD, Cubist Pharmaceuticals, 65 Hayden Ave, Lexington, MA 02421, USA

Publications and helpful links

General Publications

• Byren I, Rege S, Campanaro E, Yankelev S, Anastasiou D, Kuropatkin G, Evans R. Randomized controlled trial of the safety and efficacy of Daptomycin versus standard-of-care therapy for management of patients with osteomyelitis associated with prosthetic devices undergoing two-stage revision arthroplasty. Antimicrob Agents Chemother. 2012 Nov;56(11):5626-32. doi: 10.1128/AAC.00038-12. Epub 2012 Aug 20.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2007
• Primary Completion (Actual): March 26, 2010
• Study Completion (Actual): June 23, 2010

Study Registration Dates

• First Submitted: January 26, 2007
• First Submitted That Met QC Criteria: January 29, 2007
• First Posted (Estimate): January 30, 2007

Study Record Updates

• Last Update Posted (Actual): January 31, 2018
• Last Update Submitted That Met QC Criteria: January 7, 2018
• Last Verified: January 1, 2018

More Information

Terms related to this study

• Keywords: MRSA; Osteomyelitis; Prosthetic Hip; Prosthetic Knee; Osteomyelitis Associated with an Infected Prosthetic Hip or Knee Joint; Staphylococci
• Additional Relevant MeSH Terms: Infections; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Infectious; Osteomyelitis; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin; Daptomycin; Floxacillin; Teicoplanin; Nafcillin; Oxacillin
• Other Study ID Numbers: 3009-016; DAP-OST-06-02 (Other Identifier: Cubist Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

http://www.merck.com/clinical-trials/pdf/Merck%20Procedure%20on%20Clinical%20Trial%20Data%20Access%20Final_Updated%20July_9_2014.pdf

http://engagezone.msd.com/ds_documentation.php