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

ID: NCT00428844

Status: Completed

Phase: Phase 2

Start Date: January 01, 2007

First Submitted: January 26, 2007

Last Updated: January 05, 2016

Results: Available

Success Rate: 83%

Organization: Cubist Pharmaceuticals LLC

Sponsors & Collaborators: Cubist Pharmaceuticals LLC

Location: Russian Federation, United Kingdom, United States

Conditions: Osteomyelitis

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Study Details
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Study Description

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.

Detailed Description

Condition or disease	Intervention/treatment	Phase
Osteomyelitis	Drug: daptomycin Other Names Cubicin Drug: daptomycin Other Names Cubicin Drug: vancomycin Other Names Vancocin Drug: teicoplanin Other Names Targocid Drug: nafcillin Other Names Unipen Drug: oxacillin Other Names Bactocill Drug: flucloxacillin Other Names Fluclox	Phase 2

Tracking Information

First Submitted Date	January 26, 2007
Last Update Posted Date	January 05, 2016
Start Date	January 01, 2007
Actual Completion Date	June 01, 2010
Primary Completion Date	March 01, 2010
Results First Submitted Date	March 16, 2011
Received Results Disposit Date	N/A

Current Primary Outcome Measures

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.

Original Primary Outcome Measures

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.

Current Secondary Outcome Measures

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.
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.
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.
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.
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.

Original Secondary Outcome Measures

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.
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.
Microbiological Response
Sponsorâ€™s assessment of subject-level microbiological response at the test-of-cure visit for the modified Intent-to-Treat (mITT) population.
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.
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.

Study Design

Brief Title	Study of Daptomycin in Subjects Undergoing Surgery for Osteomyelitis Associated With an Infected Prosthetic Caused by Staphylococci
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
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.
Detailed Description
Study Type	Interventional
Study Phase	Phase 2
Estimated Enrollment	75
Allocation	Randomized
Interventional Model	Parallel Assignment
Masking	None
Primary Purpose	Treatment
Conditions	Osteomyelitis
Target Follow-Up Duration	N/A
Biospecimen:	N/A
Sampling Method	N/A
Study Population	N/A
Intervention	Drug: daptomycin 6 mg/kg Other Names Cubicin Drug: daptomycin 8 mg/kg Other Names Cubicin 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
Study Groups/Cohorts	Daptomycin 6 mg/kg Daptomycin (6 mg/kg every 24 hours [q24h]) as a 30 minute intravenous (IV) infusion for 6 weeks (Â± one week). Daptomycin 8 mg/kg Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (Â± one week). 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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).
Study Arms	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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week). Drug : vancomycin 1 gram 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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week). Drug : teicoplanin 6 mg/kg; used only at UK sites 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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week). Drug : nafcillin 1-2 gram 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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week). Drug : oxacillin 1-2 gram 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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week). Drug : flucloxacillin 1-2 mg Experimental Daptomycin 6 mg/kg Daptomycin (6 mg/kg every 24 hours [q24h]) as a 30 minute intravenous (IV) infusion for 6 weeks (Â± one week). Drug : daptomycin 6 mg/kg Experimental Daptomycin 8 mg/kg Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (Â± one week). Drug : daptomycin 8 mg/kg

Arm	Intervention/Treatment
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).	Drug : vancomycin 1 gram
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).	Drug : teicoplanin 6 mg/kg; used only at UK sites
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).	Drug : nafcillin 1-2 gram
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).	Drug : oxacillin 1-2 gram
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).	Drug : flucloxacillin 1-2 mg
Experimental Daptomycin 6 mg/kg Daptomycin (6 mg/kg every 24 hours [q24h]) as a 30 minute intravenous (IV) infusion for 6 weeks (Â± one week).	Drug : daptomycin 6 mg/kg
Experimental Daptomycin 8 mg/kg Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (Â± one week).	Drug : daptomycin 8 mg/kg

