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

• ClinicalTrials.gov Identifier: NCT02963077
• Recruitment Status: Completed
• First Posted: November 15, 2016
• Last Update Posted: November 16, 2016
• Sponsor: Albireo
• Information provided by (Responsible Party): Albireo

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 (Clinical Trial)
• 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: July 2013
• Actual Primary Completion Date: May 2014
• Actual Study Completion Date: May 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 :

1. Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following A Single Oral 10 mg A4250 Dose - Tmax [ Time Frame: 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 ]
2. Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - Cmax [ Time Frame: 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 ]
3. Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - AUC 0-t [ Time Frame: 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 ]
4. Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 4 h Post-Dose [ Time Frame: 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). ]
5. Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 24 h Post-Dose [ Time Frame: 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). ]
6. Mean (SD) Change in C4 from Day 1 Pre-Dose to 4 h Post-Dose [ Time Frame: 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). ]
7. Mean (SD) Change in C4 from Day 1 Pre-Dose to 24 h Post-Dose [ Time Frame: 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). ]
8. Mean (SD) Changes in Total Bile Acids for A4250 4 h compared to pre-dose [ Time Frame: Samples were taken pre-dose and post-dose at 4 hours and 24 hours. ]
9. Mean (SD) Changes in Total Bile Acids for A4250 24 h compared to pre-dose [ Time Frame: Samples were taken pre-dose, and post-dose at 4 hours and 24 hours. ]
10. Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma FGF19 [ Time Frame: AUC(0-12) on Day 7 (only for Part II) ]
11. Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma C4 [ Time Frame: AUC(0-12) on Day 7 (only Part II) ]
12. Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma Total Bile Acids [ Time Frame: AUC(0-12) on Day 7 (only Part II) ]
13. Mean (SD) Changes in Faecel Total Bile Acids from Day 1 Pre-Dose on Day 7 at 24 h Post-dose [ Time Frame: Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose ]
14. Mean (SD) Change in Faecal Total Bile Acids Excreted (ng) from Day 1 Pre-Dose on Day 7 Post-Dose [ Time Frame: Change from Day 1 Pre-dose to Day 7 at 24 hours Post-dose ]

Eligibility Criteria

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

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

Contacts and Locations

Sponsors and Collaborators

Albireo

Investigators

• Study Director: Mats Ekelund, MD; Albireo

More Information

• Responsible Party: Albireo
• ClinicalTrials.gov Identifier: NCT02963077
• Other Study ID Numbers: A4250-001; 2013-001175-21 ( EudraCT Number )
• First Posted: November 15, 2016
• Last Update Posted: November 16, 2016
• Last Verified: November 2016

Additional relevant MeSH terms:

Liver Diseases; Cholestasis; Liver Cirrhosis, Biliary; Cholestasis, Intrahepatic; Alagille Syndrome; Digestive System Diseases; Bile Duct Diseases; Biliary Tract Diseases; Liver Cirrhosis; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Abnormalities, Multiple; Congenital Abnormalities; Genetic Diseases, Inborn; Cholestyramine Resin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents