Clinical trial NCT04309656: Single-dose Study in Two Panels of Healthy Adult Participants to Assess Immediate-Release and Dispersible Formulations of Pretomanid
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multi-drug Resistant Tuberculosis
Keywords: MDR-TB (multi-drug resistant tuberculosis)
Extensively Resistant Pulmonary Tuberculosis
XDR-TB (extensively drug resistant tuberculosis)
pretomanid
PA-824
Lead sponsor: Global Alliance for TB Drug Development
Sponsor class: OTHER
First posted: 2020-03-16
Enrollment: 48
Sex: ALL
Minimum age (years): 19
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: 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.
Primary purpose: TREATMENT

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

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.

Eligibility criteria: 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).

Primary outcomes:
measure: Relative Bioavailability - Cmax
timeFrame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
measure: Relative Bioavailability - AUC 0-t
timeFrame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
measure: Relative Bioavailability - AUC 0-inf
timeFrame: 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 outcomes:
measure: Food Effect - Ratio of Cmax Fed Vs Fasted
timeFrame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
measure: Food Effect - Ratio of AUC 0-t Fed Vs Fasted
timeFrame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
measure: Food Effect - Ratio of AUC 0-inf Fed Vs Fasted
timeFrame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
measure: Adverse Events - Overall Incidence
timeFrame: throughout the study, approximately 33 days
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Worldwide Clinical Trials Early Phase Services, LLC
state: Texas
Study officials:
affiliation: TB Alliance
name: Antonio Lombardi, MD
role: STUDY_DIRECTOR
References:
citation: 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.