A Study to Evaluate the Effects of Multiple Doses of FG-4592 on the Exposure, Safety and Tolerability and Effect of Warfarin in Healthy Subjects

Healthy Subjects Clinical Trial

Official title:

A Phase 1, Open-label, One-sequence Crossover Study to Evaluate the Effect of Multiple Doses of FG 4592 on the Pharmacokinetics of Warfarin in Healthy Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02252731
• Other study ID #: 1517-CL-0509
• Secondary ID: 2013-001043-31
• Status: Completed
• Phase: Phase 1
• First received: June 10, 2014
• Last updated: September 26, 2014
• Start date: September 2013
• Est. completion date: November 2013

Study information

• Verified date: September 2014
• Source: Astellas Pharma Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

This study will determine the effect of multiple doses of FG-4592 on the pharmacokinetics (PK) of a single dose of warfarin. It will evaluate the safety and tolerability of warfarin alone and in combination with multiple doses of FG-4592, and will evaluate the effect of multiple doses of FG-4592 on the pharmacodynamics (PD) of warfarin.

Description:

The study consists of 2 periods, separated by a washout period (a minimum of 14 days after warfarin dosing on Day 1, Period 1). Screening takes place from Day -22 to Day -2.

Subjects are admitted to the clinical unit on Day -1 of Period 1. On Day 1 of the first period, subjects receive a single oral dose of warfarin. After completion of all assessments on Day 8, subjects are discharged from the clinical unit on the condition that there are no medical reasons for a prolonged stay. They return to the clinical unit on Day -1 of the second period, after the washout period.

In Period 2, the subjects receive multiple doses of FG 4592. On Day 7 of Period 2, FG 4592 is given concomitantly with warfarin. After completion of all assessments on Day 16 of Period 2, subjects are discharged from the clinic on the condition that there are no medical reasons for a prolonged stay. The subjects return for an End of Study Visit (ESV) 5 to 9 days after the last assessment of Period 2 (or after early withdrawal).

Safety assessments are performed throughout the study. Blood and urine samples are collected for PK and PD assessments.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Male subject and their female spouse/partners who are of childbearing potential must be using highly effective contraception consisting of two forms of birth control.

• Male subject must not donate sperm starting at screening and throughout the study period and for 90 days after the final study drug administration.

• Female subject must be either of non-childbearing potential or, if of childbearing potential, must have a negative pregnancy test at screening and Day -1 and must use two forms of birth control.

• Female subject must not donate ova starting at screening and throughout the study period and for 28 days after the final study drug administration.

Exclusion Criteria:

• Subject has a known or suspected hypersensitivity to FG 4592, warfarin, or any components of the formulations used.

• Subject has/had febrile illness or symptomatic, viral, bacterial (including upper respiratory infection), or fungal (non-cutaneous) infection within 1 week prior to admission to the clinical unit [Day -1].

• Subject is lactose intolerant.

Study Design

Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Healthy Subjects
• Pharmacokinetics of FG-4592

Intervention

Drug:
• Warfarin
Oral
• FG-4592
Oral

Locations

Country	Name	City	State
Germany	Parexel International GmbH	Berlin

Sponsors (2)

Lead Sponsor	Collaborator
Astellas Pharma Europe B.V.	FibroGen

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PK of S-warfarin and R-warfarin in plasma measured by area under the curve from the time of dosing extrapolated to time infinity (AUCinf)		Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)	No
Primary	PK of S-warfarin and R-warfarin in plasma measured by maximum concentration (Cmax)		Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)	No
Secondary	PK profile of S-warfarin and R-warfarin in plasma	area under the concentration-time curve from the time of dosing to the last measurable concentration (Clast) (AUClast), unbound AUC from the time of dosing to Clast (AUClast,u), AUC from the time of dosing extrapolated to time infinity (AUCinf), unbound AUC extrapolated to infinity (AUCinf,u), maximum unbound plasma concentration (Cmax,u), apparent total body clearance after extra-vascular dosing (CL/F), unbound apparent total body clearance after extravascular dosing (CLu/F), fraction unbound (fu), time interval between the time of dosing and the first measurable concentration (tlag), time of the maximum concentration (tmax), terminal elimination half-life (t1/2), apparent volume of distribution during the terminal elimination phase after single extravascular dosing (Vz/F), unbound apparent volume of distribution during terminal phase after oral administration (Vz,u/F)	Period 1 (Day 1 to Day 8); Period 2 (Day 7 to Day 16)	No
Secondary	PK profile of FG-4592 in plasma	AUC from time point 0 to time point 24 hours (AUC0-24h), AUClast, AUCinf , Cmax, concentration at pre-dose for repeated dosing (Ctrough), tmax, t1/2, CL/F, and Vz/F	Period 2 (Day 1 to Day 15)	No
Secondary	PK profile of FG-4592 in urine	renal clearance (CLR), unbound CLR from time point 0 to 24 hours (CLR,0-24h), cumulative amount of drug excreted unchanged into urine from time of dosing extrapolated to time infinity (Aeinf), percent of drug excreted unchanged into urine from time of dosing extrapolated to time infinity in percent of dose (Aeinf%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of the last measurable concentration (Aelast), percent of drug excreted into urine from time of dosing up to the collection time of the last measurable concentration in percent of dose (Aelast%), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours (Ae0 24h), cumulative amount of drug excreted unchanged into urine, from time of dosing up to the collection time of 24 hours in percent of dose (Ae0-24h%)	Period 2 (Day 7 to Day 8)	No
Secondary	Pharmacodynamics profile of warfarin in plasma	area under the Prothrombin Time (PT)-time curve from the time of dosing until the last sample collected (AUCPT,last), maximal PT (PTmax), time to reach PTmax (tPT,max), area under the International Normalized Ratio (INR)-time curve from the time of dosing until the last sample collected (AUCINR,last), maximal INR after Drug Administration (INRmax), time to reach the INRmax (tINR,max)	Period 1 Day 1 to to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))	No
Secondary	Safety profile	Safety profile includes Adverse Events (AEs), vital signs, physical examination, laboratory tests, electrocardiogram (ECG)	Screening (Day -22 to Day -2) to ESV (5 to 9 days after the last protocol defined assessment of Period 2 (or after early withdrawal))	No