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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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03237416
Recruitment Status : Completed
First Posted : August 2, 2017
Last Update Posted : November 6, 2018
Sponsor:
Collaborator:
Orion Corporation, Orion Pharma
Information provided by (Responsible Party):
Bayer

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

Condition or disease Intervention/treatment Phase
Prostatic Neoplasms Drug: Dabigatran etexilate Drug: Midazolam Drug: BAY1841788 (darolutamide) Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 15 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Actual Study Start Date : August 2, 2017
Actual Primary Completion Date : October 5, 2017
Actual Study Completion Date : December 18, 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Drug Reactions

Arm Intervention/treatment
Experimental: BAY1841788/Healthy subjects
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
Drug: Dabigatran etexilate
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

Drug: Midazolam
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

Drug: BAY1841788 (darolutamide)
In Period 2, Days 1-11 600 mg twice a day (as 2 x 300 mg tablets) will be administered after breakfast




Primary Outcome Measures :
  1. AUC in plasma of non-conjugated dabigatran (AUC(0-tlast), if AUC cannot be calculated) [ 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 ]
    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

  2. C(max) in plasma of non-conjugated dabigatran [ 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 ]
    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

  3. AUC in plasma of midazolam (AUC(0-tlast), if AUC cannot be calculated) [ 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 ]
    Exposure of midazolam in plasma following a single administration of midazolam

  4. C(max) in plasma 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 ]
    Maximum plasma concentration of midazolam in plasma following a single administration of midazolam


Secondary Outcome Measures :
  1. Number of subjects with study drug-related treatment-emergent Adverse Event (TEAE) [ Time Frame: 30 days following last intake of Investigational Product ]
  2. AUC in plasma of total dabigatran (AUC(0-tlast), if AUC cannot be calculated) [ 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 ]
    Exposure of total dabigatran in plasma following a single administration of dabigatran etexilate

  3. C(max) in plasma of total dabigatran [ 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 ]
    Maximum plasma concentration of total dabigatran in plasma following a single administration of dabigatran etexilate

  4. AUC in plasma of 1-OH midazolam (AUC(0-tlast), if AUC cannot be calculated) [ 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 ]
    Exposure of 1-OH midazolam in plasma following a single administration of midazolam

  5. C(max) in plasma of 1-OH 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 ]
    Maximum plasma concentration of 1-OH midazolam in plasma following a single administration of midazolam



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   45 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03237416


Locations
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Germany
CRS Clinical-Research-Services Mannheim GmbH
Mannheim, Baden-Württemberg, Germany, 68167
Sponsors and Collaborators
Bayer
Orion Corporation, Orion Pharma
Investigators
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Study Director: Bayer Study Director Bayer
Additional Information:
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT03237416    
Other Study ID Numbers: 18860
2017-001116-11 ( EudraCT Number )
First Posted: August 2, 2017    Key Record Dates
Last Update Posted: November 6, 2018
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Bayer:
Drug-drug interaction
Additional relevant MeSH terms:
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Prostatic Neoplasms
Genital Neoplasms, Male
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Prostatic Diseases
Midazolam
Dabigatran
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Physiological Effects of Drugs
Anti-Anxiety Agents
Tranquilizing Agents
Psychotropic Drugs
Anesthetics, Intravenous
Anesthetics, General
Anesthetics
GABA Modulators
GABA Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Anticoagulants