Single-Dose Study to Evaluate the PKs of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function

Study Overview
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Brief Summary
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This is a Phase I, open-label, single dose, sequential group study to compare the safety and pharmacokinetics of pretomanid in the following groups of subjects: 1) subjects with severe renal impairment including those with End Stage Renal Disease (ESRD) not needing dialysis, and subjects with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) subjects with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively. The study will be conducted following a reduced Pharmacokinetic (PK) study design in Part A and Part B. Part A will enroll subjects from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 subjects with severe renal impairment and ESRD, not on dialysis). A decision will be made after the PK of pretomanid and safety of subjects enrolled in Part A have been reviewed. If Part A demonstrated different pretomanid exposures at least a 50-100% increase in Area under the Curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched subjects with normal renal function), then the reduced PK study will extend to the full PK study to enroll subjects into Part B (i.e., to investigate mild, and moderate renal impairment) and all enrollment will be initiated concurrently in Part B groups (1B, 1C, 3 and 4). If no difference in PK and safety is observed in Part A, then no further study (Part B) is recommended The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in subjects with renal impairment compared to matched healthy controls.

Detailed Description
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This is a Phase I, open-label, single dose, sequential group study to compare the safety and pharmacokinetics of pretomanid in the following groups of subjects: 1) subjects with severe renal impairment including those with End Stage Renal Disease (ESRD) not needing dialysis, and subjects with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) subjects with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively. The study will be conducted following a reduced Pharmacokinetic (PK) study design in Part A and Part B. Part A will enroll subjects from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 subjects with severe renal impairment and ESRD, not on dialysis). A decision will be made after the PK of pretomanid and safety of subjects enrolled in Part A have been reviewed. If Part A demonstrated different pretomanid exposures at least a 50-100% increase in Area under the Curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched subjects with normal renal function), then the reduced PK study will extend to the full PK study to enroll subjects into Part B (i.e., to investigate mild, and moderate renal impairment) and all enrollment will be initiated concurrently in Part B groups (1B, 1C, 3 and 4). If no difference in PK and safety is observed in Part A, then no further study (Part B) is recommended The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine 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 evaluate the PK profiles or representative pretomanid metabolites (M19 and M50) in plasma and urine.

Official Title
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A Phase I, Open-Label, Single-Dose Study to Evaluate the Pharmacokinetics and Safety of Pretomanid in Subjects With Renal Impairment Compared to Subjects With Normal Renal Function

Conditions
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Renal Impairment, Tuberculosis

Intervention / Treatment
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* Drug: PA-824


