Pretomanid in Adults With Hepatic Impairment
Pretomanid in Adults With Hepatic Impairment
This is a Phase 1, single dose (200 mg), open-label, sequential group study comparing the
 pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic
 impairment to matched, non-hepatically impaired subjects. There will be approximately 36
 total subjects, adult males and females, 18 to 70 years of age, inclusive. The study will be
 conducted at 2 sites, study duration is approximately 15 months, and subject participation
 duration is approximately 5 weeks (including screening). Primary objective: To evaluate the
 pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and
 severe hepatic impairment (as assessed by Child-Pugh score), relative to matched
 non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single
 oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as
 assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.
This is a Phase 1, single dose (200 mg), open-label, sequential group study comparing the
 pharmacokinetics and safety of Pretomanid in subjects with mild, moderate, and severe hepatic
 impairment to matched, non-hepatically impaired subjects. This study will enroll
 approximately 6 subjects with mild hepatic impairment (Child-Pugh A), approximately 6
 subjects with moderate hepatic impairment (Child-Pugh B), approximately 6 subjects with
 severe hepatic impairment (Child-Pugh C), and approximately 18 matched non-hepatically
 impaired subjects. Non-hepatically impaired subjects in the control group will be matched to
 subjects with hepatic impairment based on age (+/- 10 years) and body weight (+/- 20 percent)
 as measured at screening (Visit 00A). There will be approximately 36 total subjects, adult
 males and females, 18 to 70 years of age, inclusive. The study will be conducted at 2 sites,
 study duration is approximately 15 months, and subject participation duration is
 approximately 5 weeks (including screening). Primary objective: To evaluate the
 pharmacokinetics of a single oral dose of Pretomanid in subjects with mild, moderate, and
 severe hepatic impairment (as assessed by Child-Pugh score), relative to matched
 non-hepatically impaired subjects. Secondary objective: To evaluate the safety of a single
 oral dose of Pretomanid in subjects with mild, moderate, and severe hepatic impairment (as
 assessed by Child-Pugh score), relative to matched non-hepatically impaired subjects.
Inclusion Criteria:

 Inclusion Criteria for Patients with Hepatic Impairment (Groups 1-3):

 1. Subject is able to give voluntary written informed consent before any study related
 procedure is performed.

 2. 18-70 years of age, inclusive.

 3. Acceptable laboratory values* obtained at screening (within 21 days prior to admission
 to the confinement/hospital unit) and either at or within 72 hours of admission to the
 confinement/hospital unit.

 -  Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase,
 albumin, and urinalysis deemed not clinically significant by the investigator.

 4. Hepatic impairment classified as Child-Pugh class A (mild), B (moderate), or C
 (severe) criteria at screening for Groups 1, 2, or 3, respectively, and documented
 evidence of hepatic cirrhosis*.

 *by biopsy, nuclear scan, CT, MRI, ultrasound, or other clinically acceptable methods

 5. If female, not of childbearing potential* or agrees to avoid becoming pregnant by
 using acceptable contraception** during the duration of the study.

 *Non-childbearing potential is defined as being post-menopausal for at least 2 years,
 status after bilateral oophorectomy or status after hysterectomy.

 -  Females of childbearing potential must agree to use two acceptable methods of
 contraceptives: bilateral tubal ligation; barrier method (condom) by the male
 partner (even if vasectomized); hormonal contraceptives; intrauterine
 contraceptive devices; diaphragm in combination with contraceptive jelly, cream,
 foam, or spermicide; and abstinence from sexual intercourse with men.

 6. If subject is male and capable of reproduction, agrees to avoid fathering a child for
 three months after dosing by using an acceptable method of birth control*.

 -  In addition to the use of a barrier method (condom) even if vasectomized,
 acceptable methods of birth control are restricted to a monogamous relationship
 with a woman who agrees to use acceptable contraception as outlined in inclusion
 criterion #5, and abstinence from sexual intercourse with women.

 7. If the subject is female, a negative serum pregnancy test at screening and a negative
 urine pregnancy test at admission to the confinement/hospital unit.

 8. Willingness to comply with all protocol requirements.

 Inclusion Criteria for Non-Hepatically Impaired Controls (Group 4):

 1. Subject is able to give voluntary written informed consent before any study related
 procedure is performed.

 2. 18-70 years of age, inclusive.

 3. Subject is a healthy volunteer as determined by no clinically significant findings
 from medical history, physical examination, vital signs, and 12-lead ECG as determined
 by the Site Investigator.

