Clinical trial NCT02422524: Pretomanid in Adults With Hepatic Impairment
Official title: A Phase I, Single Dose, Open-Label Study Comparing the Pharmacokinetics and Safety of Pretomanid in Subjects With Mild, Moderate, and Severe Hepatic Impairment to Matched, Non-Hepatically Impaired Subjects
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Tuberculosis
Keywords: Hepatic
impairment
PA-824
Pharmacokinetics
Safety
Tuberculosis
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2015-04-21
Enrollment: 14
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a Phase 1, single dose (200 mg), open-label 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 24 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.

Detailed description: This is a Phase 1, single dose (200 mg), open-label 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 24 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.

Eligibility 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, Aspartate Aminotransferase (AST), Alanine Aminotransferase (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, Aspartate Aminotransferase (AST), Alanine Aminotransferase (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. Aspartate Aminotransferase (AST) or Alanine Aminotransferase (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 Pharmacokinetics (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. A positive blood screen for HIV.
14. 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.
15. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, weightlifting, competitive sports) during the course of the study.
16. 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.
17. A Heart Rate-Corrected QT Interval (Fridericia's Formula) (QTcF) interval \> 450 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.
18. 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
19. Any clinically significant ECG abnormality, in the opinion of the site investigator, at screening and at admission to the confinement/hospital unit.
20. Donation of \> 500 mL blood within the 30 days prior to admission to the confinement/hospital unit.
21. Plans to donate blood during the study or up to 14 days after dosing.
22. 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 Pharmacokinetics (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 Central Nervous System (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. A positive blood screen for HIV.
13. A positive blood screen for hepatitis B surface antigen (HBsAg), or hepatitis C antibody.
14. 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).
15. A history of alcohol abuse or dependence within the past 1 month prior to admission to the confinement/hospital unit.
16. Unwillingness to abstain from engaging in strenuous physical activity (e.g. running, bicycling, weightlifting, 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 Heart Rate-Corrected QT Interval (Fridericia's Formula) (QTcF) interval \> 450 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 of 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.

Primary outcomes:
measure: AUC(0-infinity): Area Under the Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points
timeFrame: Day 1 to Day 5
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
timeFrame: Day 1 to Day 5
measure: CL/F: Apparent Oral Clearance Calculated From Dose/AUC(0-infinifty) at Specified Pre-dose and Post-dose Time Points
timeFrame: Day 1 to Day 5
measure: Cmax: Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points
timeFrame: Day 1 to Day 5
measure: t(1/2): Apparent Terminal Elimination Half-life at Specified Pre-dose and Post-dose Time Points
timeFrame: Day 1 to Day 5
measure: Tmax: Time of Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points
timeFrame: Day 1 to Day 5
measure: Vd/F: Apparent Volume of Distribution at Specified Pre-dose and Post-dose Time Points
timeFrame: Day 1 to Day 5
Secondary outcomes:
measure: Incidence and Severity of Related Adverse Events
timeFrame: Day 1 to Day 12
measure: Incidence and Severity of Serious Adverse Events
timeFrame: Day 1 to Day 12
measure: Number of Participants With Abnormal ECG Data
timeFrame: Day 12
measure: Number of Participants With Abnormal Physical Exam Findings
timeFrame: Day 3, 4, 5 and 12
measure: Number of Participants With Abnormal Safety Laboratory Parameters
timeFrame: Day 2, 5, and 12
measure: Number of Participants With Abnormal Vital Signs
timeFrame: Days 1, 2, 3, 4, 5, and 12
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Saint Louis University Center for Vaccine Development
state: Missouri
city: Durham
country: United States
facility: Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit
state: North Carolina
Study officials:
References: