Study of the What the Body Does to the Drug in Subjects With Mild, Moderate, and Severe Liver Dysfunction
Condition: Attention Deficit Hyperactivity Disorder (ADHD); Binge-Eating Disorder Disorder
MeSH terms: Hyperkinesis; Bulimia; Attention Deficit Disorder with Hyperactivity; Feeding and Eating Disorders; Binge-Eating Disorder
Study type: Interventional
Phase: Phase 1

Summary: 
      Study of the what the body does to the drug in subjects with mild, moderate, and sever liver
      dysfunction (not working properly)
    

Detailed description: 
      This is an open-label single-dose study. Approximately 40 total subjects will be enrolled. In
      each of the 3 hepatic impairment groups (mild hepatic dysfunction [Child-Pugh score of 5 -
      6], moderate hepatic dysfunction [Child-Pugh score of 7 - 9], severe hepatic dysfunction
      [Child Pugh score of 10 - 12]) approximately 10 subjects will be enrolled in order to achieve
      8 subjects completing the study in each group. In addition, approximately 8 12 healthy
      subjects with non-impaired hepatic function will be enrolled to match the subjects in the
      hepatic impairment groups. Subjects with non-impaired hepatic function may be matched to more
      than 1 hepatically impaired subject and may be matched to impaired subjects in different
      Child-Pugh categories; ie, mild, moderate, and/or severe. In order to obtain matched control
      subjects, after each subject with hepatic impairment has completed the study, a subject with
      non-impaired hepatic function will be sought; the already enrolled matched control subjects
      will be checked for a match prior to screening and enrollment of a new match. Each matched
      control subject will be selected to be demographically comparable to one or more hepatic
      dysfunction subjects in age (± 10 years), gender, and weight (± 20%). Subjects who do not
      complete the study may be replaced in order to achieve 8 subjects completing the study in
      each hepatic impairment group and appropriate healthy matched control subjects.

      The study will consist of Screening (Days -28 to -2), Inpatient Period (Days 1 through 7),
      and Follow-up (Days 8 28). Screening assessments will be used to classify the degree of a
      subject's hepatic impairment. The degree of impairment will be assigned based on the
      Child-Pugh category for classification for severity of liver disease. Subjects will be
      admitted to the clinical site on the day prior to administration of study drug and remain
      inpatient until discharge on Day 7 (approximately 168 hours after treatment). Subjects may be
      discharged on Day 5, if in the investigator's opinion they can be relied upon to return for
      the Day 6 and 7 visits. The following safety assessments will be performed: physical
      examination; vital signs; clinical laboratory evaluations (hematology, prothrombin time,
      serum chemistry, and urinalysis); AE collection, ECGs, and C SSRS. Blood and urine samples
      will be collected for analyses of study drug concentrations and plasma protein binding. The
      blood sampling duration (648 hours postdose [Day 28]) was chosen to determine the terminal
      half-life of dasotraline, with the expectation that this time may be extended in hepatically
      impaired subjects compared to the control subjects. A blood sample for pharmacogenetics will
      be collected only from subjects who provide separate informed consent to collect this sample.
      The sample will be utilized for potential evaluation of genetic polymorphisms upon selected
      enzymatic pathway(s) responsible for the metabolism of dasotraline; this sample is optional
      for participation in the study.

      Exclusion Criteria continued from Eligibility Section:

      Any subject with hepatic impairment meeting any of the following criteria will be excluded:

        1. Subject who does not tolerate venipuncture or has poor venous access that would cause
           difficulty for collecting blood samples.

        2. Subject with a Child-Pugh classification score ≥ 13.

        3. Subject with encephalopathy grade > 1.

        4. Subject experienced hepatic coma within the 12 months prior to screening.

        5. Subject, who has any abnormal medical history, physical examination, ECG, or laboratory
           result which, in the opinion of the investigator and medical monitor, may affect the
           safety of the subject. Subjects with abnormal medical history that is stable may be
           enrolled.

        6. Subject with clinically significant cardiovascular disease, including any of the
           following:

             1. history of cardiac surgery or myocardial infarction within 6 months prior to
                screening;

             2. unstable coronary artery disease;

             3. congestive heart failure greater than New York Heart Association (NHYA) Functional
                Class 1;

             4. cardiac arrhythmia or conduction disturbance resulting in atrioventricular block
                (AV) block, ventricular fibrillation or causing syncope, near syncope or other
                alterations of mental status;

             5. severe mitral or aortic valvular disease;

             6. moderately symptomatic peripheral vascular disorder;

             7. uncontrolled hypertension (systolic blood pressure > 200 mmHg and/or diastolic
                blood pressure > 110 mmHg). However, subjects with stable mild hypertension who are
                controlled with the same medication over the 2 months prior to screening may be
                enrolled in the study.

             8. any other cardiovascular condition which, in the opinion of the investigator or
                medical monitor, might interfere with the results or conduct of the study.

        7. Subject has had hepatic transplant or has systemic lupus erythematosus or hepatic
           carcinoma, or is on the liver transplant list.