 4. Acceptable laboratory values* obtained at screening (within 21 days prior to admission
 to the confinement/hospital unit) and either at or within 72 hours of admission to the
 confinement/hospital unit.

 *Chemistry, complete blood count, AST, ALT, total bilirubin, alkaline phosphatase,
 albumin, and urinalysis within the reference range for the test laboratory, unless
 deemed not clinically significant by the investigator.

 5. If female, not of childbearing potential* or agrees to avoid becoming pregnant by
 using acceptable contraception** during the duration of the study.

 *Non-childbearing potential is defined as being post-menopausal for at least 2 years,
 status after bilateral oophorectomy or status after hysterectomy.

 **Females of childbearing potential must agree to use two acceptable methods of
 contraceptives: bilateral tubal ligation; barrier method (condom) by the male partner
 (even if vasectomized); hormonal contraceptives; intrauterine contraceptive devices;
 diaphragm in combination with contraceptive jelly, cream, foam, or spermicide; and
 abstinence from sexual intercourse with men.

 6. If subject is male and capable of reproduction, agrees to avoid fathering a child for
 three months after dosing by using an acceptable method of birth control*.

 *In addition to the use of a barrier method (condom) even if vasectomized, acceptable
 methods of birth control are restricted to a monogamous relationship with a woman who
 agrees to use acceptable contraception as outlined in inclusion criterion #5, and
 abstinence from sexual intercourse with women.

 7. If the subject is female, a negative serum pregnancy test at screening and a negative
 urine pregnancy test at admission to the confinement/hospital unit.

 8. Willingness to comply with all protocol requirements.

 Exclusion Criteria:

 Exclusion Criteria for Patients with Hepatic Impairment (Groups 1-3):

 1. Hypokalemia (< 3.5mEq/L), severe hypomagnesemia (< 1.1 mg/dL) or severe hypocalcemia
 (< 7.5 mg/dL).

 2. AST or ALT > 10 times the upper limit of normal.

 3. Creatinine clearance < 60 ml/min.

 4. Inability to swallow tablets.

 5. Presence of any condition or finding* which would jeopardize subject safety, impact
 study result validity, or diminish the subject's ability to undergo all study
 procedures and assessments**.

 *in the opinion of the site investigator

 **e.g., inability to draw PK samples

 6. History of fever or documented fever (oral temperature > / = 100.4 degrees F or > / =
 38.0 degrees C) in the 48 hours prior to admission to the the confinement/hospital
 unit.

 7. Currently breastfeeding.

 8. History of chronic tobacco/nicotine use (> 10 cigarettes per day for 3 months minimum
 prior to admission).

 9. History of clinically significant allergy or severe side effects with nitroimidazoles
 (e.g., Metronidazole and related substances and azole antifungals or aromatase
 inhibitors).

 10. Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30
 days prior to screening.

 11. Use of any over the counter (OTC) medication* within 7 days prior to admission to the
 confinement/hospital unit, unless** the substance would not likely impact the validity
 of the study results.

 *including vitamins and herbal supplements, cough and cold medications.

 **in the opinion of the site investigator

 12. Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the
 confinement/hospital unit, unless** the substance would not likely impact the validity
 of the study results.

 *except hormonal contraceptives

 **in the opinion of the site investigator NOTE: See list of CYP450 enzyme altering
 drugs under the concomitant medications section.

 13. Treatment with any drugs* known to prolong the electrocardiographic QT interval within
 15 days prior to admission to the confinement/hospital unit..

 *Including excessive chronic caffeine (> six 8 oz cups of brewed coffee daily or > 3
 energy drinks daily), theophylline (> 600 mg/day), or ephedrine (> 300 mg/day) use.

 14. A positive blood screen for HIV.

 15. A positive alcohol breath test (or other suitable test for alcohol) or a urine screen
 test for drugs of abuse* at screening and at admission to the confinement/hospital
 unit.

 -  Amphetamines, barbiturates, cocaine metabolites, marijuana, opiates,
 phencyclidine (PCP).

 NOTE: Results of the urine screen test can be ignored if in the opinion of the PI the
 results can be explained by the concomitant medications history.

 16. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running,
 bicycling, weight lifting, competitive sports) during the course of the study.

 17. Consumption of grapefruit juice in the 48 hours before admission to the
 confinement/hospital unit, or the inability to abstain from these until completion of
 Day 12.

 18. A QTcF interval > 440 msec (males) or > 450 msec (females) at screening (Visit 00A) or
 admission to the confinement/hospital unit (Visit 00B) or a history of prolonged QTc
 interval.

