Study of Pharmacokinetics and Safety of Apraglutide in Participants With Normal and Impaired Kidney Function.

Study Overview
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Brief Summary
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Study of pharmacokinetics and safety of apraglutide in participants with normal and impaired kidney function.

Detailed Description
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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.

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 Renal Function.

Conditions
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Chronic Kidney Disease

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 ≥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 Exclusion Criteria for Healthy Subjects with Normal Renal Function Evidence or history of clinically significant abnormalities Evidence or history of clinically significant dermatological condition Additional Exclusion Criteria for Subjects with Impaired Renal Function Subjects requiring hemodialysis and/or peritoneal dialysis Subjects with other clinically significant disease Subjects with any significant hepatic, cardiac, or pulmonary disease or subjects who are clinically nephrotic. Hypertension, diabetes mellitus, hyperparathyroidism, ischemic heart disease are not cause for exclusion as long as the subject is medically stable and any drugs that are administered for these conditions are not expected to interfere with the PK of apraglutide. Screening BP ≥180 mmHg (systolic) or ≥110 mmHg (diastolic)

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: Severe Renal Impairment<br>eGFR (mL/min/1.73 m2): <30 not on hemodialysis | Drug: Apraglutide<br>* Single dose of apraglutide 5 mg.<br>|
| Experimental: Normal Healthy Match<br>eGFR (mL/min/1.73 m2): ≥90 | Drug: Apraglutide<br>* Single dose of apraglutide 5 mg.<br>|
| Experimental: Moderate Renal Impairment<br>eGFR (mL/min/1.73 m2): ≥30 to 60 | Drug: Apraglutide<br>* Single dose of apraglutide 5 mg.<br>|
| Experimental: Mild Renal Impairment<br>eGFR (mL/min/1.73 m2): ≥60 to 90 | Drug: Apraglutide<br>* Single dose of apraglutide 5 mg.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 5 minutes pre-dose up to 240 hours after dosing on Day 1 | 
| 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. | 5 minutes pre-dose up to 240 hours after dosing on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Day 1 up to Day 14 | 
| 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 | Day 1 up to Day 14 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Function, Renal Impairment, Kidney Function