Clinical trial: Effect of Moderate Hepatic Impairment on the Pharmacokinetics and Metabolism of a Single Dose of Licarbazepine (NCT00424671)

Eligibility criteria:
Inclusion Criteria:

        Control group and hepatically impaired groups:

          -  Male and/or female subjects between 18 and 65 years of age. Female subjects must be
             surgically sterilized or postmenopausal (Postmenopausal women must have no regular
             menstrual bleeding for at least 2 years prior to inclusion. Menopause will be
             confirmed by a plasma FSH level of >40 IU/L. Female subjects must have been surgically
             sterilized at least 6 months prior to screening. Surgical sterilization procedures
             must be supported with clinical documentation made available to sponsor and noted in
             the Relevant Medical History / Current Medical Conditions section of the CRF)

          -  Able to communicate well with the investigator, to understand and comply with the
             requirements of the study. The subjects must be able to provide written informed
             consent prior to study participation, thus excluding subjects with encephalopathy
             grade 3 or 4.

          -  Body mass index (BMI) must be within the range of 18 to 32. For instructions and
             tables see Appendix 5.

        Hepatically impaired group:

          -  Subjects must have liver cirrhosis (hepatic fibrosis with evidence of either micro- or
             macro-nodular regeneration) confirmed by imaging techniques, ultrasound, MRI or CT.

          -  Subjects must have physical signs consistent with a clinical diagnosis of liver
             cirrhosis (e.g., liver firmness to palpation, splenic enlargement, spider angiomata,
             palmar erythema, parotid hypertrophy, testicular atrophy, gynecomastia).

          -  Subjects must have a Child-Pugh Clinical Assessment Score between 7 and 9 at both
             screening and baseline.

          -  Vital signs (after 3 minutes resting in a supine position) which are within the
             following ranges: oral body temperature between 35.0-37.5 °C systolic blood pressure,
             100-180 mm Hg diastolic blood pressure, 60-115 mm Hg pulse rate, 60 - 100 bpm

          -  Subjects with creatinine clearance greater than 50 mL/min (based on Cockcroft and
             Gault formula)

        Control group:

          -  Subjects must be in good health as determined by past medical history, physical
             examination, vital signs, electrocardiogram, and laboratory tests at screening.

          -  Subjects should be matched to the hepatically impaired group in gender, age (±10%),
             smoking status, BMI (±10%).

          -  At Screening, and Baseline, vital signs (systolic and diastolic blood pressure and
             pulse rate) will be assessed after the subject has rested for at least three (3)
             minutes, and again when required after three (3) minutes in the standing position.
             Vital signs should be within the following ranges: oral body temperature between
             35.0-37.5 °C systolic blood pressure, 90-140 mm Hg diastolic blood pressure, 50-90 mm
             Hg pulse rate, 40 - 90 bpm When blood pressure and pulse will be taken again after 3
             minutes standing, there shall be no more than a 20 mm Hg drop in systolic or 10 mm Hg
             drop in diastolic blood pressure and increase in heart rate (>20 bpm) associated with
             clinical manifestation of postural hypotension. All blood pressure measurements at
             other time-points should be assessed with the subject supine, unless stated otherwise
             in the protocol design, and utilizing the same arm for each determination.

        Exclusion Criteria:

        Control group and hepatically impaired group:

          -  Participation in any clinical investigation with experimental drug therapy within four
             weeks prior to dosing or longer as required by local regulation.

          -  Donation or loss of 400 mL or more of blood within two months prior to dosing.

          -  Significant acute, new onset illness (ie, flu, gastroenteritis) within two weeks prior
             to dosi4. A past medical history or clinically significant ECG abnormalities or a
             family history (grandparents, parents and siblings) of a prolonged QT-interval
             syndrome.

          -  History of hyponatremia or seizures.

          -  History of autonomic dysfunction.

          -  Subjects with a consistent, abnormally low total lymphocyte count (< 10% of total
             white blood cell counts)

          -  A known hypersensitivity to the drug.

          -  History of immunocompromise, including a positive HIV (ELISA and Western blot) test
             result.