 19. A family history* of Long QT Syndrome, premature cardiac death**, or sudden death
 without a preceding diagnosis of a condition*** that could be causative of sudden
 death.

 *parents

 **due to ischemic heart disease or sudden cardiac death before 55 years of age (men)
 or 65 years of age (women)

 ***such as known coronary artery disease, congestive heart failure, or terminal cancer

 20. Any clinically significant ECG abnormality, in the opinion of the site investigator,
 at screening and at admission to the confinement/hospital unit.

 21. Donation of > 500 mL blood within the 30 days prior to admission to the
 confinement/hospital unit.

 22. Plans to donate blood during the study or up to 14 days after dosing.

 23. Persons with a transjugular intrahepatic portosystemic shunt.

 Exclusion Criteria for Non-Hepatically Impaired Controls (Group 4):

 1. Inability to swallow tablets.

 2. Presence of any condition or finding* which would jeopardize subject safety, impact
 study result validity, or diminish the subject's ability to undergo all study
 procedures and assessments**.

 *in the opinion of the site investigator

 **e.g., inability to collect PK samples

 3. History of fever or documented fever (oral temperature > / = 100.4 degrees F or > / =
 38.0 degrees C) in the 48 hours prior to admission to the confinement/hospital unit.

 4. Currently breastfeeding.

 5. History of chronic tobacco/nicotine use (> 10 cigarettes per day for 3 months minimum
 prior to admission to the confinement/hospital unit).

 6. History of seizures (other than febrile seizures during childhood) or known or
 suspected CNS disorders that may predispose to seizures.

 7. History of clinically significant allergy or severe side effects with nitroimidazoles
 (e.g., Metronidazole and related substances and azole antifungals or aromatase
 inhibitors).

 8. Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30
 days prior to screening.

 9. Use of any over the counter (OTC) medication* within 7 days prior to admission to the
 confinement/hospital unit, unless** the substance would not likely impact the validity
 of the study results.

 *including vitamins and herbal supplements, antacids, cough and cold medications.

 **in the opinion of the site investigator

 10. Use of prescription medication except hormonal contraceptives within 30 days prior to
 admission to the confinement/hospital unit, unless* the substance would not likely
 impact study result validity.

 *in the opinion of the site investigator

 11. Treatment with CYP450 enzyme altering drugs* within 7 days prior to admission to the
 confinement/hospital unit, unless** the substance would not likely impact the validity
 of the study results.

 *except hormonal contraceptives

 **in the opinion of the site investigator NOTE: See list of CYP450 enzyme altering
 drugs under the concomitant medications section.

 12. Treatment with any drugs* known to prolong the electrocardiographic QT interval within
 15 days prior to admission to the confinement/hospital unit.

 *Including excessive chronic caffeine (> six 8 oz cups of brewed coffee daily or > 3
 energy drinks daily), theophylline (> 600 mg/day), or ephedrine (> 300 mg/day) use.

 13. A positive blood screen for HIV.

 14. A positive blood screen for hepatitis B surface antigen (HBsAg), or hepatitis C
 antibody.

 15. A positive alcohol breath test (or other suitable test for alcohol) or a urine screen
 test for drugs of abuse* at screening and at admission to the confinement/hospital
 unit.

 *Amphetamines, barbiturates, benzodiazepines, cocaine metabolites, marijuana, opiates,
 phencyclidine (PCP).

 16. A history of alcohol abuse or dependence within the past 1 month prior to admission to
 the confinement/hospital unit.

 17. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running,
 bicycling, weight lifting, competitive sports) during the course of the study.

 18. Consumption of grapefruit juice in the 48 hours before admission to the
 confinement/hospital unit, or the inability to abstain from these until completion of
 Day 12.

 19. A QTcF interval > 440 msec (males) or > 450 msec (females) at screening (Visit 00A) or
 admission to the confinement/hospital unit (Visit 00B) or a history of prolonged QTc
 interval.

 20. A family history* of Long QT Syndrome, premature cardiac death**, or sudden death
 without a preceding diagnosis of a condition*** that could be causative of sudden
 death.

 *parents

 **due to ischemic heart disease or sudden cardiac death before 55 years of age (men)
 or 65 years of age (women)

 ***such as known coronary artery disease, congestive heart failure, or terminal cancer

 21. Any clinically significant ECG abnormality, in the opinion of the site investigator,
 at screening and at admission to the confinement/hospital unit.

 22. Donation of > 500 mL of blood within the 30 days prior to admission to the
 confinement/hospital unit.

 23. Plans to donate blood during the study or up to 14 days after dosing.

 24. Persons with a transjugular intrahepatic portosystemic shunt.