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject Inclusion Criteria for Patients with Renal Impairment (Groups 2-4) 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 Agree to abide by the study restrictions. Are between the ages of 18 and 70, inclusive, at the time of enrollment. Must have mild, moderate, severe or end stage renal disease but are not on dialysis. Are free from tobacco/nicotine usage (30-day minimum from screening visit). Have QTc interval on electrocardiogram (ECG) < 500 msec. Have a body mass index of 18 to 35 kg/m^2. 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). 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. 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) 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. Agree to abide by the study restrictions. Are healthy male or non-pregnant female, between the ages of 18 and 70, inclusive, with normal GFR > / = 90 at screening. Are free from tobacco/nicotine usage (30-day minimum from screening visit). Have a normal QTc interval < 500 msecs on electrocardiogram (ECG). Have a body mass index of 18 to 35 kg/m^2. 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). 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. 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) History of known active TB. History of peptic ulcer disease Have known hypersensitivity to pretomanid or any of the excipients History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI)). 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 History of or screening results show a QTc interval > / = 500 msecs. 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. Inability to swallow tablets. History of fever or documented fever (oral temperature > 100.4 degrees Fahrenheit) in the 48 hours prior to admission to the hospital. Resting pulse rate <50 or > 100 bpm at Screening. 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. Current hypokalemia or hypomagnesemia. Positive result of urine drug screen or blood alcohol screen prior to hospital admission. Significant history of drug and/or food allergies (as deemed by the PI). 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. Women who are breastfeeding or lactating. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid or delamanid. 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 Use of St. John's Wort within 7 days prior to admission and during the entire study. Consumption of products containing grapefruit within 5 days prior to dosing until discharged from the hospital. 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. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit. Hemoglobin < 9.0 g/dL in both men and women at the screening visit. Positive Screening test for HCV, HBV, or HIV. Renal transplant. Scheduled for hemodialysis or peritoneal dialysis 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 Semen donation for the duration of the study. AST and ALT > 2.0 x ULN. Hyperbilirubinemia > 1.5 x ULN. Subject Exclusion Criteria for Healthy Subjects (Groups 1A-1C) History of known active TB. History of peptic ulcer disease Have known hypersensitivity to pretomanid or any of the excipients History of any clinically significant uncontrolled cardiac abnormality (as deemed by the Principal Investigator (PI). 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 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. Inability to swallow tablets. History of fever or documented fever (oral temperature > / = 100.4 degrees Fahrenheit) in the 48 hours prior to admission to the hospital. Resting pulse rate < 50 or > 100 bpm at Screening. At Screening blood pressure > 140/90 mm Hg or < 90/65 mm Hg (sitting). History of or screening results show a QTc interval > / = 500 msecs. History of hypokalemia or hypomagnesemia. Positive result of urine drug screen or blood alcohol screen prior to hospital admission. Significant history of drug and/or food allergies (as deemed by the PI). 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. Women who are breastfeeding or lactating. Any contraindication to the use of nitromidazoles, or prior treatment with pretomanid or delamanid. 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 Use of St. John's Wort within 7 days prior to admission and during the entire study. Consumption of products containing grapefruit within 5 days prior to dosing until discharged from the hospital. 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. Participation in another interventional clinical trial within 30 days prior to dosing until after the last study visit. Hemoglobin < 10.0 g/dL in both men and women at the screening visit. Positive Screening test for HCV, HBV, or HIV. Renal transplant. 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 Semen donation for the duration of the study. AST and ALT > 2.0 x ULN. Hyperbilirubinemia > 1.5 x ULN.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Part A Group 1A<br>6 healthy participants with normal estimated Glomerular Filtration Rate (eGFR > / = 90 mL/min) matched to Group 2 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and weight at dosing (+/- 20% of weight) will receive a single oral dose of 200 mg pretomanid | Drug: PA-824<br>* PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.<br>|
| Experimental: Part A Group 2<br>6 participants with Severe renal impairment; Stage 4, Modification of Diet in Renal Disease (MDRD) (eGFR 15-29 mL/min) and End Stage Renal Disease (ESRD) not on dialysis: Stage 5, Modification of Diet in Renal Disease (MDRD) with estimated Glomerular Filtration Rate (eGFR < 15 mL/min) matched to Group 1A will receive a single oral dose of 200 mg pretomanid | Drug: PA-824<br>* PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.<br>|
| Active Comparator: Part B Group 1B<br>6 healthy participants with normal eGFR of > / = 90 mL/min matched to Group 3 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and weight at dosing (+/- 20% of weight ) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed | Drug: PA-824<br>* PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.<br>|
| Active Comparator: Part B Group 1C<br>6 healthy participants with normal eGFR > / = 90 mL/min matched to Group 4 by race, gender, age (+/- 10 years, but between 18 to 70 years of age) and weight at dosing (+/- 20% of weight) will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed | Drug: PA-824<br>* PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.<br>|
| Experimental: Part B Group 3<br>6 participants with mild renal impairment: Stage 2, MDRD (eGFR 60-89 mL/min) matched to Group 1B will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed | Drug: PA-824<br>* PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.<br>|
| Experimental: Part B Group 4<br>6 participants with moderate renal impairment: Stage 3, MDRD (eGFR = 30-59 mL/min) matched to Group 1C will receive a single oral dose of 200 mg pretomanid after the PK and safety of subjects enrolled in Part A have been reviewed | Drug: PA-824<br>* PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Apparent clearance of drug from plasma after drug administration (CL/F) |  | Up to 96 hours | 
| Apparent first-order terminal elimination rate constant (Lambda z) of pretomanid |  | Up to 96 hours | 
| Apparent volume of distribution (Vd/F) |  | Up to 96 hours | 
| Area under the plasma concentration-time curve from time zero to infinity (AUC-infinity) |  | Up to 96 hours | 
| Area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) |  | Up to 96 hours | 
| Cumulative amount of pretomanid excreted into the urine from time 0 to the time t (Ae(0-t)) |  | Up to 96 hours | 
| Fraction of pretomanid dose excreted into the urine (Ae%Dose) |  | Up to 96 hours | 
| Maximum plasma concentration of pretomanid (Cmax) |  | Up to 96 hours | 
| Renal clearance (CLR) of pretomanid |  | Up to 96 hours | 
| Terminal-phase elimination half-life (t1/2) |  | Up to 96 hours | 
| Time to peak (maximum) (Tmax) |  | Up to 96 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentrations of pretonamid metabolites (M19 and M50) in plasma and urine | As measured by validated bioanalytical methods | Up to 96 hours | 
| Excretion of representative metabolites M19 and M50 in urine |  | Up to 96 hours | 
| Mean change from baseline in alanine aminotransferase (ALT) |  | Through Day 12 | 
| Mean change from baseline in aspartate aminotransferase (AST) |  | Through Day 12 | 
| Mean change from baseline in blood urea nitrogen (BUN) |  | Through Day 12 | 
| Mean change from baseline in creatinine |  | Through Day 12 | 
| Mean change from baseline in estimated glomerular filtration rate (eGFR) |  | Through Day 12 | 
| Mean change from baseline in hemoglobin |  | Through Day 12 | 
| Mean change from baseline in magnesium |  | Through Day 12 | 
| Mean change from baseline in potassium |  | Through Day 12 | 
| Mean change from baseline in total bilirubin |  | Through Day 12 | 
| Mean change in blood pressure from baseline |  | Through Day 12 | 
| Mean change in oral temperature from baseline |  | Through Day 12 | 
| Mean change in pulse from baseline |  | Through Day 12 | 
| Mean change in the ECG QTc interval from baseline |  | Through Day 5 | 
| Number of subjects reporting adverse events (AEs) |  | Day 1 to Day 12 | 
| Plasma levels of representative metabolites M19 and M50 |  | Up to 96 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Open-Label, Pretomanid, Renal Pharmacokinetic, Safety, Single-Dose