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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Multi-drug Resistant Tuberculosis

Intervention / Treatment
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* Drug: Pretomanid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily consents to participate in this study and provides written informed consent before the start of any study-specific procedures. 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. Willing and able to remain in the study unit for the entire confinement period and return for the outpatient follow-up visit. Willing and able to consume the entire high-calorie, high-fat breakfast meal in the timeframe required during the designated study period. Willing and able to comply with the protocol and the assessments therein, including all restrictions. 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. A clinically significant abnormal finding on the physical examination, medical history, electrocardiogram (ECG), or clinical laboratory 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. On a significantly abnormal diet during the 4 weeks preceding the first dose of study medication. Participation in another clinical trial (randomized subjects only) within 30 days before the first dose of study medication. Use of any over-the-counter (OTC) medication (including nutritional or dietary supplements, herbal preparations, or vitamins) within 7 days before the first dose of study medication until the end of study visit without evaluation and approval by the Investigator. Up to 3 grams per day of acetaminophen is allowed at the discretion of the Investigator prior to dosing. Use of any prescription medication, except hormonal contraceptive or hormonal replacement therapy, from 14 days before the first dose of study medication until the end-of-study visit without evaluation and approval by the Investigator. Use of any drugs or substances known to lower the seizure threshold. 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 urine screen for drugs of abuse (amphetamines, barbiturates, benzodiazepines, cocaine, cannabinoids, opiates) or cotinine. 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. Surgery within the past 90 days prior to dosing as determined by the Investigator to be clinically relevant. 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).

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Panel 1: Pretomanid after meal<br>Each participant will receive four single-dose treatments. Panel 1 will receive a meal before dosing. | Drug: Pretomanid<br>* 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.<br>* Other names: PA-824;|
| Experimental: Panel 2: Pretomanid after fast<br>Each participant will receive four single-dose treatments. Panel 2 will fast before dosing. | Drug: Pretomanid<br>* 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.<br>* Other names: PA-824;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative bioavailability - Cmax | Bioavailability will be determined separately for each panel using Cmax (maximum plasma concentration) | 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 | 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) | 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 | 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 - Cmax | Food effect on 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 | 
| Food effect - AUC 0-t | Food effect on bioavailability will be determined separately for each panel using 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 | 
| Food effect - AUC 0-inf | Food effect on bioavailability will be determined separately for each panel using 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 | 
| Dose effect - Cmax | Dose effect on bioavailability of the dispersible pediatric formulations 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 | 
| Dose effect - AUC 0-t | Dose effect on bioavailability of the dispersible pediatric formulations will be determined separately for each panel using 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 | 
| Dose effect - AUC 0-inf | Dose effect on bioavailability of the dispersible pediatric formulations will be determined separately for each panel using 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 | 
| Taste perception of pediatric formulations by questionnaire | Formulations will be evaluated for taste, smell and mouth feel. Each item is scored on a scale of 1 to 5 with higher values indicating a more negative result. | On days 1, 8, 15, and 22 following dosing | 
| Adverse Events - relatedness using Adverse Event Attribution/Causality Ratings | Study participants will be monitored daily for adverse events. Reported adverse events (AE) will be rated for relatedness on five levels, from not related to certain. Moving higher on the scale means increased likelihood of the event being related to treatment. | throughout the study, approximately 33 days | 
| Adverse events - severity | Study participants will be monitored daily for AE. Reported events will be rated for severity using Division of Microbiology and Infectious Disease (DMID) Toxicity Tables. | throughout the study, approximately 33 days | 
| Adverse events - overall incidence | The overall number of AE will be collected. | throughout the study, approximately 33 days | 
| Adverse events - AE leading to withdrawal | The number of AE leading to withdrawal from the study will be collected. | throughout the study, approximately 33 days | 
| Adverse events - Serious Adverse Events | The number of serious adverse events (SAEs) will be collected. | throughout the study, approximately 33 days | 
| Vital signs - blood pressure | Systolic and diastolic blood pressure will be measured daily. | days 1-26 and day 33 | 
| Vital signs - pulse rate | Pulse rate will be taken daily. | days 1-26 and day 33 | 
| Vital signs - body temperature | Temperature will be taken daily. | days 1-26 and day 33 | 
| Vital signs - respiration rate | Respiration rate will be measured daily. | days 1-26 and day 33 | 
| Vital signs - pulse oximetry | Pulse oximetry measurements will be made daily. | days 1-26 and day 33 | 
| Vital signs - body weight | Body weight will be measured daily. | days 1-26 and day 33 | 
| Electrocardiogram (ECG) - Heart rate | Heart rate will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Electrocardiogram (ECG) - PR interval | PR interval will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Electrocardiogram (ECG) - RR interval | RR interval will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Electrocardiogram (ECG) - QRS complex | QRS complex will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Electrocardiogram (ECG) - QT interval | QT interval will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Electrocardiogram (ECG) - QTc interval (corrected by Bazett's formula) | QTc interval (corrected by Bazett's formula) will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Electrocardiogram (ECG) - QTc interval (corrected by Fridericia's formula) | QTc interval (corrected by Fridericia's formula) will be evaluated from an ECG. | intake (predose), day 1, day 8, day 15, day 22, and day 33 | 
| Hematology - hemoglobin | Hemoglobin will be measured in blood sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Hematocrit- hematocrit | Hematocrit will be measured in blood sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Hematology- Total and differential leukocyte count | Total and differential leukocyte count will be measured in blood sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Hematology- Red blood cell count | Red blood cell count will be measured in blood sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Hematology- Platelet count | Platelet count will be measured in blood sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - albumin | Albumin will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - blood urea nitrogen | Blood urea nitrogen will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - creatinine | Creatinine will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - total bilirubin | Total bilirubin will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - alkaline phosphatase | Alkaline phosphatase will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - aspartate transaminase | Aspartate transaminase will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - alanine transaminase | Alanine transaminase will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - sodium | Sodium will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - potassium | Potassium will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - chloride | Chloride will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - lactate dehydrogenase | Lactate dehydrogenase will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - calcium | Calcium will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - uric acid | Uric acid will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - glucose | Glucose will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - gamma-glutamyl transferase | Gamma-glutamyl transferase will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 
| Serum chemistry - magnesium | Magnesium will be measured in serum sample. | intake (predose), day 5, day 12, day 19, day 26, and day 33 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PA-824, MDR-TB (multi-drug resistant tuberculosis), Extensively Resistant Pulmonary Tuberculosis, XDR-TB (extensively drug resistant tuberculosis, pretomanid