Single-Dose Study to Evaluate the PKs of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function
Single-Dose Study to Evaluate the PKs of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function
This is a Phase I, open-label, single dose, sequential group study to compare the safety and
 pharmacokinetics of pretomanid in the following two groups of subjects: 1) those with mild,
 moderate, and severe renal impairment including those with End Stage Renal Disease (ESRD) not
 needing dialysis; and 2) matched subjects with normal renal function. The study will be
 conducted in two parts. Part A will enroll subjects from Groups 1A and 2 (i.e. 6 healthy
 matched controls and 6 subjects with ESRD, not on dialysis). A decision to enroll subjects
 into Part B (i.e. to investigate mild, moderate and severe renal impairment) will be
 conducted after the pharmacokinetics (PK) of the parent compound and safety of subjects
 enrolled in Part A have been reviewed. Part B will be conducted if the results of Part A
 demonstrate that patients with ESRD, not on dialysis have different exposures to pretomanid
 that may impact safety or efficacy relative to the exposures of healthy subjects. If the
 decision is taken to conduct Part B, 6 subjects each with mild, moderate and severe renal
 impairment (Groups 3, 4, 5) will be enrolled together with additional healthy matched
 subjects (Groups 1B-1D). Part B, treatment Groups 3, 4, and 5 will be initiated concurrently
 when each subject in Groups 1A and 2 has completed Part A of the study. The approximate
 patient involvement will be 3 months. The primary objective is to evaluate the PK of
 pretomanid after a single oral dose of 200 mg in subjects with renal impairment compared to
 matched healthy controls.
This is a Phase I, open-label, single dose, sequential group study to compare the safety and
 pharmacokinetics of pretomanid in the following two groups of subjects: 1) those with mild,
 moderate, and severe renal impairment including those with End Stage Renal Disease (ESRD) not
 needing dialysis; and 2) matched subjects with normal renal function. The study will be
 conducted in two parts. Part A will enroll subjects from Groups 1A and 2 (i.e. 6 healthy
 matched controls and 6 subjects with ESRD, not on dialysis). A decision to enroll subjects
 into Part B (i.e. to investigate mild, moderate and severe renal impairment) will be
 conducted after the pharmacokinetics (PK) of the parent compound and safety of subjects
 enrolled in Part A have been reviewed. Part B will be conducted if the results of Part A
 demonstrate that patients with ESRD, not on dialysis have different exposures to pretomanid
 that may impact safety or efficacy relative to the exposures of healthy subjects. If the
 decision is taken to conduct Part B, 6 subjects each with mild, moderate and severe renal
 impairment (Groups 3, 4, 5) will be enrolled together with additional healthy matched
 subjects (Groups 1B-1D). Part B, treatment Groups 3, 4, and 5 will be initiated concurrently
 when each subject in Groups 1A and 2 has completed Part A of the study. The approximate
 patient involvement will be 3 months. The primary objective is to evaluate the PK of
 pretomanid after a single oral dose of 200 mg in subjects with renal impairment compared to
 matched healthy controls. The secondary objectives are 1) to assess the safety profile of a
 single oral dose of 200 mg pretomanid in renally impaired subjects to matched healthy
 controls; and 2) to measure representative plasma pretomanid metabolites (M19 and M50) for
 analysis.
Inclusion Criteria:

 Subject Inclusion Criteria for Patients with Renal Impairment (Groups 2-5)

 1. Have the ability to understand the requirements of the study and have provided written
 informed consent* before any study related procedure is performed.

 *As evidence by signature on an informed consent document approved by the IRB

 2. Agree to abide by the study restrictions.

 3. Are between the ages of 18 and 70, inclusive, at the time of enrollment.

 4. Must have mild, moderate, severe or end stage renal disease but are not on dialysis.

 5. Are free from tobacco/nicotine usage (30-day minimum from screening visit).

 6. Have QTc interval on electrocardiogram (ECG) < 500 msec.

 7. Have a body mass index of 18 to 35 kg/m^2.

 8. Women of childbearing potential** must use an acceptable contraception method*** for
 the duration of the study.

 **Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy,
 hysterectomy, implanted contraceptive device placement (permanent, non-surgical,
 non-hormonal sterilization) with documented radiological confirmation test at least 90
 days after the procedure, and still menstruating or < 1 year has passed since the last
 menses if menopausal.

