End-stage Renal Disease, Renal Failure Chronic Requiring Hemodialysis
Conditions
Keywords
End-stage renal disease, hemodialysis, chronic renal failure
Brief summary
The purpose of this study is to determine whether daptomycin at a higher dose given during the last 30 minutes of a dialysis session is equal to a lower dose of daptomycin given after a dialysis session.
Interventions
DRUGdaptomycin
intradialytic: 9 mg/kg during the last 30 minutes of dialysis
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent prior to any study-related procedure not part of normal medical care; * Male or female ≥ 18 years of age; * If female of childbearing potential; willing to practice reliable birth control measures during study treatment and for at least 28 days after study completion, not lactating or pregnant, and has a documented negative pregnancy test result within 24 hours prior to study medication administration; * End-stage renal disease on stable (for at least 2 weeks) hemodialysis regimen, three times weekly using high-flux membranes; * Functioning hemodialysis access (for example, graft or fistula); * Considered to be in appropriate health for study entry by the Investigator (for example, no acute, debilitating medical problems) and appropriate candidate for completing study treatment; * If taking concomitant medications, subject must be on a relatively stable dose for at least two weeks prior to study drug administration.
Exclusion criteria
* Received an investigational drug (including experimental biologic agents) within 30 days of study drug administration; * Has received any dose of daptomycin within 7 days prior to study drug administration; * Known to be allergic or intolerant to daptomycin; * Evidence of active ongoing infection; * Known human immunodeficiency virus (HIV) infection with CD4 count ≤ 200 cells/mm3; * Active illicit drug use or alcohol abuse; * Myocardial infarction within last 6 months; * Subject with a history of muscular disease (for example, polymyositis, muscular dystrophy); * Subject with a history of neurological disease (for example, Guillain Barré, multiple sclerosis), except stroke \> 6 months prior to study entry; * Intramuscular injection within 7 days of study drug administration; * Body mass index (BMI) ≤ 18.5 or ≥ 40 kg/m2 (BMI = weight \[kg\]/height \[m2\]); * WBC ≥ 12, 000 cells/mm3 or ≤ 2500 cells/ mm3; * Neutropenic subject with absolute neutrophil count ≤ 500 cells/mm3; * Baseline CPK values ≥ 3X ULN (upper limit of normal); * Alanine aminotransferase (ALT) \> 5XULN; * Aspartate aminotransferase (AST) \> 5XULN; * Hemoglobin ≤ 9 gm/dL; * Is considered unlikely to comply with study procedures or to return for scheduled post-treatment evaluations; * History of rhabdomyolysis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of Area Under the Curve From Time 0 to Infinity | Within 30 minutes prior to the start of the infusion, mid-infusion, and end of the infusion; at 1, 2, 4, 6, 9, 24, and 48 hours after the end of the infusion; and just prior to the next hemodialysis session (i.e., 68 hours post-infusion) | Area under the plasma concentration versus time curve from time 0 to infinity for daptomycin doses |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events | Up to 9 days after the last dose of study drug administration (Day 13 to Day 17 for those dosed on Day 8 and Day 20 to Day 24 for those dosed on Day 15). | Safety was monitored throughout the study, including observation and reports of AEs as well as changes in physical findings, vital signs, ECGs, and laboratory tests. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Half-life | Up to 68 hours post dose | Apparent terminal half-life. |
| Maximum Plasma Concentration | Within 30 minutes prior to the start of the infusion, mid-infusion, and end of the infusion; at 1, 2, 4, 6, 9, 24, and 48 hours after the end of the infusion; and just prior to the next hemodialysis session (i.e., 68 hours post-infusion) | Maximum plasma concentration over the entire sampling phase directly obtained from the experimental plasma concentration time data, without interpolation. |
| Volume of Distribution | Up to 68 hours post dose | Volume of distribution at steady state (mL) calculated as the product of clearance and mean residence time. |
| Clearance of Daptomycin | Up to 68 hours post dose | Plasma clearance is dose (µg) divided by area under the concentration versus time curve from time 0 to last quantifiable concentration time. |
| Time to Maximum Concentration | Up to 68 hours post dose | Sampling time at which maximum plasma concentration occurred, obtained directly from the experimental plasma concentration time data, without interpolation. |
Countries
United States
Participant flow
Pre-assignment details
Subjects evaluated for entry within 7 days prior to randomization, washout period of 7-14 days between doses, subjects began Day 1 on Friday of Monday/Wednesday/Friday or Saturday of Tuesday/Thursday/Saturday hemodialysis schedule
