Pretomanid in Adults With Hepatic Impairment

NCT02422524 | Terminated Phase 1 Results FDA Drug

• 1 other identifier: 13-0053
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 2

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.

Conditions

Tuberculosis

Keywords

Hepatic; impairment; PA-824; Pharmacokinetics; Safety; Tuberculosis

Outcome Measures

Primary Outcomes (7)

• AUC(0-infinity): Area Under the Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points

  AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant.

  Day 1 to Day 5

• 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

  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 was calculated by noncompartmental analysis using the linear up log down method.

  Day 1 to Day 5

• CL/F: Apparent Oral Clearance Calculated From Dose/AUC(0-infinifty) at Specified Pre-dose and Post-dose Time Points

  Apparent oral clearance was calculated by noncompartmental analysis using the formula Dose/AUC(0-infinity).

  Day 1 to Day 5

• Cmax: Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points

  Maximum Pretomanid concentration is the maximum observed drug concentration in blood plasma at specified pre-dose and post-dose timepoints.

  Day 1 to Day 5

• t(1/2): Apparent Terminal Elimination Half-life at Specified Pre-dose and Post-dose Time Points

  Apparent terminal half-life at specified pre-dose and post-dose timepoints was estimated by ln(2)/Lambda\_z, where Lambda\_z is the elimination rate constant.

  Day 1 to Day 5

• Tmax: Time of Maximum Pretomanid Concentration at Specified Pre-dose and Post-dose Time Points

  Time of maximum Pretomanid concentration (Tmax) at specified pre-dose and post-dose timepoints.

  Day 1 to Day 5

• Vd/F: Apparent Volume of Distribution at Specified Pre-dose and Post-dose Time Points

  Apparent Volume of Distribution at specified pre-dose and post-dose timepoints is the volume that the total amount of administered drug would occupy to provide the same concentration as it currently is in blood plasma divided by the bioavailability. It is calculated by Dose/\[Lambda\_z x AUC(0-infinity)\]

  Day 1 to Day 5

Secondary Outcomes (6)

• Incidence and Severity of Related Adverse Events

  Day 1 to Day 12

• Incidence and Severity of Serious Adverse Events

  Day 1 to Day 12

• Number of Participants With Abnormal ECG Data

  Day 12

• Number of Participants With Abnormal Physical Exam Findings

  Day 3, 4, 5 and 12

• Number of Participants With Abnormal Safety Laboratory Parameters

  Day 2, 5, and 12

Study Arms (4)

Child-Pugh A (Mild hepatic impairment)

EXPERIMENTAL

6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1

Drug: PA-824

Child-Pugh B (Moderate hepatic impairment)

EXPERIMENTAL

6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1

Drug: PA-824

Child-Pugh C (Severe hepatic impairment)

EXPERIMENTAL

6 Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1

Drug: PA-824

Non-hepatically impaired controls

EXPERIMENTAL

18 matched Subjects will receive a single oral dose of 200mg Pretomanid tablets on day 1

Drug: PA-824

Interventions

PA-824 DRUG

Pretomanid (PA-824) is a nitroimidazooxazine. All subjects will receive a single oral dose of 200 mg Pretomanid on day 1.

Child-Pugh A (Mild hepatic impairment); Child-Pugh B (Moderate hepatic impairment); Child-Pugh C (Severe hepatic impairment); Non-hepatically impaired controls

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject is able to give voluntary written informed consent before any study related procedure is performed.
• years of age, inclusive.
• 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.
• 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
• 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.
• 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\*.
• 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.
• Willingness to comply with all protocol requirements.
• Subject is able to give voluntary written informed consent before any study related procedure is performed.
• years of age, inclusive.
• 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.

You may not qualify if:

• Hypokalemia (\< 3.5mEq/L), severe hypomagnesemia (\< 1.1 mg/dL) or severe hypocalcemia (\< 7.5 mg/dL).
• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) \> 10 times the upper limit of normal.
• Creatinine clearance \< 60 ml/min.
• Inability to swallow tablets.
• 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
• 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.
• Currently breastfeeding.
• History of chronic tobacco/nicotine use (\> 10 cigarettes per day for 3 months minimum prior to admission).
• History of clinically significant allergy or severe side effects with nitroimidazoles (e.g., Metronidazole and related substances and azole antifungals or aromatase inhibitors).
• Receipt of an investigational drug, vaccine or biologic in a clinical trial within 30 days prior to screening.
• 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

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (2)

Saint Louis University Center for Vaccine Development

St Louis, Missouri, 63104-1015, United States

Location

Duke University School of Medicine - Duke Clinical Research Institute - Duke Clinical Research Unit

Durham, North Carolina, 27710-4000, United States

Location

MeSH Terms

Conditions

Tuberculosis

Interventions

pretomanid

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Results Point of Contact

• Title: Julius Wilder, MD, PhD
• Organization: Duke University

julius.wilder@duke.edu

919-668-3063

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 16, 2015
• First Posted: April 21, 2015
• Study Start: March 29, 2018
• Primary Completion: August 26, 2023
• Study Completion: November 17, 2023
• Last Updated: June 10, 2025
• Results First Posted: March 5, 2025

Record last verified: 2017-12-14

Locations

US (2)