 ***Includes, non-male sexual relationships, abstinence from sexual intercourse with a
 male partner, monogamous relationship with vasectomized partner who has been
 vasectomized for 180 days or more prior to the subject receiving study product,
 barrier methods such as condoms or diaphragms/cervical caps with spermicide, effective
 intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants,
 injectables or oral contraceptives ("the pill").

 9. If subject is male and capable of reproduction, agrees to avoid fathering a child for
 the duration of the study by using an acceptable method of birth control****.

 ****In addition to the use of a barrier method (condom) unless 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
 #8, and/or abstinence from sexual intercourse with women.

 10. Women of childbearing potential must have a negative urine pregnancy test within 24
 hours prior to receipt of study product

 Subject Inclusion Criteria for Healthy Subjects (Groups 1A-1D)

 1. Have the ability to understand the requirements of the study and have provided written
 informed consent* before any study related procedure is performed.

 *As evidence by signature on an informed consent document approved by the IRB.

 2. Agree to abide by the study restrictions.

 3. Are healthy male or non-pregnant female, between the ages of 18 and 70, inclusive,
 with normal GFR > / = 90 at screening.

 4. Are free from tobacco/nicotine usage (30-day minimum from screening visit).

 5. Have a normal QTc interval < 500 msecs on electrocardiogram (ECG).

 6. Have a body mass index of 18 to 35 kg/m^2.

 7. Women of childbearing potential** must use an acceptable contraception method*** for
 the duration of the study.

 -  Not sterilized via tubal ligation, bilateral oophorectomy, salpingectomy,
 hysterectomy, implanted contraceptive device placement (permanent, non-surgical,
 non-hormonal sterilization) with documented radiological confirmation test at
 least 90 days after the procedure, and still menstruating or <1 year has passed
 since the last menses if menopausal.

 -  Includes, non-male sexual relationships, abstinence from sexual intercourse
 with a male partner, monogamous relationship with vasectomized partner who
 has been vasectomized for 180 days or more prior to the subject receiving
 study product, barrier methods such as condoms or diaphragms/cervical caps
 with spermicide, effective intrauterine devices, NuvaRing(R), and licensed
 hormonal methods such as implants, injectables or oral contraceptives ("the
 pill").

 8. If subject is male and capable of reproduction, agrees to avoid fathering a child for
 the duration of the study by using an acceptable method of birth control****.

 ****In addition to the use of a barrier method (condom) unless 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
 #7, and/or abstinence from sexual intercourse with women.

 9. Women of childbearing potential must have a negative urine pregnancy test within 24
 hours prior to receipt of study product

 Exclusion Criteria:

 Subject Exclusion Criteria for Patients with Renal Impairment (Groups 2-5)

 1. History of known active TB.

 2. History of peptic ulcer disease

 3. Have known hypersensitivity to pretomanid or any of the excipients

 4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by
 the Principal Investigator (PI)).

 5. Any clinically significant ECG abnormality at screening* *Note: the following can be
 considered not clinically significant:

 -  Heart rate < / = 50 beats per minute (bpm) (sinus bradycardia with heart rate
 between 45 and 49, inclusive, is acceptable only in younger athletic subjects)

 -  Mild first degree A-V block (P-R interval > 0.23 seconds)

 -  Right or left axis deviation

 -  Incomplete right bundle branch block

 -  Isolated left anterior fascicular block (left anterior hemiblock) in younger
 athletic subjects

 6. History of or screening results show a QTc interval > / = 500 msecs.

 7. Family history of Long-QT Syndrome or sudden death without a preceding diagnosis of a
 condition*** that could be causative of sudden death

 ***such as known coronary artery disease or congestive heart failure (CHF) or terminal
 cancer.

 8. Inability to swallow tablets.

 9. History of fever or documented fever (oral temperature > 100.4 degrees Fahrenheit) in
 the 48 hours prior to admission to the hospital.

 10. Resting pulse rate <50 or > 100 bpm at Screening.

 11. At Screening blood pressure > / = 20 mm Hg systolic or 10 mm Hg diastolic above
 baseline**** (sitting).

 ****Baseline is most recent blood pressure in the last 3 months if not similar to
 control group.

 12. Current hypokalemia or hypomagnesemia.

 13. Positive result of urine drug screen or blood alcohol screen prior to hospital
 admission.

 14. Significant history of drug and/or food allergies (as deemed by the PI).

 15. For women, subject is pregnant (positive test for urine HCG at Screening or Check-in),
 breastfeeding or planning to conceive for the duration of the study.

 16. Women who are breastfeeding or lactating.

 17. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid
 or delamanid.

 18. Treatment with strong CYP450 enzyme inducers or inhibitors***** within 7 days prior to
 admission or during the study, unless****** the substance would not likely impact the
 validity of the study results.

 *****except hormonal contraceptives

 ******in the opinion of the site investigator

 19. Use of any therapeutic agents known to alter any major organ function (e.g.,
 barbiturates, opiates, phenothiazines, cimetidine, etc.) within 30 days prior to
 dosing and during the entire study.

 20. Use of St. John's Wort within 7 days prior to admission and during the entire study.

 21. Consumption of products containing grapefruit within 5 days prior to dosing until
 discharged from the hospital.

 22. Donation of whole blood or blood products > 500 mL within 30 days and plans to donate
 during the study or up to 14 days after dosing.

 23. Participation in another interventional clinical trial within 30 days prior to dosing
 until after the last study visit.

 24. Hemoglobin < 9.0 g/dL in both men and women at the screening visit.

 25. Positive Screening test for HCV, HBV, or HIV.

 26. Renal transplant.

 27. Scheduled for hemodialysis or peritoneal dialysis

 28. 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 investigator

 29. Semen donation for the duration of the study.

 30. AST and ALT > 2.0 x ULN.

 31. Hyperbilirubinemia > 1.5 x ULN.

 Subject Exclusion Criteria for Healthy Subjects (Groups 1A-1D)

 1. History of known active TB.

 2. History of peptic ulcer disease

 3. Have known hypersensitivity to pretomanid or any of the excipients

 4. History of any clinically significant uncontrolled cardiac abnormality (as deemed by
 the Principal Investigator (PI).

 5. Any clinically significant ECG abnormality at screening*.

 *Note: the following can be considered not clinically significant:

 -  Heart rate > / = 50 beats per minute (bpm) (sinus bradycardia with heart rate
 between 45 and 49, inclusive, is acceptable only in younger athletic subjects)

 -  Mild first degree A-V block (P-R interval > 0.23 seconds)

 -  Right or left axis deviation

 -  Incomplete right bundle branch block

 -  Isolated left anterior fascicular block (left anterior hemiblock) in younger
 athletic subjects

 6. Family history of Long-QT Syndrome or sudden death without a preceding diagnosis of a
 condition** that could be causative of sudden death

 **such as known coronary artery disease or congestive heart failure (CHF) or terminal
 cancer.

 7. Inability to swallow tablets.

 8. History of fever or documented fever (oral temperature > / = 100.4 degrees Fahrenheit)
 in the 48 hours prior to admission to the hospital.

 9. Resting pulse rate < 50 or > 100 bpm at Screening.

 10. At Screening blood pressure > 140/90 mm Hg or < 90/65 mm Hg (sitting).

 11. History of or screening results show a QTc interval > / = 500 msecs.

 12. History of hypokalemia or hypomagnesemia.

 13. Positive result of urine drug screen or blood alcohol screen prior to hospital
 admission.

 14. Significant history of drug and/or food allergies (as deemed by the PI).

 15. For women, subject is pregnant (positive test for urine HCG at Screening or hospital
 admission), breastfeeding or planning to conceive for the duration of the study.

 16. Women who are breastfeeding or lactating.

 17. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid
 or delamanid.

 18. Treatment with strong CYP450 enzyme inducers or inhibitors*** within 7 days prior to
 admission or during the study, unless**** the substance would not likely impact the
 validity of the study results.

 ***except hormonal contraceptives

 ****in the opinion of the site investigator

 19. Use of any therapeutic agents known to alter any major organ function (e.g.,
 barbiturates, opiates, phenothiazines, cimetidine, etc.) within 30 days prior to
 dosing and during the entire study.

 20. Use of St. John's Wort within 7 days prior to admission and during the entire study.

 21. Consumption of products containing grapefruit within 5 days prior to dosing until
 discharged from the hospital.

 22. Donation of whole blood or blood products > 500 mL within 30 days and/or plans to
 donate during the study or up to 14 days after dosing.

 23. Participation in another interventional clinical trial within 30 days prior to dosing
 until after the last study visit.

 24. Hemoglobin < 10.0 g/dL in both men and women at the screening visit.

 25. Positive Screening test for HCV, HBV, or HIV.

 26. Renal transplant.

 27. 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 investigator

 28. Semen donation for the duration of the study.

 29. AST and ALT > 2.0 x ULN.

 30. Hyperbilirubinemia > 1.5 x ULN.