        8. Subject has estimated creatinine clearance ≤ 60 mL/min according to the Cockcroft-Gault
           equation.

        9. Subject with therapeutic paracentesis within 15 days prior to administration of study
           drug.

       10. Subject has had an acute illness within 30 days prior to administration of study drug.

       11. Subject who has had a febrile illness within 14 days prior to administration of study
           drug.

       12. Subject has a disorder or history of a condition that may interfere with drug
           absorption, distribution, metabolism or excretion including clinically significant
           abnormality of the renal system, a history of malabsorption, or previous
           gastrointestinal surgery that could affect drug absorption or metabolism.

       13. Subject has a presence or history of any medically diagnosed, clinically significant
           psychiatric disorder (including intellectual disability and substance-related
           disorders). Note: For subject with a history of substance-related disorder or alcohol
           related disorder as defined by DSM 5 criteria the condition must have been more than 1
           year prior to screening.

       14. Subject has an average weekly alcohol intake that exceeds 21 units per week (males up to
           age 65) and 14 units per week (males over age 65 and females). 1 unit = 12 oz or 360 mL
           or beer; 5oz or 150 mL of wine; 1.5 oz or 45 mL of distilled spirits.

       15. Subject is unwilling to stop alcohol consumption for at least 48 hours prior to
           admission on Day -1 (as confirmed by breath or urine alcohol test) through Day 7.

       16. Subject has had a portal systemic shunt including portal-systemic shunts (PSS) and
           transjugular I ntrahepatic portosystemic shunt (TIPS).

       17. Subject has shown evidence of hepatorenal syndrome.

       18. Subject has required treatment for gastrointestinal bleeding or encephalopathy within
           the 12 months prior to screening.

       19. Subject has had significant blood loss (> 500 mL) or donated blood, plasma, or other
           blood products within 30 days prior to administration of study drug.

       20. Subject with known significant bleeding diathesis, which could preclude multiple
           venipunctures (for example, history of recent bleeding from esophageal varices, or
           platelet count less than 40,000/microliters or hemoglobin < 10 g/dL).

       21. Subject has exhibited evidence of acute viral hepatitis between the start of screening
           and study drug administration.

       22. Subject answers "yes" to "Suicidal Ideation" Items 4 or 5 on the C SSRS. Subjects who
           have significant findings for suicidal ideation upon completion of the C SSRS must be
           referred to the investigator for follow-up evaluation.

       23. Subject tests positive at screening for the HIV 1 or HIV 2 antibody.

       24. Subject has a positive urine alcohol test.

       25. Subject with albumin, potassium, magnesium and/or calcium outside the normal limits of
           the reference range may be included at the investigator's discretion.

       26. Subject has used any drugs known or suspected to affect hepatic or renal clearance
           capacity within 30 days prior to administration of study drug.

       27. Subject has taken any prescription or OTC medications, herbal tea, energy drinks, herbal
           products (eg, St John's Wort, milk thistle, etc) or supplement/supra-therapeutic doses
           of vitamins within 5 half lives or 14 days (whichever is longer) prior to administration
           of study drug or is anticipated to need any medication during the study, with the
           exception of those permitted by the protocol or approved by the investigator and medical
           monitor. Note: All drugs will be reviewed on a case-by-case basis by the medical monitor
           and are prohibited unless deemed acceptable by the investigator and medical monitor.

       28. Subject who has previously received dasotraline.

       29. Subject has history of intolerance to stimulants.

       30. Subject has a history of allergic reaction or has a known or suspected sensitivity to
           any substance that is contained in the study drug formulation.

       31. Subject has taken any investigational drug within 30 days or 5 half lives (whichever is
           longer) prior to administration of study drug.

       32. Subject is currently a heavy user of nicotine, ie, smoking more than 20 cigarettes (eg,
           1 pack) per day or equivalent (eg, e-vapor cigarette, pipe, cigar, chewing tobacco,
           nicotine patch or nicotine gum).

       33. Subject cannot comply with the smoking restrictions of the study site during the
           confinement period or is unable or unwilling to refrain from smoking and tobacco use for
           2 hours prior to study drug administration and 4 hours following administration.

       34. Subject has a need for special dietary restrictions, unless the restrictions are
           approved by the investigator and medical monitor.

       35. Subject with a history or suspicion of barbiturate, amphetamine, or narcotic abuse
           and/or positive screening result for any of these substances. Subjects who are currently
           receiving prescription narcotic pain relievers may be included at the investigator's and
           medical monitor's discretion.

       36. Subject who received live vaccine(s) within 1 month prior to screening, or intends to
           during the study. Note: Influenza vaccine will be allowed, if administered > 21 days
           prior to study drug administration.
    

Intervention name(s): dasotraline
Intervention type(s): Drug
Intervention description(s): dasotraline 8mg capsule/day
Other intervention name(s): SEP225289
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Attention deficit hyperactivity disorder (ADHD),; Binge-Eating Disorder (BED)