A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384

A Phase I, Double-Blind Single and Multiple Ascending Dose Study to Assess Safety and Pharmacokinetics of A4250 as Monotherapy, and in Combination With Colonic Release Cholestyramine (A3384) or Commercially Available Cholestyramine (Questran™) in Healthy Subjects

The primary objectives of the study are to evaluate the safety, tolerability and pharmacokinetics of A4250 after single or multiple oral doses in healthy subjects. In addition, will evaluate A4250 in combination with cholestyramine.

Study Overview

• Status: Completed
• Conditions: Primary Biliary Cirrhosis; Alagille Syndrome; Progressive Familial Intrahepatic Cholestasis; Orphan Cholestatic Liver Diseases
• Intervention / Treatment: Drug: Placebo; Drug: A4250; Drug: Questran; Drug: CRC (A3384)

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Healthy males or non-pregnant, non-lactating healthy females
2. BMI of 18 to 32 kg/m2 or, if outside the range, considered not clinically significant by the investigator
3. Willing and able to communicate and participate in the whole study
4. Provided written informed consent
5. Agreed to use an adequate method of contraception

Exclusion Criteria:

1. Had participated in a clinical research study within the previous 3 months
2. Were study site employees, or immediate family members of a study site or sponsor employee
3. Had previously been enrolled in this study
4. History of any drug or alcohol abuse in the past 2 years
5. Regular alcohol consumption, in males >21 units per week and females >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
6. Current smokers and those who had smoked within the last 12 months. A breath carbon monoxide (CO) reading of greater than 10 ppm at screening
7. Females of childbearing potential who were pregnant or lactating (female subjects must have had a negative urine pregnancy test at admission)
8. Did not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
9. Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator
10. Positive drugs of abuse test result
11. Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
12. History of cardiovascular, renal, hepatic, chronic respiratory or GI disease as judged by the investigator
13. Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients eg lactose or contraindications to cholestyramine/Questran
14. Presence or history of clinically significant allergy requiring treatment as per the judgement of the investigator Hayfever was allowed unless it was active
15. Donation or loss of greater than 400 mL of blood within the previous 3 months
16. Were taking, or had taken, any prescribed or over-the-counter drug (other than up to 4 g per day paracetamol, hormone replacement therapy [HRT] and hormonal contraception) or herbal remedies in the 14 days before IMP administration unless they were not considered to have interfered with the objectives of the study, as agreed by the PI and sponsor's medical monitor on a case by case basis
17. Failed to satisfy the investigator of fitness to participate for any other reason