Recruitment Information

Recruitment Status:	Completed
Enrollment	75
Completion Date	June 01, 2010
Eligibility 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 â‰¤ 200 cells/ mm3 - Subject has an abnormal creatine phosphokinase (CPK) (elevated CPK level â‰¥ 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.
Gender	All
Age	18 Years to 80 Years
Accepts Healthy Volunteers	No
Contacts	Not Available
Listed Location Countries	Russian Federation United Kingdom United States

Administrative Information

NCT Number:	NCT00428844
Other Study ID Numbers	3009-016 DAP-OST-06-02
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: No Device Product Not Approved or Cleared by U.S. FDA: No
IPD Sharing Statement	Not Available
Responsible Party	,
Study Sponsor	Cubist Pharmaceuticals LLC
Collaborators	Not Available
Investigators	Study Director Alistair Wheeler, MD Cubist Pharmaceuticals, 65 Hayden Ave, Lexington, MA 02421, USA

Participant Flow

Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations

Not Available

Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment

Not Available

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg every 24 hours [q24h]) as a 30 minute intravenous (IV) infusion for 6 weeks (Â± one week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (Â± one week).
Comparator	Vancomycin was administered at 1 gram (gm)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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Participant Flow: Overall

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
	25	24	25
Started	25	23	24
Started	18	26	19
Completed	23	20	18
Completed	16	19	17
Not Completed	2	3	6
Not Completed	2	7	2
Adverse Event	2	0	4
Adverse Event	1	4	1
Lack of Efficacy	2	0	0
Microbiologic failure	0	1	0
Protocol Violation	0	0	1
Protocol Violation	0	1	1
Randomized Not Treated	0	0	1
Withdrawal by Subject	0	1	1
Withdrawal by Subject	0	1	0

Baseline Characteristics

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.

Not Available

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).
Total	Total of all reporting groups

Baseline Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator	Total
Overall Participants Analyzed Units: Participants
Participants Analyzed	25	24	25	74
	25	24	25	74
Age Units: participants - Number
Participants Analyzed	25	24	25	74
<=18 years	0	0	0	0
>=65 years	15	10	10	35
Between 18 and 65 years	10	14	15	39
Gender Units: participants - Number
Participants Analyzed	25	24	25	74
Female	14	10	11	35
Male	11	14	14	39

Outcome Measures

1. Primary: Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L)

Measure Type	Primary
Measure Title	Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L)
Measure Description	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 Description

Safety Population

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Outcome Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
Participants Analyzed Units: Participants
	25	24	25
Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L) Units: Participants - Number
	4	5	2

2. Secondary: Safety - Notable Laboratory Abnormalities

Measure Type	Secondary
Measure Title	Safety - Notable Laboratory Abnormalities
Measure Description	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 Description

Safety Population

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Outcome Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
Participants Analyzed Units: Participants
	25	24	25
Safety - Notable Laboratory Abnormalities Units: Participants - Number
Alanine aminotransferase (>235 U/L)	0	0	0
Albumin (<3, >6 g/dL)	7	4	4
Alkaline Phosphatase (>1350 U/L)	0	0	0
Aspartate aminotransferase (>185 U/L)	1	0	0
Blood Urea Nitrogen (>50 mg/dL)	2	0	1
Creatinine (Female >2.0; Male>2.8 mg/dL)	1	0	2
Hematocrit (<30%, >60%)	12	10	15
Hemoglobin (<9,>19 g/dL)	10	10	12
Platelets (<40, >450 x 10^9/L)	13	13	10
Red Blood Cell (Female <2.5,>6.0; Male <3.0, >6.5)	2	4	3
Total bilirubin (>2.2 mg/dL)	0	0	0
White Blood Cell (<2, >20 x 10^9/L)	1	0	0

3. Secondary: Overall Clinical Outcome

Measure Type	Secondary
Measure Title	Overall Clinical Outcome
Measure Description	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 Description

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.

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Outcome Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
Participants Analyzed Units: Participants
	24	23	21
Overall Clinical Outcome Units: Participants - Number
Failure	10	8	11
Nonevaluable	1	2	2
Success	13	13	8

4. Secondary: Microbiological Response

Measure Type	Secondary
Measure Title	Microbiological Response
Measure Description	Sponsorâ€™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 Description

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.

