Clinical trial NCT04881994: A Study to Learn How Finerenone (BAY94-8862) Moves Into, Through and Out of the Body, How it Affects the Body, and How Safe it is in Adult Participants With Different Degrees of Reduced Liver Function and in Healthy Participants With Similar Age, Weight and Gender Distribution
Official title: Investigation of the Pharmacokinetics, Safety, and Tolerability of Finerenone (BAY 94-8862) in Subjects With Hepatic Impairment (Classified as Child Pugh A or B) and in Age-, Weight-, and Gender-matched Healthy Subjects Following a Single Oral Dose in a Single-center, Non-randomized, Non-controlled, Non-blinded, Observational Study With Group Stratification
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Worsening Chronic Heart Failure
Diabetic Nephropathy
Keywords: Child Pugh A
Child Pugh B
Liver impairment
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2021-05-11
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Researchers are looking for a better way to treat people who have worsening of chronic heart failure, a long-term condition where the heart does not pump blood as well as it should, as well as to treat patients who have diabetic nephropathy, a long-term, progressive decrease in the kidneys' ability to work properly in patients with diabetes mellitus.

In this study researchers wanted to learn more about a new substance called finerenone (BAY94-8862). Finerenone is a substance that blocks the activation of a protein in the body called mineralocorticoid receptor (MR). An increased activation of MR is involved in the development of hypertension, organ damage and worsening of heart failure.

The researchers studied how finerenone moves into, through and out of the body. The researchers also looked at how safe finerenone is and how it affects the body. The main purpose of this study was to help researchers develop recommendations for the amount of the substance (the dosing) to be given to patients with reduced liver function.


Eligibility criteria: Inclusion Criteria:

All participants

* The informed consent must be signed before any study specific tests or procedures are done;
* Male and female white participants;
* Women of childbearing potential can only be included in the study if a pregnancy test is negative. Women of childbearing potential must agree to use adequate contraception when sexually active. 'Adequate contraception' is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices). This applies from signing the informed consent form until follow up visit.
* Body mass index (BMI): 18 to 34 kg/m2 (both inclusive);
* Age: 18 to 79 years (both inclusive) at the screening visit;
* Men must agree to use adequate contraception when being sexually active. This applies from signing of the informed consent until 12 weeks after the last study drug administration. 'Adequate contraception' is defined as any combination of at least 2 effective methods of birth control, of which at least one is a physical barrier (e.g. condoms with hormonal contraception or implants or combined oral contraceptives, certain intrauterine devices);
* Ability to understand and follow study-related instructions.

Participants with hepatic impairment

* Participants with documented liver cirrhosis confirmed by histopathology, e.g., previous liver biopsy, laparoscopy, ultrasound, or fibroscan;
* Participants with hepatic impairment (Child Pugh A or B);
* Participants with stable liver disease in the last 2 months.

Healthy participants

* Healthy male and female white participants;
* Mean age and body weight in the control group and in the two groups with hepatic impairment (Child Pugh A and B) should not vary by more than +/-10 years and +/-10 kg;
* Gender matched.

Exclusion Criteria:

All participants

* Participants with a medical disorder, condition, or history of such that would impair the participant's ability to participate or complete this study in the opinion of the investigator or the sponsor;
* Medical history of Kock pouch (ileostomy after proctocolectomy);
* Febrile illness within 1 week prior to admission to study center;
* Relevant diseases within the last 4 weeks prior to admission;
* Known severe allergies, non-allergic drug reactions, or multiple drug allergies;
* Known hypersensitivity to the study drugs;
* Participants with diagnosed malignancy within the past 5 years;
* Participants with psychiatric disorders which may disable the participants to consent;
* Use of the following co-medications from 2 weeks before until 4 days after study drug administration:

  * CYP3A4 inducers (e.g. St. John´s wort, rifampicin, carbamazepin, phenytoin, phenobarbital, bosentan, efavirenz, etravirine, nevirapine)
  * weak to moderate CYP3A4 inhibitors (e.g. grapefruit juice and other grapefruit containing products, erythromycin, saquinavir, amiodarone, verapamil, fluconazole, diltiazem)
  * strong inhibitors of CYP3A4 (e.g. itraconazole, ketoconazol, posaconazole, voriconazole, atazanavir, ritonavir, nelfinavir or other inhibitors of human immunodeficiency virus (HIV) protease, clarithromycin, telithromycin, nefazodon, telaprevir, boceprevir) or
  * gemfibrozil (a strong inhibitor of CYP2C8)
* Positive urine drug screening;
* For women of childbearing potential: positive pregnancy test;
* Positive results for human immunodeficiency virus 1 and 2 antibodies (HIV-Ag/Ab).

Participants with hepatic impairment

* Severe cerebrovascular or cardiac disorders, e.g., myocardial infarction less than 6 months prior to dosing, congestive heart failure of New York Heart Association grade III or IV, severe arrhythmia requiring antiarrhythmic treatment;
* Evidence of hepatic encephalopathy related to chronic liver disease \>grade 2 (exclusion by Number Connection Test (NCT);
* Participants with percutaneous transluminal coronary angioplasty or coronary artery bypass graft less than 6 months prior to study drug administration;
* History of bleeding within the past 3 months;
* Thrombotic disorder;
* Participants with diabetes mellitus with a glycohemoglobin A1c (HbA1c) \>10%;
* Severe ascites of more than 6 L (estimated by ultrasound);
* Participants with primary and secondary biliary cirrhosis;
* Participants with sclerosing cholangitis;
* Failure of any other major organ system other than the liver;
* Severe infection, malignancy, or psychosis, or any clinically significant illness within 4 weeks prior to study drug administration.

Primary outcomes:
measure: Area under the concentration versus time curve from zero to infinity (AUC) of finerenone in plasma
timeFrame: 0 hour pre-dose to 96 hour post-dose
measure: Area under the concentration versus time curve from zero to infinity of unbound finerenone (AUCu) in plasma
timeFrame: 0 hour pre-dose to 96 hour post-dose
measure: Maximum observed drug concentration (Cmax) of finerenone in plasma
timeFrame: 0 hour pre-dose to 96 hour post-dose
measure: Maximum observed drug concentration of unbound finerenone (Cmax,u) in plasma
timeFrame: 0 hour pre-dose to 96 hour post-dose
Secondary outcomes:
measure: Number of participants with adverse events
timeFrame: From the start of study treatment up to 3 days after study treatment
Other outcomes:
measure: Percentage of fraction of free (unbound) (fu) finerenone in plasma
timeFrame: 1 hour post-dose
measure: Area under the concentration versus time curve from zero to infinity divided by dose per kilogram body weight (AUCnorm) of finerenone in plasma
timeFrame: 0 hour pre-dose to 96 hour post-dose
measure: Maximum observed drug concentration divided by dose per kilogram body weight (Cmax,norm) of finerenone in plasma
timeFrame: 0 hour pre-dose to 96 hour post-dose
measure: Time to reach maximum concentration (tmax) of finerenone
timeFrame: 0 hour pre-dose to 96 hour post-dose
measure: Half-life associated with the terminal slope (t1/2) of finerenone
timeFrame: 0 hour pre-dose to 96 hour post-dose
Locations:
city: Kiel
country: Germany
state: Schleswig-Holstein
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: Heinig R, Lambelet M, Nagelschmitz J, Alatrach A, Halabi A. Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone (BAY 94-8862) in Individuals with Mild or Moderate Hepatic Impairment. Eur J Drug Metab Pharmacokinet. 2019 Oct;44(5):619-628. doi: 10.1007/s13318-019-00547-x.