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

Phase 1

Completed

• Conditions: Multi-drug Resistant Tuberculosis
• Interventions: Drug: Pretomanid

• Registration Number: NCT04309656
• Lead Sponsor: Global Alliance for TB Drug Development

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.

Study Timeline

• Study Start: 2020-01-14
• Study First Submitted: 2020-01-23
• Primary Completion: 2020-02-28
• Study Completion: 2020-02-28
• Study First Submitted QC: 2020-03-13
• Study First Posted: 2020-03-16
• Results First Submitted: 2023-09-27
• Status Verified: 2024-07
• Results First Submitted QC: 2024-07-22
• Last Update Submitted: 2024-07-22
• Results First Posted: 2024-07-24
• Last Update Posted: 2024-07-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 48

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

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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).

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Panel 1: Pretomanid after meal	Pretomanid	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.
Panel 2: Pretomanid after fast	Pretomanid	Each participant will receive four single-dose treatments with a 7-day washout period between each dose. Panel 2 will fast before dosing.

Primary Outcome Measures

Name	Time	Method
Relative Bioavailability - 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 will be determined separately for each panel using Cmax
Relative Bioavailability - AUC 0-t	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 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)
Relative Bioavailability - AUC 0-inf	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 will be determined separately for each panel using AUC 0-inf (area under the time vs concentration curve from time 0 to infinite time)

Secondary Outcome Measures

Name	Time	Method
Food Effect - Ratio of Cmax Fed Vs Fasted	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 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)
Food Effect - Ratio of AUC 0-t Fed Vs Fasted	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 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.
Food Effect - Ratio of AUC 0-inf Fed Vs Fasted	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 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
Adverse Events - Overall Incidence	throughout the study, approximately 33 days	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

Trial Locations

Locations (1)

Worldwide Clinical Trials Early Phase Services, LLC; 🇺🇸 San Antonio, Texas, United States