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

Albireo

Status and phase: Completed; Phase 1

Conditions: Progressive Familial Intrahepatic Cholestasis; Alagille Syndrome; Orphan Cholestatic Liver Diseases; Primary Biliary Cirrhosis

Treatments: Drug: Questran; Drug: A4250; Drug: CRC (A3384); Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT02963077

2013-001175-21 (EudraCT Number)

A4250-001

Details and patient eligibility

About

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.

Enrollment: 94 patients

Sex: All

Ages: 18 to 60 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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94 participants in 24 patient groups, including a placebo group

Cohort 1 SAD - 0.1 mg A4250

Experimental group

Description:

Dose: 0.1 mg of A4250. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart).

Treatment:

Drug: A4250

Cohort 2 SAD - 0.3 mg A4250

Experimental group

Description:

Dose: 0.3 mg of A4250.

Treatment:

Drug: A4250

Cohort 3 SAD - 1 mg A4250

Experimental group

Description:

Dose: 1 mg A4250.

Treatment:

Drug: A4250

Cohort 4 SAD - 3 mg A4250

Experimental group

Description:

Dose: 3 mg A4250.

Treatment:

Drug: A4250

Cohort 5 SAD - 10 mg A4250

Experimental group

Description:

Dose: 10 mg A4250.

Treatment:

Drug: A4250

Cohort 1 SAD placebo

Placebo Comparator group

Description:

Dose: 0.1 mg of A4250 matching placebo. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart).

Treatment:

Drug: Placebo

Cohort 2 SAD placebo

Placebo Comparator group

Description:

Dose: 0.3 mg A4250 matching placebo.

Treatment:

Drug: Placebo

Cohort 3 SAD placebo

Placebo Comparator group

Description:

Dose: 1 mg A4250 matching placebo.

Treatment:

Drug: Placebo

Cohort 4 SAD placebo

Placebo Comparator group

Description:

Dose: 3 mg A4250 matching placebo.

Treatment:

Drug: Placebo

Cohort 5 SAD placebo

Placebo Comparator group

Description:

Dose: 10 mg A4250 matching placebo.

Treatment:

Drug: Placebo

Cohort 1 MAD - 1 mg A4250 qd

Experimental group

Description:

Dose: 1 mg A4250 qd for 7 days.

Treatment:

Drug: A4250

Cohort 1 MAD placebo

Placebo Comparator group

Description:

Dose: 1 mg A4250 matching placebo qd for 7 days.

Treatment:

Drug: Placebo

Cohort 2 MAD - 3 mg A4250

Experimental group

Description:

Dose: 3 mg A4250 qd for 7 days

Treatment:

Drug: A4250

Cohort 2 MAD placebo

Placebo Comparator group

Description:

Dose: 3 mg A4250 matching placebo qd for 7 days.

Treatment:

Drug: Placebo

Cohort 3 MAD - 1.5 mg A4250 b.i.d for 7 days.

Experimental group

Description:

Dose: 1.5 mg A4250 b.i.d. for 7 days.

Treatment:

Drug: A4250

Cohort 3 MAD placebo

Placebo Comparator group

Description:

Dose: 1.5 A4250 matching placebo b.i.d for 7 days.

Treatment:

Drug: Placebo

Cohort 4 MAD - 3 mg A4250 qd + 1 mg Questran b.i.d

Experimental group

Description:

Dose: 3 mg A4250 qd + 1 mg Questran b.i.d for 7 days.

Treatment:

Drug: A4250

Drug: Questran

Cohort 4 MAD A4250 placebo + 1 mg Questran b.i.d

Active Comparator group

Description:

Dose: 3 mg A4250 matching placebo + 1 mg Questran b.i.d for 7 days.

Treatment:

Drug: Placebo

Drug: Questran

Cohort 5 MAD - 3 mg A4250 qd + 1 g CRC b.i.d

Experimental group

Description:

Dose: 3 mg A4250 qd + 1 g CRC b.i.d for 7 days.

Treatment:

Drug: CRC (A3384)

Drug: A4250

Cohort 5 MAD A4250 placebo + CRC placebo

Placebo Comparator group

Description:

Dose: 3 mg A4250 matching placebo qd + 1 g CRC placebo b.i.d for 7 days

Treatment:

Drug: Placebo

Cohort 6 MAD - 1 g CRC

Active Comparator group

Description:

Dose: 1 g CRC b.i.d

Treatment:

Drug: CRC (A3384)

Cohort 6 MAD CRC placebo

Placebo Comparator group

Description:

Dose: 1 g CRC matching placebo b.i.d.

Treatment:

Drug: Placebo

Cohort 7 MAD - 3 mg A4250 qd + 1 g CRC b.i.d

Experimental group

Description:

Dose: 3 mg A4250 qd + 1 g CRC b.i.d

Treatment:

Drug: CRC (A3384)

Drug: A4250

Cohort 7 MAD A4250 placebo + CRC placebo

Placebo Comparator group

Description:

Dose: 3 mg A4250 matching placebo qd + 1 g CRC matching placebo b.i.d.

Treatment:

Drug: Placebo