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

24

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1 SAD - 0.1 mg A4250; Dose: 0.1 mg of A4250. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart).	Drug: A4250
Experimental: Cohort 2 SAD - 0.3 mg A4250; Dose: 0.3 mg of A4250.	Drug: A4250
Experimental: Cohort 3 SAD - 1 mg A4250; Dose: 1 mg A4250.	Drug: A4250
Experimental: Cohort 4 SAD - 3 mg A4250; Dose: 3 mg A4250.	Drug: A4250
Experimental: Cohort 5 SAD - 10 mg A4250; Dose: 10 mg A4250.	Drug: A4250
Placebo Comparator: Cohort 1 SAD placebo; Dose: 0.1 mg of A4250 matching placebo. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart).	Drug: Placebo
Placebo Comparator: Cohort 2 SAD placebo; Dose: 0.3 mg A4250 matching placebo.	Drug: Placebo
Placebo Comparator: Cohort 3 SAD placebo; Dose: 1 mg A4250 matching placebo.	Drug: Placebo
Placebo Comparator: Cohort 4 SAD placebo; Dose: 3 mg A4250 matching placebo.	Drug: Placebo
Placebo Comparator: Cohort 5 SAD placebo; Dose: 10 mg A4250 matching placebo.	Drug: Placebo
Experimental: Cohort 1 MAD - 1 mg A4250 qd; Dose: 1 mg A4250 qd for 7 days.	Drug: A4250
Placebo Comparator: Cohort 1 MAD placebo; Dose: 1 mg A4250 matching placebo qd for 7 days.	Drug: Placebo
Experimental: Cohort 2 MAD - 3 mg A4250; Dose: 3 mg A4250 qd for 7 days	Drug: A4250
Placebo Comparator: Cohort 2 MAD placebo; Dose: 3 mg A4250 matching placebo qd for 7 days.	Drug: Placebo
Experimental: Cohort 3 MAD - 1.5 mg A4250 b.i.d for 7 days.; Dose: 1.5 mg A4250 b.i.d. for 7 days.	Drug: A4250
Placebo Comparator: Cohort 3 MAD placebo; Dose: 1.5 A4250 matching placebo b.i.d for 7 days.	Drug: Placebo
Experimental: Cohort 4 MAD - 3 mg A4250 qd + 1 mg Questran b.i.d; Dose: 3 mg A4250 qd + 1 mg Questran b.i.d for 7 days.	Drug: A4250; Drug: Questran
Active Comparator: Cohort 4 MAD A4250 placebo + 1 mg Questran b.i.d; Dose: 3 mg A4250 matching placebo + 1 mg Questran b.i.d for 7 days.	Drug: Placebo; Drug: Questran
Experimental: Cohort 5 MAD - 3 mg A4250 qd + 1 g CRC b.i.d; Dose: 3 mg A4250 qd + 1 g CRC b.i.d for 7 days.	Drug: A4250; Drug: CRC (A3384)
Placebo Comparator: Cohort 5 MAD A4250 placebo + CRC placebo; Dose: 3 mg A4250 matching placebo qd + 1 g CRC placebo b.i.d for 7 days	Drug: Placebo
Active Comparator: Cohort 6 MAD - 1 g CRC; Dose: 1 g CRC b.i.d	Drug: CRC (A3384)
Placebo Comparator: Cohort 6 MAD CRC placebo; Dose: 1 g CRC matching placebo b.i.d.	Drug: Placebo
Experimental: Cohort 7 MAD - 3 mg A4250 qd + 1 g CRC b.i.d; Dose: 3 mg A4250 qd + 1 g CRC b.i.d	Drug: A4250; Drug: CRC (A3384)
Placebo Comparator: Cohort 7 MAD A4250 placebo + CRC placebo; Dose: 3 mg A4250 matching placebo qd + 1 g CRC matching placebo b.i.d.	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following A Single Oral 10 mg A4250 Dose - Tmax	Pharmacokinetic blood samples were taken pre-dose, and post-dose at: 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours
Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - Cmax	Pharmacokinetic blood samples were taken pre-dose, and post-dose at: 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours
Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - AUC 0-t	Pharmacokinetic blood samples were taken pre-dose, and post-dose at: 0.5 hour, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours and 24 hours
Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 4 h Post-Dose	Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 24 h Post-Dose	Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Change in C4 from Day 1 Pre-Dose to 4 h Post-Dose	Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Change in C4 from Day 1 Pre-Dose to 24 h Post-Dose	Pharmacodynamic blood samples were taken pre-dose and at 4 hours and 24 hours post-dosing, and at follow-up (5-7 days after final dose).
Mean (SD) Changes in Total Bile Acids for A4250 4 h compared to pre-dose	Samples were taken pre-dose and post-dose at 4 hours and 24 hours.
Mean (SD) Changes in Total Bile Acids for A4250 24 h compared to pre-dose	Samples were taken pre-dose, and post-dose at 4 hours and 24 hours.
Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma FGF19	AUC(0-12) on Day 7 (only for Part II)
Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma C4	AUC(0-12) on Day 7 (only Part II)
Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma Total Bile Acids	AUC(0-12) on Day 7 (only Part II)
Mean (SD) Changes in Faecel Total Bile Acids from Day 1 Pre-Dose on Day 7 at 24 h Post-dose	Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose
Mean (SD) Change in Faecal Total Bile Acids Excreted (ng) from Day 1 Pre-Dose on Day 7 Post-Dose	Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose

Collaborators and Investigators

• Sponsor: Albireo
• Investigators: Study Director: Ipsen Medical Director, Ipsen

Study record dates

Study Major Dates

• Study Start: July 1, 2013
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: November 1, 2016
• First Submitted That Met QC Criteria: November 10, 2016
• First Posted (Estimated): November 15, 2016

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Cardiovascular Diseases; Congenital Abnormalities; Genetic Diseases, Inborn; Fibrosis; Biliary Tract Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Abnormalities, Multiple; Bile Duct Diseases; Liver Cirrhosis; Liver Diseases; Cholestasis; Liver Cirrhosis, Biliary; Cholestasis, Intrahepatic; Alagille Syndrome; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Cholestyramine Resin
• Other Study ID Numbers: A4250-001; 2013-001175-21 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO