A Phase 1, Open-Label Evaluation of the Pharmacokinetics and Safety of a Single Dose of Apraglutide in Subjects With Normal and Impaired Hepatic Function

Study Overview
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Brief Summary
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The primary objective is to assess the PK of apraglutide in subjects with hepatic impairment compared with matched control subjects with normal hepatic function following single SC dose administration.

Detailed Description
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A two stage design, open label, multi-center, non-randomized trial to evaluate the the safety and tolerability of a single subcutaneous dose of 5 mg 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 AUCinf or AUClast for the moderate hepatic impairment group compared to the control group is ≥2.

Official Title
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A Phase 1, Open-Label Evaluation of the Pharmacokinetics and Safety of a Single Dose of Apraglutide in Subjects With Normal and Impaired Hepatic Function

Conditions
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Hepatic Impairment

Intervention / Treatment
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* Drug: Apraglutide


Participation Criteria
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Eligibility Criteria
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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 ≥18 to ≤35 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. Participants with impaired hepatic function: Confirmed and documented diagnosis of cirrhosis Moderate liver disease (Child-Pugh B): clinically stable for at least 1 month prior to screening Mild liver disease (Child-Pugh A): clinically stable for at least 1 month prior to screening Exclusion Criteria: History of clinically significant GI, bronchopulmonary, neurological, cardiovascular, endocrine, or allergic disease Known hypersensitivity to the investigational medicinal product (IMP), any of their excipients or drugs of the same class If capable of reproduction, unwilling to use an effective form of contraception If a female of child-bearing potential, a positive urine/blood pregnancy test Breast-feeding women Positive urine/blood test for alcohol and drugs of abuse at Screening and on Day-1 Use of prohibited medications or herbal remedies Known presence or history of intestinal polyps Known presence or history of any type of cancer Pancreatic events such as acute pancreatitis, pancreatic duct stenosis, pancreas infection, and increased blood amylase and lipase (>2.0-5.0×upper limit of normal range) Participation in an investigational drug or device study within 30 days prior to Screening Donation of blood over 500 mL within 2 months prior to Screening Heavy use of tobacco products (i.e., smokes more than 10 cigarettes per day) Concomitant disease or condition that could interfere with, or for which the treatment of might interfere with, the conduct of the study, or that would, in the opinion of the Investigator, pose an unacceptable risk to the subject in this trial Any intercurrent clinically significant illness in the previous 28 days before Day 1 of this study Positive blood screen for human immunodeficiency virus (HIV) antigen/antibody combo, hepatitis A (HAV), hepatitis B surface antigen (HBsAgB), or hepatitis C virus (HCV) Unwillingness or inability to comply with the study protocol for any other reason

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Moderate hepatic impairment<br>Child-Pugh B | Drug: Apraglutide<br>* Single dose of apraglutide 5mg.<br>|
| Experimental: Normal hepatic function<br> | Drug: Apraglutide<br>* Single dose of apraglutide 5mg.<br>|
| Experimental: Mild hepatic impairment<br>Child-Pugh A | Drug: Apraglutide<br>* Single dose of apraglutide 5mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma apraglutide primary PK parameter: AUCinf or AUClast | Area under the curve to infinity (AUCinf) or area under the curve from time zero to the last quantifiable concentration (AUClast) if AUCinf cannot be reliably estimated | 0 to 312 hours | 
| Plasma apraglutide primary PK parameter: AUC0-168h | Area under the curve from time zero to 168 hours after apraglutide administration (AUC0-168h) | 0 to 168 hours | 
| Maximum observed plasma concentration (Cmax) |  | 0 to 168 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time of maximum plasma concentration (tmax) |  | 0 to 168 hours | 
| Apparent clearance after extravascular administration (CL/F) |  | 0 to 168 hours | 
| Apparent volume of distribution after extravascular administration (Vz/F) |  | 0 to 168 hours | 
| Terminal elimination rate constant (λz) |  | 0 to 168 hours | 
| Terminal half-life (t½) |  | 0 to 168 hours | 
| Incidence, nature,and severity of adverse events (AE) with apraglutide |  | Baseline to Day 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatic Impairment, Liver Function, Hepatic Function