End Stage Renal Disease on Hemodialysis
Conditions
Keywords
Difelikefalin, Pharmacokinetics
Brief summary
This is a Phase 1, single-arm, open-label study to evaluate the safety, PK, and tolerability of a repeated (3 times weekly) dose of difelikefalin administered as IV bolus injections to adult Chinese HD subjects. Treatment period is one week and there is a safety follow-up period of 1 week.
Detailed description
This is a Phase 1, single-arm, open-label study to evaluate the safety, PK, and tolerability of a repeated (3 times weekly) dose of difelikefalin administered as IV bolus injections to adult Chinese HD subjects. Total study duration for a single subject is up to 5 weeks including a screening period of up to 3 weeks, a treatment period of 1 week, and a safety follow-up period of 1 week. The duration of PK sampling is 12 days. The primary objective of the study is to evaluate the PK profile of a repeated (3 times weekly) dose of difelikefalin in Chinese HD subjects over a 1-week treatment period.
Interventions
Participants receive Difelikefalin three times a week (0,5 micrograms/kg dry body weight). Difelikefalin is administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each dialysis.
Sponsors
Tigermed Consulting Co., Ltd
Vifor Fresenius Medical Care Renal Pharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A Single-arm, Open-label Study
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* End-stage renal disease (ESRD) subjects who have been on HD for at least 3 months before enrolment in the study and are currently on HD 3 times per week. * Subjects with a prescription dry body weight between 40 and 100 kg, inclusive. * If female, is not pregnant, or nursing * If female: 1. Is surgically sterile; or 2. Has been amenorrhoeic for at least 1 year and is over the age of 55 years; or 3. Has a negative serum pregnancy test within 7 days before first dose of investigational product, and agrees to use adequate contraceptive precautions (e.g., hormonal contraceptives, barrier with spermicide, intrauterine device, vasectomised partner, or abstinence) from the time of informed consent until 7 days after the last dose of investigational product. * If male, agrees not to donate sperm from the first dose of investigational product administration (Day 1) until 7 days after last dosing, and agrees to use a condom with spermicide or abstain from heterosexual intercourse during the study until 7 days after the last dose of investigational product.
Exclusion criteria
* Planned or anticipated to receive a kidney transplant during the study. * Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) greater than 2.5 × the reference upper limit of normal (ULN), or bilirubin (total) greater than 4 × the ULN at screening. * Subjects with severe hepatic impairment (Child-Pugh Class C). * Known history of allergic reaction to opiates such as hives. Note: Side effects related to the use of opioids such as constipation or nausea would not exclude the subjects from the study. * Subject has known hypersensitivity to the study intervention or any component of the investigational product formulation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| t½ - Dose 1 | 1 week | t½ = elimination half-life |
| Evaluation of the PK Profile of Difelikefalin - AUC0-t - Dose 1 | 1 week | AUC0-t = Area under the concentration-versus-time curve (AUC) from time zero to time t |
| AUCinf - Dose 1 | 1 week | AUCinf = AUC from time zero to infinity |
| AUCextrap(%) - Dose 1 | 1 week | AUCextrap(%) = percentage of AUCinf based on extrapolation |
| Evaluation of the PK Profile of Difelikefalin - Cmax - Dose 1 | 1 week | Cmax = Maximum (peak) observed plasma concentration |
| Evaluation of the PK Profile of Difelikefalin - Tmax - Dose 1 | 1 week | Tmax = Time to reach maximum observed plasma concentration |
| Clearance - Dose 1 | 1 week | Clearance = the volume of blood or plasma that can be freed of a specified constituent in a specified time by its excretion into the urine through the kidneys |
| Vz - Dose 1 | 1 week | Vz = volume of distribution |
| Evaluation of the PK Profile of Difelikefalin - Cmax - Dose 3 | 1 week | Cmax = Maximum (peak) observed plasma concentration |
| Evaluation of the PK Profile of Difelikefalin - Tmax - Dose 3 | 1 week | Tmax = Time to reach maximum observed plasma concentration |
| Evaluation of the PK Profile of Difelikefalin - AUC0-t - Dose 3 | 1 week | AUC0-t = Area under the concentration-versus-time curve (AUC) from time zero to time t |
| AUCinf - Dose 3 | 1 week | AUCinf = AUC from time zero to infinity |
| AUCextrap(%) - Dose 3 | 1 week | AUCextrap(%) = percentage of AUCinf based on extrapolation |
| t½ - Dose 3 | 1 week | t½ = elimination half-life |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1-week, Single Arm, Open Label Treatment Phase Difelikefalin Injection: Participants receive Difelikefalin three times a week (0,5 micrograms/kg dry body weight). Difelikefalin is administered by intravenous bolus injection into the venous line of the dialysis circuit at the end of each dialysis. | 30 |
| Total | 30 |
Baseline characteristics
| Characteristic | 1-week, Single Arm, Open Label Treatment Phase |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 30 Participants |
| Race/Ethnicity, Customized Chinese | 30 Participants |
| Region of Enrollment China | 30 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 30 |
| other Total, other adverse events | 11 / 30 |
| serious Total, serious adverse events | 2 / 30 |
Outcome results
Primary
AUCextrap(%) - Dose 1
AUCextrap(%) = percentage of AUCinf based on extrapolation
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | AUCextrap(%) - Dose 1 | 23.5 percentage | Geometric Coefficient of Variation 49.3 |
Primary
AUCextrap(%) - Dose 3
AUCextrap(%) = percentage of AUCinf based on extrapolation
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | AUCextrap(%) - Dose 3 | 15.1 percentage | Geometric Coefficient of Variation 61.4 |
Primary
AUCinf - Dose 1
AUCinf = AUC from time zero to infinity
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | AUCinf - Dose 1 | 63.2 h*ng/mL | Geometric Coefficient of Variation 43.9 |
Primary
AUCinf - Dose 3
AUCinf = AUC from time zero to infinity
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | AUCinf - Dose 3 | 77.6 h*ng/mL | Geometric Coefficient of Variation 48 |
Primary
Clearance - Dose 1
Clearance = the volume of blood or plasma that can be freed of a specified constituent in a specified time by its excretion into the urine through the kidneys
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Clearance - Dose 1 | 0.510 L/H | Geometric Coefficient of Variation 43.6 |
Primary
Evaluation of the PK Profile of Difelikefalin - AUC0-t - Dose 1
AUC0-t = Area under the concentration-versus-time curve (AUC) from time zero to time t
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Evaluation of the PK Profile of Difelikefalin - AUC0-t - Dose 1 | 48.3 h*ng/mL | Geometric Coefficient of Variation 27.6 |
Primary
Evaluation of the PK Profile of Difelikefalin - AUC0-t - Dose 3
AUC0-t = Area under the concentration-versus-time curve (AUC) from time zero to time t
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Evaluation of the PK Profile of Difelikefalin - AUC0-t - Dose 3 | 65.6 h*ng/mL | Geometric Coefficient of Variation 33.8 |
Primary
Evaluation of the PK Profile of Difelikefalin - Cmax - Dose 1
Cmax = Maximum (peak) observed plasma concentration
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Evaluation of the PK Profile of Difelikefalin - Cmax - Dose 1 | 3.70 ng/mL | Geometric Coefficient of Variation 33.1 |
Primary
Evaluation of the PK Profile of Difelikefalin - Cmax - Dose 3
Cmax = Maximum (peak) observed plasma concentration
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Evaluation of the PK Profile of Difelikefalin - Cmax - Dose 3 | 4.23 ng/mL | Geometric Coefficient of Variation 23.8 |
Primary
Evaluation of the PK Profile of Difelikefalin - Tmax - Dose 1
Tmax = Time to reach maximum observed plasma concentration
Time frame: 1 week
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Evaluation of the PK Profile of Difelikefalin - Tmax - Dose 1 | 0.08 Hours |
Primary
Evaluation of the PK Profile of Difelikefalin - Tmax - Dose 3
Tmax = Time to reach maximum observed plasma concentration
Time frame: 1 week
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Evaluation of the PK Profile of Difelikefalin - Tmax - Dose 3 | 0.08 Hours |
Primary
t½ - Dose 1
t½ = elimination half-life
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | t½ - Dose 1 | 22.2 Hours | Geometric Coefficient of Variation 36.4 |
Primary
t½ - Dose 3
t½ = elimination half-life
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | t½ - Dose 3 | 25.0 Hours | Geometric Coefficient of Variation 37.7 |
Primary
Vz - Dose 1
Vz = volume of distribution
Time frame: 1 week
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1-week, Single Arm, Open Label Treatment Phase | Vz - Dose 1 | 16.3 L | Geometric Coefficient of Variation 20.4 |