          -  Evidence of active alcohol or drug abuse as indicated by the laboratory assays
             conducted during the screening or baseline evaluations.

          -  Smokers who report cigarette use of more than 20 cigarettes per day. Urine cotinine
             levels will be measured during screening.

        Hepatically impaired group:

          -  Subjects with a history of unstable, severe, or clinically significant cardiovascular
             disease

          -  Polymorphonuclears <1000/µL or platelets <100'000/µL at inclusion.

          -  Subjects with clinically significant abnormal findings, not consistent with underlying
             disease, upon physical examination, ECG or laboratory evaluation.

          -  Subjects with frank symptoms of encephalopathy or ataxia.

          -  A recent history of acute or chronic bronchospastic disease, including asthma and
             chronic obstructive pulmonary disease, treated or not treated.

          -  Any surgical or medical condition which might significantly alter the absorption,
             distribution, or excretion of any drug.

          -  Current drug treatment with other mood stabilizers, psychotropic drugs and
             antiepileptics.

        Patients must be willing and able to forgo treatment with restricted medications throughout
        the study. Approved prescription medications will be allowed during the course of the study
        on a case by case basis only if the patient has been on a standard treatment regimen for at
        least 3 months and will continue their regular regimen without change throughout the study
        (unless required by protocol or to treat an adverse event) Treatments in table 5.1 are
        allowed in the hepatically impaired group only.

        Control group

          -  Use of any prescription medication within 1 month prior to dosing.

          -  Use of over-the-counter medications or vitamins during 14 days prior to dosing
             (Paracetamol, aspirin or ibuprofen are acceptable, but must be documented in the CRF).

          -  History or presence of liver disease or liver injury as indicated by an abnormal liver
             function profile such as SGOT, SGPT, GGT, alkaline phosphate, or serum bilirubin.

          -  Hepatitis B as indicated by positive HBs Ag or positive anti-HBc IgM result, or
             Hepatitis C as indicated by positive anti-HCV result.

          -  History of acute or chronic bronchospastic disease, including asthma and chronic
             obstructive pulmonary disease, treated or not treated.

          -  Any surgical or medical condition which might significantly alter the absorption,
             distribution, or excretion of any drug. The investigator should be guided by evidence
             of any of the following: History of inflammatory bowel syndrome, gastritis, ulcers,
             gastrointestinal or rectal bleeding, chronic diarrhoea; History of major
             gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel
             resection; History of pancreatic injury or pancreatitis; indications of impaired
             pancreatic function/injury as indicated by abnormal lipase or amylase; History or
             presence of impaired renal function as indicated by abnormal creatinine or BUN values
             or abnormal urinary constituents (e.g., albuminuria); History of urinary obstruction
             or difficulty in voiding polymorphonuclears <1000/µL or platelets <100'000/µL at
             inclusion.

          -  Known history of autoimmune disease such as SLE Other protocol-defined
             inclusion/exclusion criteria may apply
No condition on gender to be admitted to the trial.
Accepts Healthy Volunteers
Subject must be at least 18 Years old.
Subject must be at most 65 Years

Patient description (medical language): A 20-year-old man comes to the emergency due to bleeding after a tooth extraction.  The bleeding has persisted for approximately 30 minutes despite constant direct pressure.  He is a known case of Hemophilia type A treated with FVIII. Blood pressure is 95/60 mm Hg and pulse is 105/min. His weight is 70 Kg. Family history is positive for Hemophilia type A in his maternal uncle. He also has a lipoma on his left arm which he plans to remove surgically. His FVIII activity is 40%.

Patient description (patient's own words): I got my tooth extracted and I could not stop bleeding for 30 min. I'm a 20 yo dude but I have Hemophilia type A treated with FVIII. My blood pressure was 95/60 and my pulse 105/min. I'm 70 kg. My uncle on my mom's side also has type A hemophilia. I also have a fatty swelling on my left arm and I was supposed to remove it. My FVIII activity was 40%.

Does the patient match the trial criteria? Contradiction