Participants by arm
| Arm | Count |
|---|---|
| Sequence BA All subjects received 1 dose of daptomycin 6 mg/kg after hemodialysis (Regimen B) and 1 dose of daptomycin 9 mg/kg during the last 30 minutes of hemodialysis (Regimen A). | 8 |
| Sequence AB All subjects received 1 dose of daptomycin 9 mg/kg during the last 30 minutes of hemodialysis (Regimen A) and 1 dose of daptomycin 6 mg/kg after hemodialysis (Regimen B). | 7 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Randomized Not Treated | 0 | 1 |
| Overall Study | Trouble with Vein Access | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Sequence BA | Sequence AB | Total |
|---|---|---|---|
| Age, Continuous | 51.6 years STANDARD_DEVIATION 13.19 | 55.3 years STANDARD_DEVIATION 6.05 | 53.3 years STANDARD_DEVIATION 10.31 |
| Sex: Female, Male Female | 3 Participants | 1 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 6 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 3 / 7 |
| serious Total, serious adverse events | 0 / 8 | 0 / 7 |
Outcome results
Primary
Evaluation of Area Under the Curve From Time 0 to Infinity
Area under the plasma concentration versus time curve from time 0 to infinity for daptomycin doses
Time frame: Within 30 minutes prior to the start of the infusion, mid-infusion, and end of the infusion; at 1, 2, 4, 6, 9, 24, and 48 hours after the end of the infusion; and just prior to the next hemodialysis session (i.e., 68 hours post-infusion)
Population: The primary endpoints are measured on the PK population, defined as all subjects who received both the 6 mg/kg dose and 9 mg/kg dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Evaluation of Area Under the Curve From Time 0 to Infinity | 1692 hr*ug/mL |
| 9 mg/kg During Hemodialysis (Regimen A) | Evaluation of Area Under the Curve From Time 0 to Infinity | 2708 hr*ug/mL |
Secondary
Treatment-emergent Adverse Events
Safety was monitored throughout the study, including observation and reports of AEs as well as changes in physical findings, vital signs, ECGs, and laboratory tests.
Time frame: Up to 9 days after the last dose of study drug administration (Day 13 to Day 17 for those dosed on Day 8 and Day 20 to Day 24 for those dosed on Day 15).
Population: Safety population, defined as all subjects who received at least one dose of daptomycin
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Treatment-emergent Adverse Events | 2 participants |
| 9 mg/kg During Hemodialysis (Regimen A) | Treatment-emergent Adverse Events | 3 participants |
Other Pre-specified
Clearance of Daptomycin
Plasma clearance is dose (µg) divided by area under the concentration versus time curve from time 0 to last quantifiable concentration time.
Time frame: Up to 68 hours post dose
Population: PK Population - defined as all subjects who received both doses of daptomycin
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Clearance of Daptomycin | 3.54 mL/hr/kg |
| 9 mg/kg During Hemodialysis (Regimen A) | Clearance of Daptomycin | 3.32 mL/hr/kg |
Other Pre-specified
Half-life
Apparent terminal half-life.
Time frame: Up to 68 hours post dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Half-life | 29.8 Hours |
| 9 mg/kg During Hemodialysis (Regimen A) | Half-life | 31.1 Hours |
Other Pre-specified
Maximum Plasma Concentration
Maximum plasma concentration over the entire sampling phase directly obtained from the experimental plasma concentration time data, without interpolation.
Time frame: Within 30 minutes prior to the start of the infusion, mid-infusion, and end of the infusion; at 1, 2, 4, 6, 9, 24, and 48 hours after the end of the infusion; and just prior to the next hemodialysis session (i.e., 68 hours post-infusion)
Population: PK Population - defined as all subjects who received both doses of daptomycin
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Maximum Plasma Concentration | 70.5 ug/mL |
| 9 mg/kg During Hemodialysis (Regimen A) | Maximum Plasma Concentration | 100 ug/mL |
Other Pre-specified
Time to Maximum Concentration
Sampling time at which maximum plasma concentration occurred, obtained directly from the experimental plasma concentration time data, without interpolation.
Time frame: Up to 68 hours post dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Time to Maximum Concentration | 0.50 Hours |
| 9 mg/kg During Hemodialysis (Regimen A) | Time to Maximum Concentration | 0.50 Hours |
Other Pre-specified
Volume of Distribution
Volume of distribution at steady state (mL) calculated as the product of clearance and mean residence time.
Time frame: Up to 68 hours post dose
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 6 mg/kg After Hemodialysis (Regimen B) | Volume of Distribution | 137 mL/kg |
| 9 mg/kg During Hemodialysis (Regimen A) | Volume of Distribution | 145 mL/kg |