Study of Daptomycin Safety and Efficacy for Complicated Skin and Skin Structure Infections (cSSSI) and Bacteremia in Renal Impairment (RENSE)

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

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.

Study Overview

• Status: Terminated
• Conditions: Renal Impairment; Complicated Skin and Skin Structure Infections; S. Aureus Bacteremia
• Intervention / Treatment: Drug: Vancomycin; Drug: Daptomycin; Drug: Semi-Synthetic Penicillin

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Azusa, California, United States
    • Los Angeles, California, United States
    • Torrance, California, United States
  • District of Columbia
    • Washington, District of Columbia, United States
  • Georgia
    • Decatur, Georgia, United States
  • New Jersey
    • Somers Point, New Jersey, United States
  • North Carolina
    • Winston-Salem, North Carolina, United States
  • Ohio
    • Columbus, Ohio, United States
  • Pennsylvania
    • West Reading, Pennsylvania, United States
  • Texas
    • Mission, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
• Infection of sufficient severity to require parenteral antimicrobial therapy

Specific inclusion criteria for S. aureus bacteremia:

• Documented S. aureus bacteremia defined as at least one positive blood culture for S. aureus obtained within 96 hours prior to the first dose of study medication

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
• Moribund clinical condition (high likelihood of death during next 3 days)
• Shock or hypotension (supine systolic blood pressure <80 millimeters of mercury [mmHg])
• Body mass index (BMI) <18 or >40 kilograms per meter squared (kg/m^2) [BMI = weight (kg)/height (m^2)]
• Known human immunodeficiency virus (HIV) infection with CD4 count ≤200 cells/millimeter (mm)^3
• Neutropenic participants with an absolute neutrophil count ≤500 cells/mm^3
• Anticipated to develop neutropenia absolute neutrophil count ≤500 due to prior or planned chemotherapy
• Alanine aminotransferase (ALT) value >3 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) value >3 × ULN
• Total bilirubin values ≥ 1.5 x ULN associated with ALT values >3 x ULN
• Creatine phosphokinase (CPK) value >2 × ULN
• Hemoglobin <8 grams per deciliter (gm/dL)
• Unlikely to comply with study procedures or to return for evaluations
• History of rhabdomyolysis
• Prior enrollment into this study
• Infections caused by Gram-positive pathogens known to be resistant to daptomycin or selected comparator agent

Specific exclusion criteria for cSSSI:

• Minor or superficial skin infections as the primary site of infection
• Cellulitis or erysipelas not associated with complicating factor as primary site of infection
• Perirectal abscess, hidradenitis suppurativa, concomitant gangrene, myositis, multiple infected ulcers at distant sites, necrotizing fasciitis, or infected third-degree burn wounds
• Infections requiring emergency surgery
• Infections suspected or documented to be due exclusively to gram-negative, anaerobic, or fungal organism
• Confirmed or suspected disorder that could interfere with the evaluations (for example, primary skin disorders)
• Use of a topical antibiotic at the site of the infection
• Use of systemic antibacterial therapy for the infection for >24 hours within 48 hours prior to start of study drug unless (a) infecting Gram-positive pathogen resistant to therapy or (b) therapy administered for 3 or more days with worsening or no improvement
• Planned surgical treatment that is considered curative of the infection

Specific exclusion criteria for S. aureus bacteremia:

• Has intravascular foreign material at the time the positive blood culture was drawn (for example., intracardiac pacemaker wires, percutaneous or implanted venous catheters, vascular grafts) unless material removed within 4 days after first dose of study medication or approval of medical monitor (exceptions: vascular stents in place for >6 months, permanent pacemaker attached via epicardial leads, or any dialysis access device unless this material is felt to be infected)
• Prosthetic heart valve
• Cardiac decompensation or valve damage or both with high likelihood of valve surgery in the 3 days after randomization
• Polymicrobial blood infection

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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.	Drug: Daptomycin; Other Names: Cubicin
Active Comparator: 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.	Drug: Vancomycin; Drug: Semi-Synthetic Penicillin; Other Names: SSP, nafcillin, oxacillin, cloxacillin
Experimental: 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.	Drug: Daptomycin; Other Names: Cubicin
Active Comparator: 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.	Drug: Vancomycin; Drug: Semi-Synthetic Penicillin; Other Names: SSP, nafcillin, oxacillin, cloxacillin
Experimental: 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.	Drug: Daptomycin; Other Names: Cubicin
Active Comparator: 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.	Drug: Vancomycin; Drug: Semi-Synthetic Penicillin; Other Names: SSP, nafcillin, oxacillin, cloxacillin
Experimental: 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.	Drug: Daptomycin; Other Names: Cubicin
Active Comparator: 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.	Drug: Vancomycin; Drug: Semi-Synthetic Penicillin; Other Names: SSP, nafcillin, oxacillin, cloxacillin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (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.	Baseline through EOT/ET

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit	Participants were assigned a Sponsor-assessed clinical outcome based on the following definitions at the TOC/Safety visit: Failure: Assessed as a failure at any time by the Investigator or received non-study antimicrobial therapy for lack of efficacy or had the primary site of infection removed completely by surgery or underwent surgery to treat the infection >4 days after starting study medication. Success: Were not assessed as a failure at any time and were assessed as a cure or improvement by the Investigator at the TOC visit. Non-evaluable: Received potentially effective antimicrobial therapy during the study period for reasons other than lack of efficacy or received <4 days of study medication or were not assessed by the Investigator.	Baseline through TOC/Safety Visit

Collaborators and Investigators

• Sponsor: Cubist Pharmaceuticals LLC
• Investigators: Study Director: Ellie Hershberger, Pharm.D., Cubist Pharmaceuticals LLC

Study record dates

Study Major Dates

• Study Start (Actual): April 19, 2010
• Primary Completion (Actual): June 12, 2012
• Study Completion (Actual): June 12, 2012

Study Registration Dates

• First Submitted: April 2, 2010
• First Submitted That Met QC Criteria: April 14, 2010
• First Posted (Estimate): April 15, 2010

Study Record Updates

• Last Update Posted (Actual): September 5, 2018
• Last Update Submitted That Met QC Criteria: August 6, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Skin Diseases; Kidney Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Bacterial Infections; Bacterial Infections and Mycoses; Sepsis; Skin Diseases, Infectious; Infections; Communicable Diseases; Renal Insufficiency; Bacteremia; Skin Diseases, Bacterial; Anti-Infective Agents; Anti-Bacterial Agents; Vancomycin; Daptomycin; Cloxacillin; Penicillins; Nafcillin; Oxacillin
• Other Study ID Numbers: 3009-022; DAP-RENSE-08-05 (Other Identifier: Cubist Study Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf