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Drug-drug-interaction Study to Assess the Effect of Darolutamide on the Pharmacokinetics of Probe Substrates of CYP3A4 and P-gp in Healthy Male Volunteers

Primary Purpose

Prostatic Neoplasms

Status
Completed
Phase
Phase 1
Locations
Germany
Study Type
Interventional
Intervention
Dabigatran etexilate
Midazolam
BAY1841788 (darolutamide)
Sponsored by
Bayer
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional other trial for Prostatic Neoplasms focused on measuring Drug-drug interaction

Eligibility Criteria

45 Years - 65 Years (Adult, Older Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  • Healthy subject - as determined by the investigator or medically qualified designee based on medical evaluations including medical history, physical examination, laboratory tests and cardiac monitoring.
  • Gender: Male.
  • Age: 45 to 65 years (inclusive) at the screening visit.
  • Race: White.
  • Body mass index (BMI): ≥18.0 and ≤30.0 kg/m2.
  • Agree to use condoms as an effective contraception barrier method and refrain from sperm donation during the whole study (starting after informed consent) and for 3 months after the end of treatment with darolutamide.

In addition, participants must agree to utilize a second reliable method of contraception simultaneously. The second method which has to be used by a female partner of childbearing potential can be one of the following methods: diaphragm or cervical cap with spermicide or intra-uterine device or hormone-based contraception. Therefore, contraception methods to be used by male subjects and female partners are in line with clinical trial facilitation group recommendations related to contraception in clinical trials.

  • Ability to understand and follow study-related instructions.
  • Results of alcohol tests are negative at screening and on Study Day -1.
  • Confirmation of the subject's health insurance coverage prior to the first screening examination/visit.

Exclusion Criteria:

  • Existing relevant diseases of vital organs (e.g. liver diseases, heart diseases), central nervous system (for example seizures) or other organs (e.g. diabetes mellitus).
  • Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, elimination and effects of the study drugs will not be normal.
  • Known history of hypersensitivity (or known allergic reaction) to medications including any ingredient of midazolam, benzodiazepines, dabigatran etexilate, or darolutamide.
  • Relevant hepatic disorders like cholestasis, disturbances of bilirubin metabolism, any progressive liver disease.
  • Relevant renal disorders like recurrent glomerulonephritis, renal injury, and renal insufficiency. However, a history of a single episode of uncomplicated nephrolithiasis will not prevent participation.
  • CYP3A4 inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
  • CYP3A4 inducers as well as St John's Wort within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
  • Known BCRP and OATP substrates within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
  • P-gp inducers (e.g. rifampin) within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
  • P-gp inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.

Sites / Locations

  • CRS Clinical-Research-Services Mannheim GmbH

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

BAY1841788/Healthy subjects

Arm Description

Period 1: intake of Midazolam and Dabigatran etexilate at day 1 followed by Period 2: intake of Darolutamide at days 1-11 (twice daily), intake of dabigatran etexilate at days 3 and 9, intake of Midazolam at day 9

Outcomes

Primary Outcome Measures

AUC in plasma of non-conjugated dabigatran (AUC(0-tlast), if AUC cannot be calculated)
Exposure of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose AUC(0-tlast): AUC from time 0 to the last data point > LLOQ
C(max) in plasma of non-conjugated dabigatran
Maximum plasma concentration of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate Cmax: maximum observed drug concentration in measured matrix after single dose administration
AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated)
Exposure of midazolam in plasma following a single administration of midazolam
C(max) in plasma of midazolam
Maximum plasma concentration of midazolam in plasma following a single administration of midazolam

Secondary Outcome Measures

Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE)
AUC in plasma of total dabigatran (AUC(0-tlast), if AUC cannot be calculated)
Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate
C(max) in plasma of total dabigatran
Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate
AUC in plasma of 1-OH midazolam (AUC(0-tlast), if AUC cannot be calculated)
Exposure of 1-OH midazolam in plasma following a single administration of midazolam
C(max) in plasma of 1-OH midazolam
Maximum plasma concentration of 1-OH midazolam in plasma following a single administration of midazolam

Full Information

First Posted
July 26, 2017
Last Updated
November 5, 2018
Sponsor
Bayer
Collaborators
Orion Corporation, Orion Pharma
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1. Study Identification

Unique Protocol Identification Number
NCT03237416
Brief Title
Drug-drug-interaction Study to Assess the Effect of Darolutamide on the Pharmacokinetics of Probe Substrates of CYP3A4 and P-gp in Healthy Male Volunteers
Official Title
A Phase I, Non-randomized, Open-label, Fixed-sequence Study to Investigate the Effect of Darolutamide (ODM-201) on the Pharmacokinetics of a Probe Substrate of CYP3A4 and P-gp in Healthy Male Volunteers
Study Type
Interventional

2. Study Status

Record Verification Date
November 2018
Overall Recruitment Status
Completed
Study Start Date
August 2, 2017 (Actual)
Primary Completion Date
October 5, 2017 (Actual)
Study Completion Date
December 18, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Bayer
Collaborators
Orion Corporation, Orion Pharma

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Evaluate the effect of darolutamide on the pharmacokinetics of a probe CYP3A4 substrate and Pgp substrate

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostatic Neoplasms
Keywords
Drug-drug interaction

7. Study Design

Primary Purpose
Other
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
15 (Actual)

