Chronic Kidney Disease
Conditions
Keywords
Renal Function, Renal Impairment, Kidney Function
Brief summary
Study of pharmacokinetics and safety of apraglutide in participants with normal and impaired kidney function.
Detailed description
A two stage design, open label, multi-center, non-randomized trial to evaluate the PK and safety of a single subcutaneous dose of 5 mg apraglutide in subjects with varying degrees of renal function. The renal function was calculated by the estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology (CKD-EPI) Creatinine Equation. Part 1: 8 subjects with severe renal impairment (Cohort 1) and 8 subjects with normal renal function (Cohort 2). Part 2: 8 subjects with moderate (Cohort 3) and 8 subjects with mild (Cohort 4). Enrollment into Part 2 was conditional on the results of Part 1.
Interventions
DRUGApraglutide
Single dose of apraglutide 5 mg.
Sponsors
VectivBio AG
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
All Participants * Age between 18 and 75 years inclusive * Subjects who are willing and able to comply with the study procedures * Subjects able to understand and willing to sign the informed consent * Body mass index (BMI) of ≥17.5 to ≤40 kg/m2; and a total body weight of \>50 kg (110 lb). * Women of childbearing potential (WOCBP) on highly effective method of contraception during the trial and for 1 month after the end of trial (EOT) visit. Sterilized or infertile or postmenopausal females. * Male subjects with a female partner of childbearing potential: highly effective methods of contraception and no sperm donation during the trial and for 1 month after (EOT) visit. Healthy participants * No clinically relevant abnormalities (medical history, vital signs, ECG, safety labs) * eGFR measured by CKD-EPI ≥90 mL/min/1.73 m2) at two screening visits * Demographically comparable to the group of subjects with impaired renal function: Participants with impaired renal function * Severe renal impairment: eGFR \<30 mL/min/1.73 m2, but not requiring hemodialysis * Moderate renal impairment: eGFR ≥30 mL/min/1.73 m2 and \<60 mL/min/1.73 m2 * Mild renal impairment: eGFR ≥60 and \<90 mL/min/1.73 m2
Exclusion criteria
All Subjects * Renal transplant recipients * History of systemic infection * Any active malignancies or history of malignancies within the past 2 years * Acute or chronic medical or psychiatric condition * Treatment with an IMP within 30 days or 5 half-lives (whichever is longer) preceding the dose of IMP * Male subjects partners of WOCBP who are unable to comply with the contraceptive measures * History of clinically significant intestinal adhesions and/or chronic abdominal pain * History of known colon polyps or family history of familial adenomatous polyposis * Positive blood screen for hepatitis C antibody, hepatitis B surface antigen or human immunodeficiency virus (HIV)-1 and -2 antibodies * Serum albumin concentration \<25 g/L (2.5 g/dL) * Hemoglobin concentration \<90 g/L (9.0 g/dL) * Aspartate amino transaminase (AST) or alanine amino transaminase (ALT) values \>2 × upper limit of normal (ULN) * Proteinuria of \>3 g total bilirubin \>1.5 × ULN * Positive urine test for alcohol or illicit drugs at either Screening or admission. * Clinically significant abnormalities on 12-lead ECG * Use of prescription or non-prescription drugs and dietary supplements within 7 days or five half-lives (whichever is longer) prior to Day 1. Stable concomitant medications may be given to subjects with renal impairment, if they are considered necessary for the welfare of the subjects. * History of regular alcohol consumption exceeding seven drinks/week for females or 14 drinks/week for males (1 drink = 5 ounces \[150 mL\] of wine, or 12 ounces \[360 mL\] of beer, or 1.5 ounces \[45 mL\] of hard liquor) within 3 months of Screening * Female subjects of childbearing potential who are unwilling or unable to use highly effective methods of contraception for the duration of the trial and for at least 1 month after the administration of the IMP; pregnant female subjects; female subjects planning to become pregnant during the duration of the trial and until 1 month after the administration of the IMP; breastfeeding female subjects * Blood donation of approximately 500 mL or more within 60 days prior to the dose of IMP. Plasma donations of approximately 500 mL or more within 28 days prior to the dose of IMP Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Apraglutide | 5 minutes pre-dose up to 240 hours after dosing on Day 1 | Pharmacokinetic (PK) samples collected for the measurement of plasma concentration of apraglutide were analyzed using a validated analytical method in compliance with applicable standard operating procedures. |
| Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Apraglutide | 5 minutes pre-dose up to 240 hours after dosing on Day 1 | PK samples collected for the measurement of plasma concentration of apraglutide were analyzed using a validated analytical method in compliance with applicable standard operating procedures. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Day 1 up to Day 14 | TEAEs were defined as adverse events (AEs) that occurred after dosing the participant with the study drug. Participants with more than one TEAE were counted only once using the most severe event. Vital signs, triplicate 12-lead electrocardiograms, or clinical laboratory assessments considered clinically significant by the Investigator were reported as AEs. |
| Number of TEAEs | Day 1 up to Day 14 | The Investigator used the adjectives mild, moderate, or severe to describe the maximum intensity of the AE. These were defined as follows: * Mild: did not interfere with participant's usual function * Moderate: interfered to some extent with participant's usual function * Severe: interfered significantly with participant's usual function. The Investigator systematically assessed the causal relationship of AEs to IMP/trial treatment using the definitions below: * Not related: Not reasonably related to the IMP. The AE could not medically (pharmacologically/clinically) be attributed to the IMP * Related: Reasonably related to the IMP. The AE could medically (pharmacologically/clinically) be attributed to the IMP. A serious AE (SAE) was classified as any AE that: * Resulted in death * Was life-threatening * Required or prolonged in-patient hospitalization * Resulted in persistent or significant disability/incapacity * Was a congenital anomaly/birth defect in a neo |
Countries
United States
Participant flow
Recruitment details
This study was performed in the United States of America between 08 December 2020 and 05 July 2021.
