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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Osteomyelitis	Drug: daptomycin; Drug: vancomycin; Drug: teicoplanin; Drug: nafcillin; Drug: oxacillin; Drug: flucloxacillin	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	75 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	June 26, 2007
Actual Primary Completion Date :	March 26, 2010
Actual Study Completion Date :	June 23, 2010

Arms and Interventions

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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 Name: Cubicin
Experimental: Daptomycin 8 mg/kg; Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (± one week).	Drug: daptomycin; 8 mg/kg; Other Name: 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 Name: Vancocin Drug: teicoplanin; 6 mg/kg; used only at UK sites; Other Name: Targocid Drug: nafcillin; 1-2 gram; Other Name: Unipen Drug: oxacillin; 1-2 gram; Other Name: Bactocill Drug: flucloxacillin; 1-2 mg; Other Name: Fluclox

Outcome Measures

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Primary Outcome Measures :

1. Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L) [ Time Frame: 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 Outcome Measures :

1. Safety - Notable Laboratory Abnormalities [ Time Frame: 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.
2. Overall Clinical Outcome [ Time Frame: 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.
3. Microbiological Response [ Time Frame: 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.
4. Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax) [ Time Frame: 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.
5. Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss) [ Time Frame: 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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  Show 26 Study Locations

Sponsors and Collaborators

Cubist Pharmaceuticals LLC

Investigators

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

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Cubist Pharmaceuticals LLC
ClinicalTrials.gov Identifier:	NCT00428844 History of Changes
Other Study ID Numbers:	3009-016; DAP-OST-06-02 ( Other Identifier: Cubist Study Number )
First Posted:	January 30, 2007
Results First Posted:	June 14, 2011
Last Update Posted:	January 31, 2018
Last Verified:	January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
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
URL:	http://

Keywords provided by Cubist Pharmaceuticals LLC:

Osteomyelitis; Prosthetic Hip; Prosthetic Knee	MRSA; Osteomyelitis Associated with an Infected Prosthetic Hip or Knee Joint; Staphylococci

Additional relevant MeSH terms:

Osteomyelitis; Bone Diseases, Infectious; Infection; Bone Diseases; Musculoskeletal Diseases; Vancomycin; Daptomycin	Teicoplanin; Floxacillin; Oxacillin; Nafcillin; Anti-Bacterial Agents; Anti-Infective Agents