A Prospective, Multicenter, Randomized, Evaluator-blinded, Comparator-controlled Study to Describe the Safety and Efficacy of Daptomycin for the Treatment of Complicated Skin and Skin Structure Infections (cSSSI) and Staphylococcus Aureus Bacteremia Among Subjects With Moderate or Severe Renal Impairment
Overview
- Phase
- Phase 4
- Intervention
- Daptomycin
- Conditions
- Complicated Skin and Skin Structure Infections
- Sponsor
- Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
- Enrollment
- 92
- Primary Endpoint
- Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET)
- Status
- Terminated
- Last Updated
- 7 years ago
Overview
Brief Summary
This is a multicenter, randomized, evaluator-blinded, comparator-controlled study. Participants were to be randomized (1:1) to daptomycin or comparator, stratified by degree of renal impairment (creatinine clearance [CLcr] 30 - 50 milliliters per minute [mL/min] [moderate impairment] and <30 mL/min [severe impairment]) and by type of infection (bacteremia and complicated skin and skin structure infections [cSSSI]) to create 4 cohorts defined as follows:
- Cohort 1: Bacteremia and CLcr <30 mL/min
- Cohort 2: Bacteremia and CLcr 30 - 50 mL/min
- Cohort 3: cSSSI and CLcr <30 mL/min
- Cohort 4: cSSSI and CLcr 30 - 50 mL/min
Participants will be treated and evaluated for safety and microbiological and clinical efficacy in accordance with their type of infection and degree of renal impairment. Peak and trough samples will be collected to assess exposure to daptomycin for participants on Day 1 and following the 5th dose.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Written informed consent
- •Male or female ≥18 years of age
- •Diagnosis of cSSSI or Staphylococcus aureus (S. aureus) bacteremia
- •Renal impairment of CLcr of 30 - 50 mL/min or CLcr \<30 mL/min per Cockcroft-Gault equation using actual body weight
- •Functioning hemodialysis access and on stable regimen for those receiving dialysis
- •In appropriate health for the study with no acute or chronic illnesses that could adversely impact safety or ability to complete the study
- •Specific inclusion criteria for cSSSI:
- •Presence of a wound infection, major abscess, severe carbunculosis, infected ulcers, dialysis access site infection, or other type of infection in presence of complicating factor
- •At least 3 of the following symptoms, signs, or laboratory values of a skin infection: elevated temperature; elevated white blood cell (WBC) count; pain; tenderness; swelling; erythema greater than 1 centimeter (cm) beyond wound edge; induration; pus formation
- •Evidence of a Gram-positive infecting pathogen as indicated by positive Gram stain or culture obtained within 96 hours prior to study drug administration
Exclusion Criteria
- •Pregnant or lactating females, or unwilling to practice barrier methods of birth control
- •Received an investigational drug (including experimental biologic agents) within 30 days of study entry
- •Unable to discontinue use of HMG-CoA reductase inhibitor therapy while on study
- •Known allergy or intolerance to daptomycin, penicillin, or vancomycin
- •Active intravenous (IV) drug abuse
- •Confirmed or suspected osteomyelitis, septic arthritis, meningitis, epidural abscess, intra-abdominal infection, pneumonia, or infective endocarditis
- •Required use of non-study systemic antibacterial agent with activity against target pathogen
- •History of muscular disease
- •Neurological disease except stroke \>6 months prior to study entry
- •Intramuscular injection within 7 days of study drug administration
Arms & Interventions
Daptomycin, Bacteremia, Severe Renal Impairment
Cohort 1. Daptomycin was given intravenously 6 milligrams per kilogram (mg/kg) per administration. For bacteremia participants with Creatinine Clearance (CLcr) below 30 milliliters per minute (mL/min) and currently receiving hemodialysis, daptomycin was administered immediately following each hemodialysis session (3 per week) for 14 to 42 days based on disease resolution or Investigator discretion. For participants not receiving dialysis, daptomycin was administered every 48 hours for 14 to 42 days based on disease resolution or Investigator discretion.
Intervention: Daptomycin
Vancomycin or SSP, Bacteremia, Severe Renal Impairment
Cohort 1. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by Methicillin-Susceptible Staphylococcus Aureus (MSSA) could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered intravenously (IV) until end of antibiotic therapy for bacteremia or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Vancomycin
Vancomycin or SSP, Bacteremia, Severe Renal Impairment
Cohort 1. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by Methicillin-Susceptible Staphylococcus Aureus (MSSA) could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered intravenously (IV) until end of antibiotic therapy for bacteremia or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Semi-Synthetic Penicillin
Daptomycin, Bacteremia, Moderate Renal Impairment
Cohort 2. Daptomycin was given intravenously 6 milligrams per kilogram (mg/kg) per administration. For bacteremia participants with CLcr values between 30 and 50 mL/min not receiving dialysis, daptomycin was administered every 24 hours for 14 to 42 days based on disease resolution or Investigator discretion.
Intervention: Daptomycin
Vancomycin or SSP , Bacteremia, Moderate Renal Impairment
Cohort 2. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by MSSA could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered IV until end of antibiotic therapy for bacteremia or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Vancomycin
Vancomycin or SSP , Bacteremia, Moderate Renal Impairment
Cohort 2. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by MSSA could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered IV until end of antibiotic therapy for bacteremia or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Semi-Synthetic Penicillin
Daptomycin, cSSSI, Severe Renal Impairment
Cohort 3. Daptomycin was given intravenously 4 milligrams per kilogram (mg/kg) per administration. For cSSSI participants with CLcr below 30 mL/min and currently receiving hemodialysis, daptomycin was administered immediately following each hemodialysis session (3 per week) for 7 to 14 days based on disease resolution or Investigator discretion. For participants not receiving dialysis, daptomycin was administered every 48 hours for 7 to 14 days based on disease resolution or Investigator discretion.
Intervention: Daptomycin
Vancomycin or SSP , cSSSI, Severe Renal Impairment
Cohort 3. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by MSSA could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered IV until end of antibiotic therapy for cSSSI or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Vancomycin
Vancomycin or SSP , cSSSI, Severe Renal Impairment
Cohort 3. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by MSSA could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered IV until end of antibiotic therapy for cSSSI or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Semi-Synthetic Penicillin
Daptomycin, cSSSI, Moderate Renal Impairment
Cohort 4. Daptomycin was given intravenously 4 milligrams per kilogram (mg/kg) per administration. For cSSSI participants with CLcr values between 30 and 50 mL/min not receiving dialysis, daptomycin was administered every 24 hours for 7 to 14 days based on disease resolution or Investigator discretion.
Intervention: Daptomycin
Vancomycin or SSP , cSSSI, Moderate Renal Impairment
Cohort 4. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by MSSA could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered IV until end of antibiotic therapy for cSSSI or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Vancomycin
Vancomycin or SSP , cSSSI, Moderate Renal Impairment
Cohort 4. Participants randomized to the comparator therapy group received vancomycin or penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin). Investigators were allowed to select an agent based on local availability and normal treatment practices. Participants randomized to comparator subsequently found to have an infection caused by MSSA could have switched from vancomycin to penicillinase-resistant penicillin (nafcillin, oxacillin, or cloxacillin) at the Investigator's discretion. All treatments were dosed per Investigator's discretion and were administered IV until end of antibiotic therapy for cSSSI or until hospital discharge, whichever occurred first. Investigators treated participants according to their usual decision-making and discretion.
Intervention: Semi-Synthetic Penicillin
Outcomes
Primary Outcomes
Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET)
Time Frame: Baseline through EOT/ET
The number of participants with CPK elevations of \>500 units per liter (U/L) above baseline at any time from Day 1 through the EOT/ET visit are presented.
Secondary Outcomes
- Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit(Baseline through TOC/Safety Visit)