| Eligibility |
Inclusion Criteria:
Subject Inclusion Criteria for Patients with Renal Impairment (Groups 2-4)
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-1C)
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 2-4)
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 St. John's Wort within 7 days prior to admission and during the entire study.
20. Consumption of products containing grapefruit within 5 days prior to dosing until
discharged from the hospital.
21. 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.
22. Participation in another interventional clinical trial within 30 days prior to dosing
until after the last study visit.
23. Hemoglobin < 9.0 g/dL in both men and women at the screening visit.
24. Positive Screening test for HCV, HBV, or HIV.
25. Renal transplant.
26. Scheduled for hemodialysis or peritoneal dialysis
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.
Subject Exclusion Criteria for Healthy Subjects (Groups 1A-1C)
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 St. John's Wort within 7 days prior to admission and during the entire study.
20. Consumption of products containing grapefruit within 5 days prior to dosing until
discharged from the hospital.
21. 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.
22. Participation in another interventional clinical trial within 30 days prior to dosing
until after the last study visit.
23. Hemoglobin < 10.0 g/dL in both men and women at the screening visit.
24. Positive Screening test for HCV, HBV, or HIV.
25. Renal transplant.
26. 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
27. Semen donation for the duration of the study.
28. AST and ALT > 2.0 x ULN.
29. Hyperbilirubinemia > 1.5 x ULN.
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