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

NCT04309656 | Completed Phase 1 Results FDA Drug

• 1 other identifier: Pa-824-CL-011
• Study Type: interventional
• Target: 48
• Locations: 1 country
• Sites: 1

Brief Summary

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

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

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (4)

• 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 - 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 - 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

• Adverse Events - Overall Incidence

  throughout the study, approximately 33 days

Study Arms (2)

Panel 1: Pretomanid after meal

EXPERIMENTAL

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

Panel 2: Pretomanid after fast

EXPERIMENTAL

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

Interventions

Pretomanid DRUG

1. Treatment A (reference) = 200 mg given as a single 200 mg tablet (using the immediate release formulation), orally administered. 2. Treatment B (test) = 200 mg given as four 50-mg tablets (using the dispersible pediatric formulation), orally administered. 3. Treatment C (test) = single 50-mg dispersible tablet, orally administered. 4. Treatment D (test) = single 10-mg dispersible tablet, orally administered.

Also known as: PA-824

Panel 1: Pretomanid after meal; Panel 2: Pretomanid after fast

Eligibility Criteria

• Age: 19 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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).

Sponsors & Collaborators

• Global Alliance for TB Drug Development: lead

Study Sites (1)

Worldwide Clinical Trials Early Phase Services, LLC

San Antonio, Texas, 78217, United States

Location

Related Publications (1)

• 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.

  PMID: 36180816 DERIVED

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant; Extensively Drug-Resistant Tuberculosis

Interventions

pretomanid

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Erica Egizi
• Organization: TB Alliance

erica.egizi@tballiance.org

917-696-4984

Study Officials

• Antonio Lombardi, MD

  TB Alliance

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

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

Model Details: 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 Record Dates

• First Submitted: January 23, 2020
• First Posted: March 16, 2020
• Study Start: January 14, 2020
• Primary Completion: February 28, 2020
• Study Completion: February 28, 2020
• Last Updated: July 24, 2024
• Results First Posted: July 24, 2024

Record last verified: 2024-07

Locations

US (1)