Durham, North Carolina 27710


Purpose:

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.


Study summary:

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.


Criteria:

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.


Study is Available At:


Original ID:

13-0053


NCT ID:

NCT02422524


Secondary ID:

HHSN272201300017I


Study Acronym:


Brief Title:

Pretomanid in Adults With Hepatic Impairment


Official Title:

A Phase I, Single Dose, 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


Overall Status:

Recruiting


Study Phase:

Phase 1


Genders:

N/A


Minimum Age:

18 Years


Maximum Age:

70 Years


Quick Facts

Healthy Volunteers
Oversight Has DMC
Study Is FDA Regulated
Study Is Section 801
Has Expanded Access

Study Source:

National Institute of Allergy and Infectious Diseases (NIAID)


Oversight Authority:

  • United States: Federal Government
  • United States: Institutional Review Board
  • United States: Food and Drug Administration


Reasons Why Stopped:


Study Type:

Interventional


Study Design:


Number of Arms:

4


Number of Groups:

0


Total Enrollment:

36


Enrollment Type:

Anticipated


Overall Contact Information

Primary Contact:Julius Wilder
19196848111
julius.wilder@dm.duke.edu

Study Dates

Start Date:December 11, 2017
Completion Date:July 11, 2020
Completion Type:Anticipated
Primary Completion Date:June 11, 2020
Primary Completion Type:Anticipated
Verification Date:January 2020
Last Changed Date:January 16, 2020
First Received Date:April 16, 2015

Study Outcomes

Outcome Type:Primary Outcome
Measure:AUC(0-infinity): Area under the concentration time-curve extrapolated to infinity at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Primary Outcome
Measure:AUC(0-last): Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Primary Outcome
Measure:CL/F: Apparent oral clearance calculated from Dose/AUC(0-infinifty) at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Cmax: Maximum Pretomanid concentration at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Primary Outcome
Measure:t(1/2): Apparent terminal elimination half-life at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Tmax: Time of maximum Pretomanid concentration at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Primary Outcome
Measure:Vd/F: Apparent Volume of Distribution at specified pre-dose and post-dose time points
Time Frame:Day 1 to Day 5
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Incidence of related adverse events
Time Frame:Day 1 to Day 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Incidence of serious adverse events
Time Frame:Day 1 to Day 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Severity of related adverse events
Time Frame:Day 1 to Day 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Severity of serious adverse events
Time Frame:Day 1 to Day 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Summary of ECG data
Time Frame:Day -1 and Day 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Summary of physical examination findings (height at baseline, and weight at serial time points)
Time Frame:Day -1 to Day 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Summary of safety laboratory parameters
Time Frame:Day -1, 2, 5, and 12
Safety Issues:False
Outcome Type:Secondary Outcome
Measure:Summary of vital signs at serial time points
Time Frame:Day -1 to Day 12
Safety Issues:False

Study Interventions

Intervention Type:Drug
Name:PA-824
Description:Pretomanid (PA-824) is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg Pretomanid on day 1.
Arm Name:Child-Pugh A (Mild hepatic impairment)

Study Arms

Study Arm Type:Experimental
Arm Name:Child-Pugh A (Mild hepatic impairment)
Description:6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
Study Arm Type:Experimental
Arm Name:Child-Pugh B (Moderate hepatic impairment)
Description:6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
Study Arm Type:Experimental
Arm Name:Child-Pugh C (Severe hepatic impairment)
Description:6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1
Study Arm Type:Experimental
Arm Name:Non-hepatically impaired controls
Description:18 matched Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1

Study Agencies

Agency Class:NIH
Agency Type:Lead Sponsor
Agency Name:National Institute of Allergy and Infectious Diseases (NIAID)

Sample and Retention Information

There are no available Sample and Retention Information

Study References

There are no available Study References

Data Source: ClinicalTrials.gov

Date Processed: January 21, 2020

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