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

Study Overview
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Brief Summary
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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.

Official Title
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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

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

Intervention / Treatment
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* Drug: A4250
* Drug: CRC (A3384)
* Drug: Questran
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 SAD - 0.1 mg A4250<br>Dose: 0.1 mg of A4250. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart). | Drug: A4250<br> <br> |
| Experimental: Cohort 2 SAD - 0.3 mg A4250<br>Dose: 0.3 mg of A4250. | Drug: A4250<br> <br> |
| Experimental: Cohort 3 SAD - 1 mg A4250<br>Dose: 1 mg A4250. | Drug: A4250<br> <br> |
| Experimental: Cohort 4 SAD - 3 mg A4250<br>Dose: 3 mg A4250. | Drug: A4250<br> <br> |
| Experimental: Cohort 5 SAD - 10 mg A4250<br>Dose: 10 mg A4250. | Drug: A4250<br> <br> |
| Placebo Comparator: Cohort 1 SAD placebo<br>Dose: 0.1 mg of A4250 matching placebo. Sentinel dosing was used (2 sub-cohorts dosed a minimum of 24 h apart). | Drug: Placebo<br> <br> |
| Placebo Comparator: Cohort 2 SAD placebo<br>Dose: 0.3 mg A4250 matching placebo. | Drug: Placebo<br> <br> |
| Placebo Comparator: Cohort 3 SAD placebo<br>Dose: 1 mg A4250 matching placebo. | Drug: Placebo<br> <br> |
| Placebo Comparator: Cohort 4 SAD placebo<br>Dose: 3 mg A4250 matching placebo. | Drug: Placebo<br> <br> |
| Placebo Comparator: Cohort 5 SAD placebo<br>Dose: 10 mg A4250 matching placebo. | Drug: Placebo<br> <br> |
| Experimental: Cohort 1 MAD - 1 mg A4250 qd<br>Dose: 1 mg A4250 qd for 7 days. | Drug: A4250<br> <br> |
| Placebo Comparator: Cohort 1 MAD placebo<br>Dose: 1 mg A4250 matching placebo qd for 7 days. | Drug: Placebo<br> <br> |
| Experimental: Cohort 2 MAD - 3 mg A4250<br>Dose: 3 mg A4250 qd for 7 days | Drug: A4250<br> <br> |
| Placebo Comparator: Cohort 2 MAD placebo<br>Dose: 3 mg A4250 matching placebo qd for 7 days. | Drug: Placebo<br> <br> |
| Experimental: Cohort 3 MAD - 1.5 mg A4250 b.i.d for 7 days.<br>Dose: 1.5 mg A4250 b.i.d. for 7 days. | Drug: A4250<br> <br> |
| Placebo Comparator: Cohort 3 MAD placebo<br>Dose: 1.5 A4250 matching placebo b.i.d for 7 days. | Drug: Placebo<br> <br> |
| Experimental: Cohort 4 MAD - 3 mg A4250 qd + 1 mg Questran b.i.d<br>Dose: 3 mg A4250 qd + 1 mg Questran b.i.d for 7 days. | Drug: A4250<br> <br> Drug: Questran<br> <br> |
| Active Comparator: Cohort 4 MAD A4250 placebo + 1 mg Questran b.i.d<br>Dose: 3 mg A4250 matching placebo + 1 mg Questran b.i.d for 7 days. | Drug: Questran<br> <br> Drug: Placebo<br> <br> |
| Experimental: Cohort 5 MAD - 3 mg A4250 qd + 1 g CRC b.i.d<br>Dose: 3 mg A4250 qd + 1 g CRC b.i.d for 7 days. | Drug: A4250<br> <br> Drug: CRC (A3384)<br> <br> |
| Placebo Comparator: Cohort 5 MAD A4250 placebo + CRC placebo<br>Dose: 3 mg A4250 matching placebo qd + 1 g CRC placebo b.i.d for 7 days | Drug: Placebo<br> <br> |
| Active Comparator: Cohort 6 MAD - 1 g CRC<br>Dose: 1 g CRC b.i.d | Drug: CRC (A3384)<br> <br> |
| Placebo Comparator: Cohort 6 MAD CRC placebo<br>Dose: 1 g CRC matching placebo b.i.d. | Drug: Placebo<br> <br> |
| Experimental: Cohort 7 MAD - 3 mg A4250 qd + 1 g CRC b.i.d<br>Dose: 3 mg A4250 qd + 1 g CRC b.i.d | Drug: A4250<br> <br> Drug: CRC (A3384)<br> <br> |
| Placebo Comparator: Cohort 7 MAD A4250 placebo + CRC placebo<br>Dose: 3 mg A4250 matching placebo qd + 1 g CRC matching placebo b.i.d. | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 |