Complicated Skin and Skin Structure Infections, Renal Impairment, S. Aureus Bacteremia
Conditions
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.
Interventions
DRUGVancomycin
DRUGDaptomycin
DRUGSemi-Synthetic Penicillin
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 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
| Measure | Time frame | Description |
|---|---|---|
| Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Baseline through 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 17 |
| 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 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. | 17 |
| 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. | 4 |
| 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. | 4 |
| 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. | 15 |
| 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. | 15 |
| 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. | 5 |
| 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. | 6 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 2 | 0 | 1 | 1 | 1 | 0 | 0 |
| Overall Study | Clinical Failure | 1 | 0 | 0 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Participant left investigator's care | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Randomized but not treated | 3 | 4 | 1 | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Reason not specified | 3 | 3 | 0 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Vancomycin or SSP, cSSSI, Moderate Renal Impairment | Total | Daptomycin, Bacteremia, Severe Renal Impairment | Vancomycin or SSP, Bacteremia, Severe Renal Impairment | Daptomycin, Bacteremia, Moderate Renal Impairment | Vancomycin or SSP, Bacteremia, Moderate Renal Impairment | Daptomycin, cSSSI, Severe Renal Impairment | Vancomycin or SSP, cSSSI, Severe Renal Impairment | Daptomycin, cSSSI, Moderate Renal Impairment |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical BTWN | 3 Participants | 56 Participants | 14 Participants | 12 Participants | 1 Participants | 3 Participants | 11 Participants | 11 Participants | 1 Participants |
| Age, Categorical GTE65 | 3 Participants | 27 Participants | 3 Participants | 5 Participants | 3 Participants | 1 Participants | 4 Participants | 4 Participants | 4 Participants |
| Age, Categorical LTE18 | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 1 Participants | 28 Participants | 7 Participants | 5 Participants | 2 Participants | 2 Participants | 5 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 55 Participants | 10 Participants | 12 Participants | 2 Participants | 2 Participants | 10 Participants | 12 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 17 | 15 / 17 | 4 / 4 | 4 / 4 | 4 / 15 | 5 / 15 | 2 / 5 | 4 / 6 |
| serious Total, serious adverse events | 2 / 17 | 6 / 17 | 2 / 4 | 1 / 4 | 1 / 15 | 5 / 15 | 0 / 5 | 2 / 6 |
Outcome results
Primary
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.
Time frame: Baseline through EOT/ET
Population: Participants who received at least 1 dose of study drug and had a baseline CPK value and at least 1 post-baseline CPK assessment between Day 1 post-dosing and EOT visit.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Daptomycin, Bacteremia, Severe Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 0 participants |
| Vancomycin or SSP, Bacteremia, Severe Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 1 participants |
| Daptomycin, Bacteremia, Moderate Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 0 participants |
| Vancomycin or SSP, Bacteremia, Moderate Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 0 participants |
| Daptomycin, cSSSI, Severe Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 1 participants |
| Vancomycin or SSP, cSSSI, Severe Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 0 participants |
| Daptomycin, cSSSI, Moderate Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 0 participants |
| Vancomycin or SSP, cSSSI, Moderate Renal Impairment | Number of Participants With Treatment-emergent Creatine Phosphokinase (CPK) Elevations Through End of Therapy/Early Termination (EOT/ET) | 0 participants |
Secondary
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.
Time frame: Baseline through TOC/Safety Visit
Population: Participants who received at least 1 dose of study drug and had at least 1 Gram-positive baseline infecting pathogen for cSSSI participants or S. aureus bacteremia for bacteremia participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Daptomycin, Bacteremia, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 9 participants |
| Daptomycin, Bacteremia, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 4 participants |
| Daptomycin, Bacteremia, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 2 participants |
| Vancomycin or SSP, Bacteremia, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 6 participants |
| Vancomycin or SSP, Bacteremia, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 1 participants |
| Vancomycin or SSP, Bacteremia, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 9 participants |
| Daptomycin, Bacteremia, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 1 participants |
| Daptomycin, Bacteremia, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 1 participants |
| Daptomycin, Bacteremia, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 2 participants |
| Vancomycin or SSP, Bacteremia, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 3 participants |
| Vancomycin or SSP, Bacteremia, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 0 participants |
| Vancomycin or SSP, Bacteremia, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 1 participants |
| Daptomycin, cSSSI, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 3 participants |
| Daptomycin, cSSSI, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 10 participants |
| Daptomycin, cSSSI, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 2 participants |
| Vancomycin or SSP, cSSSI, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 2 participants |
| Vancomycin or SSP, cSSSI, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 9 participants |
| Vancomycin or SSP, cSSSI, Severe Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 4 participants |
| Daptomycin, cSSSI, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 0 participants |
| Daptomycin, cSSSI, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 5 participants |
| Daptomycin, cSSSI, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 0 participants |
| Vancomycin or SSP, cSSSI, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Success | 4 participants |
| Vancomycin or SSP, cSSSI, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Failure | 2 participants |
| Vancomycin or SSP, cSSSI, Moderate Renal Impairment | Overall Therapeutic Outcome at Test of Cure (TOC)/Safety Visit | Non-evaluable | 0 participants |