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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00428844
Recruitment Status : Completed
First Posted : January 30, 2007
Results First Posted : June 14, 2011
Last Update Posted : January 31, 2018
Sponsor:
Information provided by (Responsible Party):
Cubist Pharmaceuticals LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Osteomyelitis
Interventions Drug: daptomycin
Drug: vancomycin
Drug: teicoplanin
Drug: nafcillin
Drug: oxacillin
Drug: flucloxacillin
Enrollment 75
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Hide Arm/Group Description Daptomycin (6 mg/kg every 24 hours [q24h]) as a 30 minute intravenous (IV) infusion for 6 weeks (± one week). Daptomycin (8 mg/kg q24h) as a 30 minute IV infusion for 6 weeks (± one week). 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 (±1 week). Semi-synthetic penicillin (nafcillin, oxacillin, or flucloxacillin) was administered according to standard of care for 6 weeks (±1 week).
Period Title: Completed Study Drug Treatment
Started 25 24 26
Received First Dose 25 24 25
Completed 23 18 19
Not Completed 2 6 7
Reason Not Completed
Adverse Event             2             4             4
Protocol Violation             0             1             1
Withdrawal by Subject             0             1             1
Randomized Not Treated             0             0             1
Period Title: Completed Test of Cure (TOC) Visit
Started 23 18 19
Completed 20 16 17
Not Completed 3 2 2
Reason Not Completed
Adverse Event             0             1             1
Protocol Violation             0             0             1
Withdrawal by Subject             1             0             0
Lack of Efficacy             2             0             0
Microbiologic failure             0             1             0
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator Total
Hide Arm/Group Description Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week). Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week). 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). Total of all reporting groups
Overall Number of Baseline Participants 25 24 25 74
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 24 participants 25 participants 74 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
10
  40.0%
14
  58.3%
15
  60.0%
39
  52.7%
>=65 years
15
  60.0%
10
  41.7%
10
  40.0%
35
  47.3%
[1]
Measure Description: Safety/Intent to Treat Population (1 patient included in the Overall Number of Baseline Participants was randomized to comparator but not treated)
Sex: Female, Male   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 25 participants 24 participants 25 participants 74 participants
Female
14
  56.0%
10
  41.7%
11
  44.0%
35
  47.3%
Male
11
  44.0%
14
  58.3%
14
  56.0%
39
  52.7%
[1]
Measure Description: Safety/Intent to Treat Population (1 patient included in the Overall Number of Baseline Participants was randomized to comparator but not treated)
1.Primary Outcome
Title Any Creatine Phosphokinase (CPK) Elevation > 500 Units Per Liter (U/L)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Hide Arm/Group Description:
Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
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).
Overall Number of Participants Analyzed 25 24 25
Measure Type: Number
Unit of Measure: Participants
4 5 2
2.Secondary Outcome
Title Safety - Notable Laboratory Abnormalities
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Hide Arm/Group Description:
Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
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).
Overall Number of Participants Analyzed 25 24 25
Measure Type: Number
Unit of Measure: Participants
Hematocrit (<30%, >60%) 12 10 15
Hemoglobin (<9,>19 g/dL) 10 10 12
Red Blood Cell (Female <2.5,>6.0; Male <3.0, >6.5) 2 4 3
White Blood Cell (<2, >20 x 10^9/L) 1 0 0
Platelets (<40, >450 x 10^9/L) 13 13 10
Albumin (<3, >6 g/dL) 7 4 4
Alkaline Phosphatase (>1350 U/L) 0 0 0
Alanine aminotransferase (>235 U/L) 0 0 0
Aspartate aminotransferase (>185 U/L) 1 0 0
Total bilirubin (>2.2 mg/dL) 0 0 0
Blood Urea Nitrogen (>50 mg/dL) 2 0 1
Creatinine (Female >2.0; Male>2.8 mg/dL) 1 0 2
3.Secondary Outcome
Title Overall Clinical Outcome
Hide 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)
Hide Outcome Measure Data
Hide Analysis 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.
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Hide Arm/Group Description:
Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
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).
Overall Number of Participants Analyzed 24 23 21
Measure Type: Number
Unit of Measure: Participants
Success 13 13 8
Failure 10 8 11
Nonevaluable 1 2 2
4.Secondary Outcome
Title Microbiological Response
Hide Description 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)
Hide Outcome Measure Data
Hide Analysis 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.
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Hide Arm/Group Description:
Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
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).
Overall Number of Participants Analyzed 24 23 21
Measure Type: Number
Unit of Measure: Participants
Success 12 12 8
Failure 8 3 6
Non-evaluable 4 8 7
5.Secondary Outcome
Title Pharmacokinetic Parameter: Maximum Plasma Concentration (Cmax)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic evaluable population. Pharmacokinetics not analyzed for the comparator group.
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg
Hide Arm/Group Description:
Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Overall Number of Participants Analyzed 22 20
Median (Full Range)
Unit of Measure: µg/mL
59.1
(22.5 to 156)
92.3
(56.1 to 172)
6.Secondary Outcome
Title Pharmacokinetic Parameter: Area Under the Concentration-time Curve During a Dosing Interval at Steady State (AUCss)
Hide 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)
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic evaluable population. Pharmacokinetics not analyzed for the comparator group.
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg
Hide Arm/Group Description:
Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week).
Overall Number of Participants Analyzed 22 20
Median (Full Range)
Unit of Measure: µg•hr/mL
499
(166 to 1205)
821
(292 to 1606)
Time Frame From the 1st day of therapy to maximum of 23 weeks post last dose (up to maximum of week 30)
Adverse Event Reporting Description Subjects who prematurely discontinue study drug will undergo follow-up safety evaluations within 30 days (±5 days) of administration of the last dose of study drug.
 
Arm/Group Title Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Hide Arm/Group Description Daptomycin (6 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week). Daptomycin (8 mg/kg q24h) as a 30-minute IV infusion for 6 weeks (±1 week). 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).
All-Cause Mortality
Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   8/25 (32.00%)      4/24 (16.67%)      8/25 (32.00%)    
Blood and lymphatic system disorders       
Anaemia † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Cardiac disorders       
Cardiac arrest † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  3
General disorders       
Wound necrosis † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Hepatobiliary disorders       
Cholecystitis acute † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Immune system disorders       
Anaphylactic reaction † 1  0/25 (0.00%)  0 1/24 (4.17%)  1 0/25 (0.00%)  0
Hypersensitivity † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Infections and infestations       
Device related infection † 1  0/25 (0.00%)  0 1/24 (4.17%)  1 0/25 (0.00%)  0
Sepsis † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Urinary tract infection † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 2/25 (8.00%)  2
Viral infection † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Injury, poisoning and procedural complications       
Device dislocation † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Dislocation of joint prosthesis † 1  2/25 (8.00%)  2 0/24 (0.00%)  0 0/25 (0.00%)  0
Femur fracture † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Joint dislocation † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Subcutaneous haematoma † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Musculoskeletal and connective tissue disorders       
Arthropathy † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Rhabdomyolysis † 1  1/25 (4.00%)  1 1/24 (4.17%)  1 0/25 (0.00%)  0
Renal and urinary disorders       
Renal failure † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 1/25 (4.00%)  1
Respiratory, thoracic and mediastinal disorders       
Pulmonary embolism † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Respiratory failure † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
Skin and subcutaneous tissue disorders       
Decubitus ulcer † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Rash † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 0/25 (0.00%)  0
Vascular disorders       