8. Arms, Groups, and Interventions

Arm Title
BAY1841788/Healthy subjects
Arm Type
Experimental
Arm Description
Period 1: intake of Midazolam and Dabigatran etexilate at day 1 followed by Period 2: intake of Darolutamide at days 1-11 (twice daily), intake of dabigatran etexilate at days 3 and 9, intake of Midazolam at day 9
Intervention Type
Drug
Intervention Name(s)
Dabigatran etexilate
Intervention Description
In Period 1, Day 1 a single dose of 75 mg will be administered after breakfast In Period 2, Day 3 a single dose of 75 mg will be administered prior to breakfast In Period 2, Day 9 a single dose of 75 mg will be administered after breakfast
Intervention Type
Drug
Intervention Name(s)
Midazolam
Intervention Description
In Period 1, Day 1 a single dose of 1 mg will be administered after breakfast In Period 2, Day 9 a single dose of 1 mg will be administered after breakfast
Intervention Type
Drug
Intervention Name(s)
BAY1841788 (darolutamide)
Intervention Description
In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast
Primary Outcome Measure Information:
Title
AUC in plasma of non-conjugated dabigatran (AUC(0-tlast), if AUC cannot be calculated)
Description
Exposure of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate AUC: area under the concentration vs. time curve from zero to infinity after single (first) dose AUC(0-tlast): AUC from time 0 to the last data point > LLOQ
Time Frame
Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Title
C(max) in plasma of non-conjugated dabigatran
Description
Maximum plasma concentration of non-conjugated dabigatran in plasma following a single administration of dabigatran etexilate Cmax: maximum observed drug concentration in measured matrix after single dose administration
Time Frame
Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Title
AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated)
Description
Exposure of midazolam in plasma following a single administration of midazolam
Time Frame
PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Title
C(max) in plasma of midazolam
Description
Maximum plasma concentration of midazolam in plasma following a single administration of midazolam
Time Frame
Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Secondary Outcome Measure Information:
Title
Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE)
Time Frame
30 days following last intake of Investigational Product
Title
AUC in plasma of total dabigatran (AUC(0-tlast), if AUC cannot be calculated)
Description
Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate
Time Frame
Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Title
C(max) in plasma of total dabigatran
Description
Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate
Time Frame
Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Title
AUC in plasma of 1-OH midazolam (AUC(0-tlast), if AUC cannot be calculated)
Description
Exposure of 1-OH midazolam in plasma following a single administration of midazolam
Time Frame
Period 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing
Title
C(max) in plasma of 1-OH midazolam
Description
Maximum plasma concentration of 1-OH midazolam in plasma following a single administration of midazolam
Time Frame
PPeriod 1, Day 1: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing Period 2, Day 3 and 9: Predose, and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12, 15, 24, 36, 48, 72 hours post dosing

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
45 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy subject - as determined by the investigator or medically qualified designee based on medical evaluations including medical history, physical examination, laboratory tests and cardiac monitoring. Gender: Male. Age: 45 to 65 years (inclusive) at the screening visit. Race: White. Body mass index (BMI): ≥18.0 and ≤30.0 kg/m2. Agree to use condoms as an effective contraception barrier method and refrain from sperm donation during the whole study (starting after informed consent) and for 3 months after the end of treatment with darolutamide. In addition, participants must agree to utilize a second reliable method of contraception simultaneously. The second method which has to be used by a female partner of childbearing potential can be one of the following methods: diaphragm or cervical cap with spermicide or intra-uterine device or hormone-based contraception. Therefore, contraception methods to be used by male subjects and female partners are in line with clinical trial facilitation group recommendations related to contraception in clinical trials. Ability to understand and follow study-related instructions. Results of alcohol tests are negative at screening and on Study Day -1. Confirmation of the subject's health insurance coverage prior to the first screening examination/visit. Exclusion Criteria: Existing relevant diseases of vital organs (e.g. liver diseases, heart diseases), central nervous system (for example seizures) or other organs (e.g. diabetes mellitus). Incompletely cured pre-existing diseases for which it can be assumed that the absorption, distribution, metabolism, elimination and effects of the study drugs will not be normal. Known history of hypersensitivity (or known allergic reaction) to medications including any ingredient of midazolam, benzodiazepines, dabigatran etexilate, or darolutamide. Relevant hepatic disorders like cholestasis, disturbances of bilirubin metabolism, any progressive liver disease. Relevant renal disorders like recurrent glomerulonephritis, renal injury, and renal insufficiency. However, a history of a single episode of uncomplicated nephrolithiasis will not prevent participation. CYP3A4 inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start of study treatment or during the study. CYP3A4 inducers as well as St John's Wort within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study. Known BCRP and OATP substrates within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study. P-gp inducers (e.g. rifampin) within 28 days or 5 drug half-lives, whichever is longer, before start of study treatment or during the study. P-gp inhibitors within 1 week or 5 drug half-lives, whichever is longer, before start of study treatment or during the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Bayer Study Director
Organizational Affiliation
Bayer
Official's Role
Study Director
Facility Information:
Facility Name
CRS Clinical-Research-Services Mannheim GmbH
City
Mannheim
State/Province
Baden-Württemberg
ZIP/Postal Code
68167
Country
Germany

12. IPD Sharing Statement

Links:
URL
https://clinicaltrials.bayer.com/
Description
Click here to find results for studies related to Bayer Healthcare products.

Learn more about this trial

Drug-drug-interaction Study to Assess the Effect of Darolutamide on the Pharmacokinetics of Probe Substrates of CYP3A4 and P-gp in Healthy Male Volunteers

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