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Outcome Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
Participants Analyzed Units: Participants
	24	23	21
Microbiological Response Units: Participants - Number
Failure	8	3	6
Non-evaluable	4	8	7
Success	12	12	8

5. Secondary: Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax)

Measure Type	Secondary
Measure Title	Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax)
Measure Description	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 Description

Pharmacokinetic evaluable population. Pharmacokinetics not analyzed for the comparator group.

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).

Outcome Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg
Participants Analyzed Units: Participants
	22	20
Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax) Units: Âµg/mL - Median (Full Range)
	59.1	92.3

6. Secondary: Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss)

Measure Type	Secondary
Measure Title	Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss)
Measure Description	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 Description

Pharmacokinetic evaluable population. Pharmacokinetics not analyzed for the comparator group.

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).

Outcome Measures

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg
Participants Analyzed Units: Participants
	22	20
Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss) Units: Âµgâ€¢hr/mL - Median (Full Range)
	499	821

Serious Adverse Events

Time Frame	From the 1st day of therapy to maximum of 23 weeks post last dose (up to maximum of week 30)
Additional Description	Subjects who prematurely discontinue study drug will undergo follow-up safety evaluations within 30 days (Â±5 days) of administration of the last dose of study drug.
Frequency Threshold	0% (Threshold above which other adverse events are reported)

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Serious Adverse Events

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
Total, serious adverse events
No. of participants affected / at risk	8/25 (0.00%)	4/24 (0.00%)	8/25 (0.00%)
Anaemia
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Cardiac arrest
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Wound necrosis
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Cholecystitis acute
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Anaphylactic reaction
No. of participants affected / at risk	0/25 (0.00%)	1/24 (0.00%)	0/25 (0.00%)
Hypersensitivity
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Device related infection
No. of participants affected / at risk	0/25 (0.00%)	1/24 (0.00%)	0/25 (0.00%)
Sepsis
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Urinary tract infection
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Viral infection
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Device dislocation
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Dislocation of joint prosthesis
No. of participants affected / at risk	2/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Femur fracture
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Joint dislocation
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Subcutaneous haematoma
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Arthropathy
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Rhabdomyolysis
No. of participants affected / at risk	1/25 (0.00%)	1/24 (0.00%)	0/25 (0.00%)
Renal failure
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Pulmonary embolism
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Respiratory failure
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)
Decubitus ulcer
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Rash
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Deep vein thrombosis
No. of participants affected / at risk	1/25 (0.00%)	1/24 (0.00%)	1/25 (0.00%)
Haematoma
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	1/25 (0.00%)

Other Adverse Events

Time Frame	From the 1st day of therapy to maximum of 23 weeks post last dose (up to maximum of week 30)
Additional Description	Subjects who prematurely discontinue study drug will undergo follow-up safety evaluations within 30 days (Â±5 days) of administration of the last dose of study drug.
Frequency Threshold	5% (Threshold above which other adverse events are reported)

Reporting Groups

Title	Description
Daptomycin 6 mg/kg	Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
Daptomycin 8 mg/kg	Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (Â±1 week).
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 (Â±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (Â±1 week).

