Clinical trial NCT02963077: A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Orphan Cholestatic Liver Diseases
Primary Biliary Cirrhosis
Progressive Familial Intrahepatic Cholestasis
Alagille Syndrome
Lead sponsor: Ipsen
Sponsor class: INDUSTRY
First posted: 2016-11-15
Enrollment: 94
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following A Single Oral 10 mg A4250 Dose - Tmax
timeFrame: 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
measure: Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - Cmax
timeFrame: 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
measure: Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - AUC 0-t
timeFrame: 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
measure: Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 4 h Post-Dose
timeFrame: 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).
measure: Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 24 h Post-Dose
timeFrame: 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).
measure: Mean (SD) Change in C4 from Day 1 Pre-Dose to 4 h Post-Dose
timeFrame: 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).
measure: Mean (SD) Change in C4 from Day 1 Pre-Dose to 24 h Post-Dose
timeFrame: 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).
measure: Mean (SD) Changes in Total Bile Acids for A4250 4 h compared to pre-dose
timeFrame: Samples were taken pre-dose and post-dose at 4 hours and 24 hours.
measure: Mean (SD) Changes in Total Bile Acids for A4250 24 h compared to pre-dose
timeFrame: Samples were taken pre-dose, and post-dose at 4 hours and 24 hours.
measure: Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma FGF19
timeFrame: AUC(0-12) on Day 7 (only for Part II)
measure: Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma C4
timeFrame: AUC(0-12) on Day 7 (only Part II)
measure: Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma Total Bile Acids
timeFrame: AUC(0-12) on Day 7 (only Part II)
measure: Mean (SD) Changes in Faecel Total Bile Acids from Day 1 Pre-Dose on Day 7 at 24 h Post-dose
timeFrame: Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose
measure: Mean (SD) Change in Faecal Total Bile Acids Excreted (ng) from Day 1 Pre-Dose on Day 7 Post-Dose
timeFrame: Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose
Secondary outcomes:
Other outcomes:
Locations:
Study officials:
affiliation: Ipsen
name: Ipsen Medical Director
role: STUDY_DIRECTOR
References: