PK Study in Subjects With Severe Hepatic Impairment
Condition: Severe Hepatic Impairment; Healthy
MeSH terms: Liver Diseases
Intervention: MCI-186
Intervention description: 30 mg MCI-186 will be administered intravenously over 60 minutes.
Intervention MeSH terms: Edaravone
Phase: Phase 1
Study type: Interventional
Primary purpose: Other
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 12.0
Sex: All
Minimum age: 18 Years
Maximum age: 75 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Severe Hepatic Impairment; Healthy

Summary:

      This is an open-label, single-dose study in male and female subjects with severe hepatic
      impairment and in male and female subjects with normal hepatic function.
    

Eligibility criteria:

        Inclusion Criteria:

        All subjects

          -  1. Able to provide written informed consent to participate in this study after reading
             the participant information sheet and Informed Consent Form (ICF), and after having
             the opportunity to discuss the study with the Investigator or designee.

          -  2. Male or female subjects age 18 to 75 years (inclusive) at signature of the ICF.

          -  3. In the Investigator's opinion, subject is able to understand the nature of the
             study and any risks involved in participation, and willing to cooperate and comply
             with the Protocol restrictions and requirements.

          -  4. A body weight of ≥50 kg and a body mass index (Quetelet index) ranging from 18 to
             37 kg/m2 (inclusive) at Screening and Day -1.

          -  5. Female subjects who are:

               1. postmenopausal for at least 1 year, confirmed by follicle-stimulating hormone
                  assessment (>40 mIU/mL), or

               2. surgically sterilised (hysterectomy, bilateral oophorectomy or salpingectomy), or

               3. congenital sterility. Female subjects of child-bearing potential must practice
                  effective contraception (see Protocol body) from the Screening Visit or at least
                  2 weeks before IMP administration, until 30 days after IMP dosing. Male subject
                  must practice effective contraception from the time of IMP dosing until 90 days
                  after IMP dosing. Adhering to strict abstinence is considered an accepted
                  contraceptive method.

        Hepatic impaired subjects (in addition)

          -  6. Diagnosis of cirrhosis due to parenchymal liver disease, which is documented in the
             medical history and physical examination and confirmed by at least one of the
             following: hepatic ultrasound, computed axial tomography scan, magnetic resonance
             imaging and/or liver biopsy. A Child-Pugh classification score of 10 to 14 obtained
             during the Screening period (i.e., within 21 days of IMP administration).

          -  7. Chronic (>6 months) and stable hepatic impairment defined as no clinically
             significant change in disease status at least 14 days before Screening.

          -  8. Acceptable clinical conditions in the opinion of the Investigator on the basis of a
             physical examination, medical history, 12-lead electrocardiogram (ECG), vital signs
             and clinical laboratory tests (biochemistry, haematology, coagulation and urinalysis)
             at Screening, Day -1 and pre-dose on Day 1. Subjects with stable mild chronic
             concurrent diseases, such as degenerative joint disease, controlled diabetes,
             hypertension or hyperlipidaemia, etc. may be included.

        Healthy subjects (in addition)

          -  9. Subjects with normal hepatic function confirmed with tests within the normal
             reference range or results with minor deviations which are not considered by the
             Investigator to be clinically significant.

          -  10. Good health and free from clinically significant illness or disease in the opinion
             of the Investigator on the basis of a physical examination, medical history, ECG,
             vital signs and clinical laboratory tests (biochemistry, haematology, coagulation and
             urinalysis) at Screening, Day -1 and pre-dose on Day 1.

        Exclusion Criteria:

        All subjects

          -  1. Presence or history of severe allergy to food, or any medical product or relevant
             excipient that is of clinical significance.

          -  2. Subjects who have previously been administered MCI-186.

          -  3. As a result of the medical screening process, the Investigator considers the
             subject not suitable for the study.

          -  4. Clinically significant 12-lead ECG abnormalities, including but not limited to,
             corrected QT interval using Fridericia's formula (QTcF) of >450 ms (male subjects) or
             >470 ms (female subjects) at Screening, Day -1 or before dosing.

          -  5. Any other history or condition (surgical or medical) of disease which will increase
             the risk to the subject, will affect the PK of the study drug, or will otherwise
             influence the assessments to be made in this study, in the opinion of the
             Investigator. Subjects who have undergone cholecystectomy may be included.

          -  6. History of drug abuse or tested positive for alcohol or drugs of abuse at Screening
             and Day -1, excluding drugs which may cause a positive drug or abuse test if medically
             indicated or prescribed.

          -  7. Subjects who regularly, or on average, drink more than 35 units of alcohol per week
             (one unit is equivalent to 300 mL of beer, 25 mL of spirits or 150 mL of wine).

          -  8. Presence of active infection requiring antibiotics.

          -  9. Positive test for human immunodeficiency virus antigen/antibody at Screening.

          -  10. Donation of one or more units of blood (450 mL) within 3 months prior to
             Screening, or plasma in the 7 days prior to Screening, or platelets in the 6 weeks
             prior to Screening, or the intention to donate blood within 3 months after the last
             Follow-up assessment.

          -  11. Participation in another study within the last month (if single dose), or at least
             4 months (if multiple dose), or within 10 times the half-life of the respective drug
             (whichever is longer) before Screening. For biologics, the minimum period is at least
             6 months before Screening, the period of the pharmacodynamic effect, or 10 times the
             half life of the respective drug, whichever is longer.

          -  12. Subject is currently taking non-permitted concomitant medication. The subjects
             with normal hepatic function are restricted from use of any concomitant medications
             (including paracetamol) unless discussed and agreed with the Sponsor. In subjects with
             hepatic impairment, the use of prescribed medications is permitted for hepatic or
             concomitant disease as described in the Protocol body.

          -  13. Not willing to abstain from consumption of coffee, tea, cola, energy drinks or
             chocolates from admission to the unit (Day -1) to discharge from the unit (Day 3).

          -  14. Uncontrolled, or untreated hypertension defined as a mean of three repeated
             measurements of systolic blood pressure >180 mmHg and/or diastolic blood pressure >100
             mmHg.

          -  15. Subjects have estimated glomerular filtration rate <60 mL/min/1.73 m2 as
             determined by Modification of Diet in Renal Disease formula.

          -  16. Any condition associated with dehydration.

          -  17. Female subjects:

               1. who have a positive pregnancy test at Screening or on Day -1.

               2. who are pregnant, lactating or planning to become pregnant during the study.

        Hepatic impaired subjects (in addition)

          -  18. Subjects with severe ascites or pleural effusion which will, in the opinion of the
             Investigator, adversely affect the subject's ability to participate in the study.

          -  19. Subjects with severe encephalopathy (Grade III or IV).

          -  20. Subjects with sclerosing cholangitis.

          -  21. Serum albumin <2.0 g/dL.

          -  22. Haemoglobin <10 g/dL.

          -  23. Start of any new medication or any changes to a current dosage within 14 days
             before IMP administration.

        Healthy subjects (in addition)

          -  24. History or presence of any parenchymal hepatic disease.

          -  25. Positive test for hepatitis B surface antigen or hepatitis C virus antibody.

          -  26. History of or active suicidal ideation, or suicide attempt as evidenced by
             positive response to either Question 4 (active suicidal ideation with some intent to
             act) or Question 5 (active suicidal ideation with specific plan and intent) on the
             Columbia-Suicide Severity Rating Scale (C-SSRS; Screening Version).