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

Overview

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.

Full Title of Study: “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

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Triple (Participant, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: May 2014

Interventions

  • Drug: A4250
  • Drug: CRC (A3384)
  • Drug: Questran
  • Drug: Placebo

Arms, Groups and Cohorts

  • 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).
  • Experimental: Cohort 2 SAD – 0.3 mg A4250
    • Dose: 0.3 mg of A4250.
  • Experimental: Cohort 3 SAD – 1 mg A4250
    • Dose: 1 mg A4250.
  • Experimental: Cohort 4 SAD – 3 mg A4250
    • Dose: 3 mg A4250.
  • Experimental: Cohort 5 SAD – 10 mg A4250
    • Dose: 10 mg 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).
  • Placebo Comparator: Cohort 2 SAD placebo
    • Dose: 0.3 mg A4250 matching placebo.
  • Placebo Comparator: Cohort 3 SAD placebo
    • Dose: 1 mg A4250 matching placebo.
  • Placebo Comparator: Cohort 4 SAD placebo
    • Dose: 3 mg A4250 matching placebo.
  • Placebo Comparator: Cohort 5 SAD placebo
    • Dose: 10 mg A4250 matching placebo.
  • Experimental: Cohort 1 MAD – 1 mg A4250 qd
    • Dose: 1 mg A4250 qd for 7 days.
  • Placebo Comparator: Cohort 1 MAD placebo
    • Dose: 1 mg A4250 matching placebo qd for 7 days.
  • Experimental: Cohort 2 MAD – 3 mg A4250
    • Dose: 3 mg A4250 qd for 7 days
  • Placebo Comparator: Cohort 2 MAD placebo
    • Dose: 3 mg A4250 matching placebo qd for 7 days.
  • 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.
  • Placebo Comparator: Cohort 3 MAD placebo
    • Dose: 1.5 A4250 matching placebo b.i.d for 7 days.
  • 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.
  • 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.
  • 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.
  • 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
  • Active Comparator: Cohort 6 MAD – 1 g CRC
    • Dose: 1 g CRC b.i.d
  • Placebo Comparator: Cohort 6 MAD CRC placebo
    • Dose: 1 g CRC matching placebo b.i.d.
  • 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
  • Placebo Comparator: Cohort 7 MAD A4250 placebo + CRC placebo
    • Dose: 3 mg A4250 matching placebo qd + 1 g CRC matching placebo b.i.d.

Clinical Trial Outcome Measures

Primary Measures

  • 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
  • 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
  • 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
  • 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).
  • 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).
  • 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).
  • 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).
  • 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.
  • 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.
  • 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)
  • 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)
  • 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)
  • 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
  • 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

Participating in This Clinical Trial

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

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: 60 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Albireo
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Mats Ekelund, MD, Study Director, Albireo

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