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

Sponsor

Albireo (Industry)

Overall Status

Completed

CT.gov ID

NCT02963077

Collaborator

(none)

Enrollment

Arms

Duration (Months)

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Orphan Cholestatic Liver Diseases Primary Biliary Cirrhosis Progressive Familial Intrahepatic Cholestasis Alagille Syndrome	Drug: A4250 Drug: CRC (A3384) Drug: Questran Drug: Placebo	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

94 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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 Start Date :

Jul 1, 2013

Actual Primary Completion Date :

May 1, 2014

Actual Study Completion Date :

May 1, 2014

Arms and Interventions

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: Questran Drug: Placebo
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

Outcome Measures

Primary Outcome Measures

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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 60 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria:

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

Exclusion Criteria:

Had participated in a clinical research study within the previous 3 months
Were study site employees, or immediate family members of a study site or sponsor employee
Had previously been enrolled in this study
History of any drug or alcohol abuse in the past 2 years
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)
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
Females of childbearing potential who were pregnant or lactating (female subjects must have had a negative urine pregnancy test at admission)
Did not have suitable veins for multiple venepunctures/cannulation as assessed by the investigator at screening
Clinically significant abnormal biochemistry, haematology or urinalysis as judged by the investigator
Positive drugs of abuse test result
Positive hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCV Ab) or human immunodeficiency virus (HIV) results
History of cardiovascular, renal, hepatic, chronic respiratory or GI disease as judged by the investigator
Serious adverse reaction or serious hypersensitivity to any drug or the formulation excipients eg lactose or contraindications to cholestyramine/Questran
Presence or history of clinically significant allergy requiring treatment as per the judgement of the investigator Hayfever was allowed unless it was active
Donation or loss of greater than 400 mL of blood within the previous 3 months
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
Failed to satisfy the investigator of fitness to participate for any other reason