Pre-assignment details
16 participants were included in Part 1 of the study and received 5 mg subcutaneous (SC) apraglutide on Day 1. Of the 16 participants who were included in Part 1, eight had normal renal function and eight had severely impaired renal function. Enrollment into Part 2 of the study was conditional on the results of Part 1. No participants were enrolled into Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Severely Impaired Renal Function Participants with eGFR values \<30 mL/min/1.73 m\^2, but not requiring hemodialysis, received 5 mg SC apraglutide on Day 1. | 8 |
| Normal Renal Function Participants with eGFR values ≥90 mL/min/1.73 m\^2 received 5 mg SC apraglutide on Day 1. | 8 |
| Total | 16 |
Baseline characteristics
| Characteristic | Severely Impaired Renal Function | Normal Renal Function | Total |
|---|---|---|---|
| Age, Continuous | 66 years | 60 years | 63 years |
| Body mass index | 30.6 kg/m^2 | 28.3 kg/m^2 | 29.4 kg/m^2 |
| Estimated glomerular filtration rate | 21.3 mL/min/1.73m^2 | 96.3 mL/min/1.73m^2 | 58.8 mL/min/1.73m^2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 7 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height | 171.9 cm | 174.9 cm | 173.4 cm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 3 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
| Weight | 90.1 kg | 86.7 kg | 88.4 kg |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 3 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Apraglutide
PK samples collected for the measurement of plasma concentration of apraglutide were analyzed using a validated analytical method in compliance with applicable standard operating procedures.
Time frame: 5 minutes pre-dose up to 240 hours after dosing on Day 1
Population: The PK parameter analysis population included all participants assigned to the IMP who were treated and had at least one of the PK parameters of primary interest measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severely Impaired Renal Function | Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Apraglutide | 3330 h*ng/mL | Standard Deviation 1150 |
| Normal Renal Function | Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) of Apraglutide | 5050 h*ng/mL | Standard Deviation 3170 |
90% CI: [0.458, 1.05]
Primary
Maximum Plasma Concentration (Cmax) of Apraglutide
Pharmacokinetic (PK) samples collected for the measurement of plasma concentration of apraglutide were analyzed using a validated analytical method in compliance with applicable standard operating procedures.
Time frame: 5 minutes pre-dose up to 240 hours after dosing on Day 1
Population: The PK parameter analysis population included all participants assigned to the investigational medicinal product (IMP) who were treated and had at least one of the PK parameters of primary interest measured.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Severely Impaired Renal Function | Maximum Plasma Concentration (Cmax) of Apraglutide | 39.5 ng/mL | Standard Deviation 13.7 |
| Normal Renal Function | Maximum Plasma Concentration (Cmax) of Apraglutide | 65.8 ng/mL | Standard Deviation 37.5 |
90% CI: [0.423, 0.909]
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as adverse events (AEs) that occurred after dosing the participant with the study drug. Participants with more than one TEAE were counted only once using the most severe event. Vital signs, triplicate 12-lead electrocardiograms, or clinical laboratory assessments considered clinically significant by the Investigator were reported as AEs.
Time frame: Day 1 up to Day 14
Population: The Safety Set included all participants who received at least one dose of the IMP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Severely Impaired Renal Function | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 3 Participants |
| Normal Renal Function | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 2 Participants |
Secondary
Number of TEAEs
The Investigator used the adjectives mild, moderate, or severe to describe the maximum intensity of the AE. These were defined as follows: * Mild: did not interfere with participant's usual function * Moderate: interfered to some extent with participant's usual function * Severe: interfered significantly with participant's usual function. The Investigator systematically assessed the causal relationship of AEs to IMP/trial treatment using the definitions below: * Not related: Not reasonably related to the IMP. The AE could not medically (pharmacologically/clinically) be attributed to the IMP * Related: Reasonably related to the IMP. The AE could medically (pharmacologically/clinically) be attributed to the IMP. A serious AE (SAE) was classified as any AE that: * Resulted in death * Was life-threatening * Required or prolonged in-patient hospitalization * Resulted in persistent or significant disability/incapacity * Was a congenital anomaly/birth defect in a neo
Time frame: Day 1 up to Day 14
Population: The Safety Set included all participants who received at least one dose of the IMP.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Severely Impaired Renal Function | Number of TEAEs | Any Moderate TEAEs | 3 events |
| Severely Impaired Renal Function | Number of TEAEs | Any Treatment-Related TEAEs | 5 events |
| Severely Impaired Renal Function | Number of TEAEs | Any Mild TEAEs | 4 events |
| Severely Impaired Renal Function | Number of TEAEs | Any Serious TEAEs | 0 events |
| Severely Impaired Renal Function | Number of TEAEs | Any Severe TEAEs | 0 events |
| Severely Impaired Renal Function | Number of TEAEs | Any TEAEs leading to study discontinuation | 0 events |
| Severely Impaired Renal Function | Number of TEAEs | Any TEAEs | 7 events |
| Normal Renal Function | Number of TEAEs | Any TEAEs leading to study discontinuation | 0 events |
| Normal Renal Function | Number of TEAEs | Any TEAEs | 3 events |
| Normal Renal Function | Number of TEAEs | Any Mild TEAEs | 1 events |
| Normal Renal Function | Number of TEAEs | Any Moderate TEAEs | 2 events |
| Normal Renal Function | Number of TEAEs | Any Severe TEAEs | 0 events |
| Normal Renal Function | Number of TEAEs | Any Treatment-Related TEAEs | 0 events |
| Normal Renal Function | Number of TEAEs | Any Serious TEAEs | 0 events |