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The primary objective is to assess the pharmacokinetics (PK) of apraglutide in subjects with hepatic impairment compared with matched control subjects with normal hepatic function following single subcutaneous (SC) dose administration.
A two stage design, open label, multi-center, non-randomized trial to evaluate the the safety and tolerability of a single subcutaneous dose of apraglutide in subjects with varying degrees of hepatic function. The hepatic function will estimated with the Child-Pugh classification.
Part 1: 8 subjects with moderate hepatic impairment (Cohort 1) and 8 subjects with normal hepatic function (Cohort 2).
Part 2: 8 subjects with mild hepatic impairment (Cohort 3) and 8 subjects with normal hepatic function (from Cohort 2 where possible and additional subject). Part 2 will be conducted only if the geometric mean ratio (GMR) of area under the curve extrapolated to infinity (AUCinf) or area under the curve from zero to the last measurable point (AUClast) for the moderate hepatic impairment group compared to the control group is ≥2.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Part 1: Moderate hepatic impairment | Experimental | Child-Pugh B |
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| Part 1: Normal hepatic function | Experimental |
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| Part 2: Mild hepatic impairment | Experimental | Child-Pugh A |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Apraglutide | Drug | Single dose of apraglutide |
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| Measure | Description | Time Frame |
|---|---|---|
| Area Under the Curve to Infinity (AUCinf) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a lower limit of quantification (LLOQ) of 1 ng/mL and an upper limit of 200 ng/mL. Plasma pharmacokinetic (PK) parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. AUCinf was calculated as: AUCinf = AUC from time zero to the last quantifiable concentration (AUClast) + (Clast/kel) where Clast was the observed concentration at the last time point with concentrations above the lower limit of quantification and kel was the terminal elimination rate constant. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Area Under the Curve (AUC) From Time Zero to 168 Hours Post-dose (AUC0-168h) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, and 168 hours post-dose |
| Maximum Observed Plasma Concentration (Cmax) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. Cmax was the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Measure | Description | Time Frame |
|---|---|---|
| Time of Maximum Plasma Concentration (Tmax) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. Tmax was the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units. |
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Inclusion Criteria:
All Participants:
Participants with impaired hepatic function:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Tomasz Masior | VectivBio AG | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| APEX | Münich | Germany | ||||
| Summit Clinical Research |
In Part 1, participants with normal hepatic function were matched 1:1 for age (±10 years), body mass index (BMI; ±15%), and sex (1:1) to participants with moderate hepatic impairment. Part 2 was to be conducted dependent on the outcome of Part 1 and planned to enroll participants with mild hepatic impairment. No participants enrolled in Part 2.
Participants were enrolled in 2 study sites in Slovakia and Germany and participated from February 2023 to April 2023.
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| ID | Title | Description |
|---|---|---|
| FG000 | Normal Hepatic Function Group | Participants with normal hepatic function received a single subcutaneous (SC) dose of apraglutide on Day 1. |
| FG001 | Moderate Hepatic Impairment Group |
| Title | Milestones | Reasons Not Completed | |||||
|---|---|---|---|---|---|---|---|
| Overall Study |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 6, 2022 | May 28, 2025 |
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| Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Apparent Clearance After Extravascular Administration (CL/F) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Terminal Elimination Rate Constant (Kel) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. Terminal elimination rate constant calculated by linear regression of the terminal log-linear portion of the concentration vs. time curve. Linear regression of at least three points and an adjusted r^2 greater than or equal to 0.80 were required to obtain a reliable kel. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Terminal Half-life (t1/2) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Apparent Volume of Distribution After Extravascular Administration (Vz/F) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | A TEAE was any unfavorable and unintended sign, symptom, or disease temporally associated with apraglutide, whether or not related, that occurred or worsened after the dose of apraglutide. A serious TEAE was defined as any TEAE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were graded for severity based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 as follows from Grade 1 (mild) to Grade 5 (AE resulted in death). Clinically significant changes in physical examination findings, laboratory results, vital signs, and 12-lead electrocardiograms (ECGs) were also recorded as TEAEs. | Day 1 to Day 14 |
| Bratislava |
| Slovakia |
Participants with moderate hepatic impairment received a single SC dose of apraglutide on Day 1.