Other Adverse Events

	Daptomycin 6 mg/kg	Daptomycin 8 mg/kg	Comparator
Total, other adverse events
No. of participants affected / at risk	23/25 (0.00%)	18/24 (0.00%)	22/25 (0.00%)
Vision blurred
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Constipation
No. of participants affected / at risk	4/25 (0.00%)	2/24 (0.00%)	1/25 (0.00%)
Diarrhoea
No. of participants affected / at risk	2/25 (0.00%)	2/24 (0.00%)	2/25 (0.00%)
Dyspepsia
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Nausea
No. of participants affected / at risk	5/25 (0.00%)	3/24 (0.00%)	4/25 (0.00%)
Stomach discomfort
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Vomiting
No. of participants affected / at risk	1/25 (0.00%)	1/24 (0.00%)	2/25 (0.00%)
Asthenia
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Catheter related complication
No. of participants affected / at risk	1/25 (0.00%)	2/24 (0.00%)	2/25 (0.00%)
Chest pain
No. of participants affected / at risk	2/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Fatigue
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Oedema peripheral
No. of participants affected / at risk	2/25 (0.00%)	2/24 (0.00%)	4/25 (0.00%)
Pyrexia
No. of participants affected / at risk	4/25 (0.00%)	2/24 (0.00%)	4/25 (0.00%)
Arthritis infective
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Bacteriuria
No. of participants affected / at risk	2/25 (0.00%)	1/24 (0.00%)	0/25 (0.00%)
Urinary tract infection
No. of participants affected / at risk	3/25 (0.00%)	1/24 (0.00%)	2/25 (0.00%)
Blood alkaline phosphatase increased
No. of participants affected / at risk	2/25 (0.00%)	1/24 (0.00%)	2/25 (0.00%)
Blood creatine phosphokinase increased
No. of participants affected / at risk	3/25 (0.00%)	2/24 (0.00%)	1/25 (0.00%)
Blood pressure increased
No. of participants affected / at risk	0/25 (0.00%)	2/24 (0.00%)	1/25 (0.00%)
Haematocrit decreased
No. of participants affected / at risk	0/25 (0.00%)	2/24 (0.00%)	1/25 (0.00%)
Haemoglobin decreased
No. of participants affected / at risk	0/25 (0.00%)	2/24 (0.00%)	1/25 (0.00%)
Urine output decreased
No. of participants affected / at risk	0/25 (0.00%)	2/24 (0.00%)	0/25 (0.00%)
Hypokalaemia
No. of participants affected / at risk	2/25 (0.00%)	1/24 (0.00%)	1/25 (0.00%)
Arthralgia
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Pain in extremity
No. of participants affected / at risk	0/25 (0.00%)	1/24 (0.00%)	2/25 (0.00%)
Dizziness
No. of participants affected / at risk	2/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Headache
No. of participants affected / at risk	3/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Tremor
No. of participants affected / at risk	2/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Anxiety
No. of participants affected / at risk	2/25 (0.00%)	1/24 (0.00%)	1/25 (0.00%)
Hallucination
No. of participants affected / at risk	0/25 (0.00%)	0/24 (0.00%)	2/25 (0.00%)
Cough
No. of participants affected / at risk	2/25 (0.00%)	2/24 (0.00%)	2/25 (0.00%)
Dyspnoea
No. of participants affected / at risk	1/25 (0.00%)	0/24 (0.00%)	3/25 (0.00%)
Erythema
No. of participants affected / at risk	2/25 (0.00%)	1/24 (0.00%)	2/25 (0.00%)
Pruritus
No. of participants affected / at risk	1/25 (0.00%)	3/24 (0.00%)	2/25 (0.00%)
Rash
No. of participants affected / at risk	0/25 (0.00%)	3/24 (0.00%)	2/25 (0.00%)
Deep vein thrombosis
No. of participants affected / at risk	3/25 (0.00%)	0/24 (0.00%)	0/25 (0.00%)
Hypertension
No. of participants affected / at risk	2/25 (0.00%)	1/24 (0.00%)	1/25 (0.00%)
Hypertensive crisis
No. of participants affected / at risk	1/25 (0.00%)	2/24 (0.00%)	0/25 (0.00%)
Hypotension
No. of participants affected / at risk	1/25 (0.00%)	2/24 (0.00%)	3/25 (0.00%)

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The first publication is initiated by Cubist. If first publication not published within 1 year of study conclusion or termination, Investigator has right to publish and disclose the Data. Prior to any submission for publication, presentation, or communication of results or information arising from the Study, Investigator shall provide Cubist at least 90 days for review and comment upon the manuscript or other material for such publication or presentation.

Results Point of Contact

Name/Title	Organization	Phone	Email
Ed Campanaro, VP Clinical Operations	Cubist Pharmaceuticals, Inc.	781-860-8318	[email protected]