Deep vein thrombosis † 1  1/25 (4.00%)  1 1/24 (4.17%)  1 1/25 (4.00%)  1
Haematoma † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 1/25 (4.00%)  1
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Daptomycin 6 mg/kg Daptomycin 8 mg/kg Comparator
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   23/25 (92.00%)      18/24 (75.00%)      22/25 (88.00%)    
Eye disorders       
Vision blurred † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 2/25 (8.00%)  2
Gastrointestinal disorders       
Constipation † 1  4/25 (16.00%)  5 2/24 (8.33%)  2 1/25 (4.00%)  1
Diarrhoea † 1  2/25 (8.00%)  2 2/24 (8.33%)  3 2/25 (8.00%)  3
Dyspepsia † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 2/25 (8.00%)  2
Nausea † 1  5/25 (20.00%)  5 3/24 (12.50%)  3 4/25 (16.00%)  7
Stomach discomfort † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 2/25 (8.00%)  2
Vomiting † 1  1/25 (4.00%)  1 1/24 (4.17%)  2 2/25 (8.00%)  5
General disorders       
Asthenia † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 2/25 (8.00%)  2
Catheter related complication † 1  1/25 (4.00%)  1 2/24 (8.33%)  3 2/25 (8.00%)  9
Chest pain † 1  2/25 (8.00%)  2 0/24 (0.00%)  0 0/25 (0.00%)  0
Fatigue † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 2/25 (8.00%)  3
Oedema peripheral † 1  2/25 (8.00%)  5 2/24 (8.33%)  4 4/25 (16.00%)  7
Pyrexia † 1  4/25 (16.00%)  5 2/24 (8.33%)  2 4/25 (16.00%)  7
Infections and infestations       
Arthritis infective † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 2/25 (8.00%)  2
Bacteriuria † 1  2/25 (8.00%)  2 1/24 (4.17%)  1 0/25 (0.00%)  0
Urinary tract infection † 1  3/25 (12.00%)  4 1/24 (4.17%)  1 2/25 (8.00%)  2
Investigations       
Blood alkaline phosphatase increased † 1  2/25 (8.00%)  2 1/24 (4.17%)  1 2/25 (8.00%)  2
Blood creatine phosphokinase increased † 1  3/25 (12.00%)  3 2/24 (8.33%)  2 1/25 (4.00%)  1
Blood pressure increased † 1  0/25 (0.00%)  0 2/24 (8.33%)  2 1/25 (4.00%)  1
Haematocrit decreased † 1  0/25 (0.00%)  0 2/24 (8.33%)  2 1/25 (4.00%)  1
Haemoglobin decreased † 1  0/25 (0.00%)  0 2/24 (8.33%)  2 1/25 (4.00%)  1
Urine output decreased † 1  0/25 (0.00%)  0 2/24 (8.33%)  2 0/25 (0.00%)  0
Metabolism and nutrition disorders       
Hypokalaemia † 1  2/25 (8.00%)  2 1/24 (4.17%)  2 1/25 (4.00%)  1
Musculoskeletal and connective tissue disorders       
Arthralgia † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 2/25 (8.00%)  2
Pain in extremity † 1  0/25 (0.00%)  0 1/24 (4.17%)  1 2/25 (8.00%)  2
Nervous system disorders       
Dizziness † 1  2/25 (8.00%)  2 0/24 (0.00%)  0 2/25 (8.00%)  3
Headache † 1  3/25 (12.00%)  5 0/24 (0.00%)  0 2/25 (8.00%)  2
Tremor † 1  2/25 (8.00%)  3 0/24 (0.00%)  0 0/25 (0.00%)  0
Psychiatric disorders       
Anxiety † 1  2/25 (8.00%)  2 1/24 (4.17%)  1 1/25 (4.00%)  1
Hallucination † 1  0/25 (0.00%)  0 0/24 (0.00%)  0 2/25 (8.00%)  2
Respiratory, thoracic and mediastinal disorders       
Cough † 1  2/25 (8.00%)  2 2/24 (8.33%)  2 2/25 (8.00%)  2
Dyspnoea † 1  1/25 (4.00%)  1 0/24 (0.00%)  0 3/25 (12.00%)  4
Skin and subcutaneous tissue disorders       
Erythema † 1  2/25 (8.00%)  2 1/24 (4.17%)  1 2/25 (8.00%)  3
Pruritus † 1  1/25 (4.00%)  2 3/24 (12.50%)  3 2/25 (8.00%)  2
Rash † 1  0/25 (0.00%)  0 3/24 (12.50%)  4 2/25 (8.00%)  2
Vascular disorders       
Deep vein thrombosis † 1  3/25 (12.00%)  3 0/24 (0.00%)  0 0/25 (0.00%)  0
Hypertension † 1  2/25 (8.00%)  2 1/24 (4.17%)  2 1/25 (4.00%)  1
Hypertensive crisis † 1  1/25 (4.00%)  1 2/24 (8.33%)  2 0/25 (0.00%)  0
Hypotension † 1  1/25 (4.00%)  1 2/24 (8.33%)  2 3/25 (12.00%)  3
†
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9.1
[Not Specified]
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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
Layout table for Results Point of Contact information
Name/Title: Ed Campanaro, VP Clinical Operations
Organization: Cubist Pharmaceuticals, Inc.
Phone: 781-860-8318
EMail: ed.campanaro@cubist.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
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 Submitted: January 26, 2007
First Posted: January 30, 2007
Results First Submitted: March 16, 2011
Results First Posted: June 14, 2011
Last Update Posted: January 31, 2018