| Dosed With Apraglutide |
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| COMPLETED |
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| NOT COMPLETED |
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| ID | Title | Description |
|---|---|---|
| BG000 | Normal Hepatic Function Group | Participants with normal hepatic function received a single SC dose of apraglutide on Day 1. |
| BG001 | Moderate Hepatic Impairment Group | Participants with moderate hepatic impairment received a single SC dose of apraglutide on Day 1. |
| BG002 | Total | Total of all reporting groups |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean | Full Range | years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Ethnicity (NIH/OMB) | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Primary | Area Under the Curve to Infinity (AUCinf) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a lower limit of quantification (LLOQ) of 1 ng/mL and an upper limit of 200 ng/mL. Plasma pharmacokinetic (PK) parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. AUCinf was calculated as: AUCinf = AUC from time zero to the last quantifiable concentration (AUClast) + (Clast/kel) where Clast was the observed concentration at the last time point with concentrations above the lower limit of quantification and kel was the terminal elimination rate constant. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Primary | Area Under the Curve (AUC) From Time Zero to 168 Hours Post-dose (AUC0-168h) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | h*ng/mL | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, and 168 hours post-dose |
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| Primary | Maximum Observed Plasma Concentration (Cmax) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. Cmax was the observed peak analyte concentration obtained directly from the experimental data without interpolation, expressed in concentration units. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | ng/mL | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Secondary | Time of Maximum Plasma Concentration (Tmax) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. Tmax was the first observed time to reach peak analyte concentration obtained directly from the experimental data without interpolation, expressed in time units. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Median | Full Range | hours | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Secondary | Apparent Clearance After Extravascular Administration (CL/F) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | L/h | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Secondary | Terminal Elimination Rate Constant (Kel) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. Terminal elimination rate constant calculated by linear regression of the terminal log-linear portion of the concentration vs. time curve. Linear regression of at least three points and an adjusted r^2 greater than or equal to 0.80 were required to obtain a reliable kel. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | 1/h | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Secondary | Terminal Half-life (t1/2) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | hours | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Secondary | Apparent Volume of Distribution After Extravascular Administration (Vz/F) of Apraglutide | Apraglutide was quantified in human plasma samples using a fully validated liquid chromatography mass spectrometry-based method, with a LLOQ of 1 ng/mL and an upper limit of 200 ng/mL. Plasma PK parameters for apraglutide were estimated using non-compartmental methods from the concentration-time profiles. Actual sampling times, rather than scheduled sampling times, were used. | The PK parameter set included participants who received at least one dose of apraglutide and who had at least one PK parameter of interest estimated. | Posted | Geometric Mean | Geometric Coefficient of Variation | liters | Pre-dose Day 1; 6, 12, 24, 28, 36, 40, 48, 60, 72, 96, 120, 144, 168, 240, and 312 hours post-dose |
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| Secondary | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | A TEAE was any unfavorable and unintended sign, symptom, or disease temporally associated with apraglutide, whether or not related, that occurred or worsened after the dose of apraglutide. A serious TEAE was defined as any TEAE that resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. TEAEs were graded for severity based on the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0 as follows from Grade 1 (mild) to Grade 5 (AE resulted in death). Clinically significant changes in physical examination findings, laboratory results, vital signs, and 12-lead electrocardiograms (ECGs) were also recorded as TEAEs. | The safety analysis set included all participants who received at least one dose of apraglutide. | Posted | Count of Participants | Participants | No | Day 1 to Day 14 |
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Day 1 to Day 14
The safety analysis set included all participants who received at least one dose of apraglutide.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Normal Hepatic Function Group | Participants with normal hepatic function received a single SC dose of apraglutide on Day 1. | 0 | 8 | 0 | 8 | 0 | 8 |
| EG001 | Moderate Hepatic Impairment Group | Participants with moderate hepatic impairment received a single SC dose of apraglutide on Day 1. | 0 | 8 | 0 | 8 | 1 | 8 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA 26.0 | Systematic Assessment |
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| Pruritus | Skin and subcutaneous tissue disorders | MedDRA 26.0 | Systematic Assessment |
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Part 2 was to be conducted if the geometric mean ratio (GMR) point estimate of apraglutide AUCinf or AUClast for the moderate hepatic impairment group compared with the control group was ≥2. As the GMR point estimate of AUCinf was <2, the trial stopped after Part 1.
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Clinical Trial Information Desk | VectivBio AG | 617.621.7722 | ClinicalTrialEnquiries@ironwoodpharma.com |
| Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 3, 2023 | May 28, 2025 | SAP_001.pdf |
| ID | Term |
|---|---|
| C000710330 | apraglutide |
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| Male |
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| Not Hispanic or Latino |
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| Unknown or Not Reported |
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| Asian |
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| Native Hawaiian or Other Pacific Islander |
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| Black or African American |
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| White |
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| More than one race |
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| Unknown or Not Reported |
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