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

Primary Purpose

Orphan Cholestatic Liver Diseases, Primary Biliary Cirrhosis, Progressive Familial Intrahepatic Cholestasis

Status

Completed

Phase

Phase 1

Locations

Study Type

Interventional

Intervention

A4250

CRC (A3384)

Questran

Placebo

About this trial

This is an interventional treatment trial for Orphan Cholestatic Liver Diseases

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm 10

Arm 11

Arm 12

Arm 13

Arm 14

Arm 15

Arm 16

Arm 17

Arm 18

Arm 19

Arm 20

Arm 21

Arm 22

Arm 23

Arm 24

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Active Comparator

Experimental

Placebo Comparator

Active Comparator

Placebo Comparator

Experimental

Placebo Comparator

Arm Label

Cohort 1 SAD - 0.1 mg A4250

Cohort 2 SAD - 0.3 mg A4250

Cohort 3 SAD - 1 mg A4250

Cohort 4 SAD - 3 mg A4250

Cohort 5 SAD - 10 mg A4250

Cohort 1 SAD placebo

Cohort 2 SAD placebo

Cohort 3 SAD placebo

Cohort 4 SAD placebo

Cohort 5 SAD placebo

Cohort 1 MAD - 1 mg A4250 qd

Cohort 1 MAD placebo

Cohort 2 MAD - 3 mg A4250

Cohort 2 MAD placebo

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

Cohort 3 MAD placebo

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

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

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

Cohort 5 MAD A4250 placebo + CRC placebo

Cohort 6 MAD - 1 g CRC

Cohort 6 MAD CRC placebo

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

Cohort 7 MAD A4250 placebo + CRC placebo

Arm Description

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

Dose: 0.3 mg of A4250.

Dose: 1 mg A4250.

Dose: 3 mg A4250.

Dose: 10 mg A4250.

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

Dose: 0.3 mg A4250 matching placebo.

Dose: 1 mg A4250 matching placebo.

Dose: 3 mg A4250 matching placebo.

Dose: 10 mg A4250 matching placebo.

Dose: 1 mg A4250 qd for 7 days.

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

Dose: 3 mg A4250 qd for 7 days

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

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

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

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

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

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

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

Dose: 1 g CRC b.i.d

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

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

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

Outcomes

Primary Outcome Measures

Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following A Single Oral 10 mg A4250 Dose - Tmax

Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - Cmax

Mean (± SD) Plasma Pharmacokinetic Concentrations of A4250 Following a Single Oral 10 mg A4250 Dose - AUC 0-t

Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 4 h Post-Dose

Mean (SD) Change in FGF19 from Day 1 Pre-Dose to 24 h Post-Dose

Mean (SD) Change in C4 from Day 1 Pre-Dose to 4 h Post-Dose

Mean (SD) Change in C4 from Day 1 Pre-Dose to 24 h Post-Dose

Mean (SD) Changes in Total Bile Acids for A4250 4 h compared to pre-dose

Mean (SD) Changes in Total Bile Acids for A4250 24 h compared to pre-dose

Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma FGF19

Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma C4

Geometric (geometric CV%) Mean for AUC(0-12) on Day 7 for plasma Total Bile Acids

Mean (SD) Changes in Faecel Total Bile Acids from Day 1 Pre-Dose on Day 7 at 24 h Post-dose

Mean (SD) Change in Faecal Total Bile Acids Excreted (ng) from Day 1 Pre-Dose on Day 7 Post-Dose

Secondary Outcome Measures

Full Information

NCT ID

NCT02963077

First Posted

November 1, 2016

Last Updated

November 15, 2016

Sponsor

Albireo

1. Study Identification

Unique Protocol Identification Number

NCT02963077

Brief Title

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

2. Study Status

Record Verification Date

November 2016

Overall Recruitment Status

Completed

Study Start Date

July 2013 (undefined)

Primary Completion Date

May 2014 (Actual)

Study Completion Date

May 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Albireo

4. Oversight

Data Monitoring Committee

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Orphan Cholestatic Liver Diseases, Primary Biliary Cirrhosis, Progressive Familial Intrahepatic Cholestasis, Alagille Syndrome

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

94 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1 SAD - 0.1 mg A4250

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 2 SAD - 0.3 mg A4250

Arm Type

Experimental

Arm Description

Dose: 0.3 mg of A4250.

Arm Title

Cohort 3 SAD - 1 mg A4250

Arm Type

Experimental

Arm Description

Dose: 1 mg A4250.

Arm Title

Cohort 4 SAD - 3 mg A4250

Arm Type

Experimental

Arm Description

Dose: 3 mg A4250.

Arm Title

Cohort 5 SAD - 10 mg A4250

Arm Type

Experimental

Arm Description

Dose: 10 mg A4250.

Arm Title

Cohort 1 SAD placebo

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

Cohort 2 SAD placebo

Arm Type

Placebo Comparator

Arm Description

Dose: 0.3 mg A4250 matching placebo.

Arm Title

Cohort 3 SAD placebo

Arm Type

Placebo Comparator

Arm Description

Dose: 1 mg A4250 matching placebo.

Arm Title

Cohort 4 SAD placebo

Arm Type

Placebo Comparator

Arm Description

Dose: 3 mg A4250 matching placebo.

Arm Title

Cohort 5 SAD placebo

Arm Type

Placebo Comparator

Arm Description

Dose: 10 mg A4250 matching placebo.

Arm Title

Cohort 1 MAD - 1 mg A4250 qd

Arm Type

Experimental

Arm Description

Dose: 1 mg A4250 qd for 7 days.

Arm Title

Cohort 1 MAD placebo

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

Cohort 2 MAD - 3 mg A4250

Arm Type

Experimental

Arm Description

Dose: 3 mg A4250 qd for 7 days

Arm Title

Cohort 2 MAD placebo

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

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

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 3 MAD placebo

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

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

Arm Type

Experimental

Arm Description

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

Arm Title

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

Arm Type

Active Comparator

Arm Description

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

Arm Title

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

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 5 MAD A4250 placebo + CRC placebo

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

Cohort 6 MAD - 1 g CRC

Arm Type

Active Comparator

Arm Description

Dose: 1 g CRC b.i.d

Arm Title

Cohort 6 MAD CRC placebo

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

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

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 7 MAD A4250 placebo + CRC placebo

Arm Type

Placebo Comparator

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

A4250

Intervention Type

Drug

Intervention Name(s)

CRC (A3384)

Intervention Type

Drug

Intervention Name(s)

Questran

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

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

Title

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

Title

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

Title

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).

Title

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).

Title

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).

Title

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).

Title

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.

Title

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.

Title

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)

Title

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)

Title

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)

Title

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

Title

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Mats Ekelund, MD

Organizational Affiliation

Albireo

Official's Role

Study Director

12. IPD Sharing Statement

Learn more about this trial

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

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