Single-dose Study in Two Panels of Healthy Adult Participants to Assess Immediate-Release and Dispersible Formulations of Pretomanid

An Open-label, Randomized, Four-period, Crossover Study in Two Panels of Healthy Adult Subjects to Assess the Relative Bioavailability, Food Effect, and Dose-dependence of Single-dose Immediate-release and Single-dose Dispersible Formulations of Pretomanid

This is a single-dose, open-label, randomized, four-period, four-treatment, crossover study in healthy adult subjects.

Study Overview

• Status: Completed
• Conditions: Multi-drug Resistant Tuberculosis
• Intervention / Treatment: Drug: Pretomanid

Detailed Description

This is a single-dose, open-label, randomized, four-period, four-treatment, crossover study in healthy adult subjects. Each panel of 24 subjects will be randomized according to the same 4-sequence, 4- period Williams design, in which each participant will receive four single-dose treatments. Subjects in Panel 1 will receive all treatments after consuming an FDA standard high-fat, high-calorie breakfast following an overnight fast of at least 10 hours. Subjects in Panel 2 will receive all treatments directly following an overnight fast of at least 10 hours. The two panels will be investigated concurrently.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78217
      • Worldwide Clinical Trials Early Phase Services, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Key Inclusion Criteria:

• Male or female. Females must not be pregnant or breastfeeding.
• Willing and able to comply with the contraception requirements.
• Between 19 and 50 years of age (inclusive) at the time of screening.
• Body mass index (BMI) between 18.50 and 32 kg/m2 (inclusive) and weighs a minimum of 50 kg.

Key Exclusion Criteria:

• History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, oncologic, or psychiatric disease or any other condition that, in the opinion of the Investigator, would jeopardize the safety of the subject or the validity of the study results.
• Vital signs at screening (measured sitting after a minimum 3 minutes rest) as follows: blood pressure is less than 90/40 mmHg or greater than 140/90 mmHg or a heart rate lower than 40 bpm or higher than 99 bpm. Out-of-range vital signs may be repeated once.
• History or presence of allergic or adverse response to pretomanid or related drugs.
• Use of any drugs or treatment with any known drugs that are moderate or strong inducers or inhibitors of cytochrome P450 (CYP) enzymes (e.g., barbiturates, phenothiazines, cimetidine, carbamazepine) and/or P-gp, including St. John's Wort, within 30 days before the first dose of study medication, and that, in the Investigator's judgment, may impact subject safety or the validity of the study results.
• Female with a positive pregnancy test result.
• Positive test for hepatitis B surface antigen, hepatitis C antibody, or human immunodeficiency virus (HIV) at screening or has been previously treated for hepatitis B, hepatitis C, or HIV infection.
• Hemoglobin <10.0 g/dL.
• ALT (alanine transaminase) or AST (aspartate aminotransferase) >2.0 x the upper limit of normal (ULN).
• Hyperbilirubinemia >1.5 x ULN.
• History or presence of alcoholism or drug abuse within the past 2 years as determined by the Investigator to be clinically relevant.
• Any clinically significant electrocardiogram abnormality at Screening (as deemed by decision of the Investigator and the Study Sponsor's Medical Monitor).
• QTcF interval >450 msec for males or >470 msec for females at screening, Day -1, or Day 1 (pre-dose), or history of prolonged QT syndrome.
• 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, congestive heart failure or terminal cancer).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Panel 1: Pretomanid after meal; Each participant will receive four single-dose treatments with a 7-day washout period between each dose. Panel 1 will receive a meal before dosing.	Drug: Pretomanid; Treatment A (reference) = 200 mg given as a single 200 mg tablet (using the immediate release formulation), orally administered.; Treatment B (test) = 200 mg given as four 50-mg tablets (using the dispersible pediatric formulation), orally administered.; Treatment C (test) = single 50-mg dispersible tablet, orally administered.; Treatment D (test) = single 10-mg dispersible tablet, orally administered.; Other Names: PA-824
Experimental: Panel 2: Pretomanid after fast; Each participant will receive four single-dose treatments with a 7-day washout period between each dose. Panel 2 will fast before dosing.	Drug: Pretomanid; Treatment A (reference) = 200 mg given as a single 200 mg tablet (using the immediate release formulation), orally administered.; Treatment B (test) = 200 mg given as four 50-mg tablets (using the dispersible pediatric formulation), orally administered.; Treatment C (test) = single 50-mg dispersible tablet, orally administered.; Treatment D (test) = single 10-mg dispersible tablet, orally administered.; Other Names: PA-824

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Bioavailability - Cmax	Relative bioavailability will be determined separately for each panel using Cmax	intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Relative Bioavailability - AUC 0-t	Relative bioavailability will be determined separately for each panel using AUC 0-t (area under the time vs concentration curve from time 0 to time t : h*ng/mL)	intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Relative Bioavailability - AUC 0-inf	Relative bioavailability will be determined separately for each panel using AUC 0-inf (area under the time vs concentration curve from time 0 to infinite time)	intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Food Effect - Ratio of Cmax Fed Vs Fasted	Food effect on bioavailability will be determined across panels using Cmax. Reported in Ratio(%) of the Geometric Mean (Fed)/Geometric Mean (Fasted) based on Least Squares Mean of log-transformed parameter values (ng/mL)	intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Food Effect - Ratio of AUC 0-t Fed Vs Fasted	Food effect on bioavailability was assessed across panels based on the 90% confidence intervals (CIs) for estimates of the geometric mean ratios between AUC 0-t of fed versus fasted across panels. An analysis of variance was used for each treatment with panel as the fixed effect.	intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Food Effect - Ratio of AUC 0-inf Fed Vs Fasted	Food effect on bioavailability was assessed across panels based on the 90% confidence intervals (CIs) for estimates of the geometric mean ratios between AUC 0-inf of fed versus fasted across panels. An analysis of variance was used for each treatment with panel as the fixed effect	intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Adverse Events - Overall Incidence	All listed adverse events (AEs) are treatment emergent adverse events (TEAE) which are defined as AEs that started or worsened at or after the first administration of IMP up to and including	throughout the study, approximately 33 days

Collaborators and Investigators

• Sponsor: Global Alliance for TB Drug Development
• Investigators: Study Director: Antonio Lombardi, MD, TB Alliance

Publications and helpful links

General Publications

• Zou Y, Nedelman J, Lombardi A, Pappas F, Karlsson MO, Svensson EM. Characterizing Absorption Properties of Dispersible Pretomanid Tablets Using Population Pharmacokinetic Modelling. Clin Pharmacokinet. 2022 Nov;61(11):1585-1593. doi: 10.1007/s40262-022-01163-w. Epub 2022 Sep 30.

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2020
• Primary Completion (Actual): February 28, 2020
• Study Completion (Actual): February 28, 2020

Study Registration Dates

• First Submitted: January 23, 2020
• First Submitted That Met QC Criteria: March 13, 2020
• First Posted (Actual): March 16, 2020

Study Record Updates

• Last Update Posted (Actual): July 24, 2024
• Last Update Submitted That Met QC Criteria: July 22, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: PA-824; pretomanid; MDR-TB (multi-drug resistant tuberculosis); Extensively Resistant Pulmonary Tuberculosis; XDR-TB (extensively drug resistant tuberculosis)
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis; Tuberculosis, Multidrug-Resistant
• Other Study ID Numbers: Pa-824-CL-011

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No