Multi-drug Resistant Tuberculosis
Conditions
Keywords
MDR-TB (multi-drug resistant tuberculosis), Extensively Resistant Pulmonary Tuberculosis, XDR-TB (extensively drug resistant tuberculosis), pretomanid, PA-824
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.
Interventions
DRUGPretomanid
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.
Sponsors
Global Alliance for TB Drug Development
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
19 Years to 50 Years
Healthy volunteers
Yes
Inclusion 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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) |
| 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 |
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Panel 1: Pretomanid After Meal Each participant will receive four single-dose treatments. Panel 1 will receive a required FDA standard high fat, high-calorie meal before dosing. | 24 |
| Panel 2: Pretomanid After Fast Each participant will receive four single-dose treatments. Panel 2 will fast before dosing. | 24 |
| Total | 48 |
Baseline characteristics
| Characteristic | Panel 1: Pretomanid After Meal | Total | Panel 2: Pretomanid After Fast |
|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 8.5 | 37.0 years STANDARD_DEVIATION 7.82 | 36.4 years STANDARD_DEVIATION 7.2 |
| BMI at Screening | 27.08 kilogram per meter squared STANDARD_DEVIATION 2.882 | 26.92 kilogram per meter squared STANDARD_DEVIATION 2.913 | 26.76 kilogram per meter squared STANDARD_DEVIATION 2.996 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 21 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 27 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Height at Screening | 170.70 centimeter STANDARD_DEVIATION 7.962 | 170.83 centimeter STANDARD_DEVIATION 10.048 | 170.96 centimeter STANDARD_DEVIATION 11.953 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 23 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 14 Participants | 23 Participants | 9 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 16 Participants | 32 Participants | 16 Participants |
| Weight at Screening | 79.06 kilogram STANDARD_DEVIATION 11.601 | 78.77 kilogram STANDARD_DEVIATION 12.526 | 78.49 kilogram STANDARD_DEVIATION 13.633 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 5 / 24 | 9 / 24 | 2 / 24 | 6 / 24 | 3 / 24 | 3 / 24 | 1 / 24 | 4 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 | 0 / 24 |
Outcome results
Primary
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)
Time frame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Population: Quantifiable predose concentrations that were below 5% of the respective Cmax values were included in the pharmacokinetic analyses without adjustment. Data for subjects with quantifiable predose concentrations that were above 5% of the respective Cmax values were excluded from concentration-time descriptive statistics and mean concentration-time profiles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-inf | Treatment A | 57400 h*ng/mL | Standard Deviation 12300 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-inf | Treatment B | 57900 h*ng/mL | Standard Deviation 12400 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-inf | Treatment C | 12700 h*ng/mL | Standard Deviation 3210 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-inf | Treatment D | 2100 h*ng/mL | Standard Deviation 552 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-inf | Treatment D | 2530 h*ng/mL | Standard Deviation 551 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-inf | Treatment A | 34700 h*ng/mL | Standard Deviation 8330 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-inf | Treatment C | 11400 h*ng/mL | Standard Deviation 3440 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-inf | Treatment B | 31900 h*ng/mL | Standard Deviation 10200 |
p-value: 0.468390% CI: [98.65, 103.47]ANOVA
p-value: 0.073490% CI: [81.1, 99.05]ANOVA
Primary
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)
Time frame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Population: Quantifiable predose concentrations that were below 5% of the respective Cmax values were included in the pharmacokinetic analyses without adjustment. Data for subjects with quantifiable predose concentrations that were above 5% of the respective Cmax values were excluded from concentration-time descriptive statistics and mean concentration-time profiles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-t | Treatment C | 12300 h*ng/mL | Standard Deviation 2790 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-t | Treatment B | 55200 h*ng/mL | Standard Deviation 10800 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-t | Treatment D | 2040 h*ng/mL | Standard Deviation 514 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - AUC 0-t | Treatment A | 54900 h*ng/mL | Standard Deviation 10700 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-t | Treatment D | 2460 h*ng/mL | Standard Deviation 513 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-t | Treatment B | 30200 h*ng/mL | Standard Deviation 9030 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-t | Treatment C | 10900 h*ng/mL | Standard Deviation 3150 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - AUC 0-t | Treatment A | 32900 h*ng/mL | Standard Deviation 7580 |
p-value: 0.668690% CI: [98.23, 103.03]ANOVA
p-value: 0.074590% CI: [81.2, 99.1]ANOVA
Primary
Relative Bioavailability - Cmax
Relative bioavailability will be determined separately for each panel using Cmax
Time frame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Population: Quantifiable predose concentrations that were below 5% of the respective Cmax values were included in the pharmacokinetic analyses without adjustment. Data for subjects with quantifiable predose concentrations that were above 5% of the respective Cmax values were excluded from concentration-time descriptive statistics and mean concentration-time profiles
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Panel 1: Pretomanid After Meal | Relative Bioavailability - Cmax | Treatment A | 2170 ng/mL | Standard Deviation 484 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - Cmax | Treatment B | 1850 ng/mL | Standard Deviation 354 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - Cmax | Treatment C | 389 ng/mL | Standard Deviation 58.8 |
| Panel 1: Pretomanid After Meal | Relative Bioavailability - Cmax | Treatment D | 76.7 ng/mL | Standard Deviation 14.2 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - Cmax | Treatment D | 110 ng/mL | Standard Deviation 20.2 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - Cmax | Treatment A | 1180 ng/mL | Standard Deviation 401 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - Cmax | Treatment C | 427 ng/mL | Standard Deviation 111 |
| Panel 2: Pretomanid After Fast | Relative Bioavailability - Cmax | Treatment B | 1090 ng/mL | Standard Deviation 334 |
p-value: 0.000190% CI: [81.21, 90.75]ANOVA
p-value: 0.300190% CI: [82.65, 104.62]ANOVA
Secondary
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
Time frame: throughout the study, approximately 33 days
Population: All participants randomized
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Panel 1: Pretomanid After Meal | Adverse Events - Overall Incidence | 5 Participants |
| Panel 2: Pretomanid After Fast | Adverse Events - Overall Incidence | 9 Participants |
| Treatment C Fed and Fasted | Adverse Events - Overall Incidence | 2 Participants |
| Treatment D Fed and Fasted | Adverse Events - Overall Incidence | 6 Participants |
| Panel 2:Treatment A | Adverse Events - Overall Incidence | 3 Participants |
| Panel 2: Treatment B | Adverse Events - Overall Incidence | 3 Participants |
| Panel 2: Treatment C | Adverse Events - Overall Incidence | 1 Participants |
| Panel 2: Treatment D | Adverse Events - Overall Incidence | 4 Participants |
Secondary
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
Time frame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panel 1: Pretomanid After Meal | Food Effect - Ratio of AUC 0-inf Fed Vs Fasted | 166.38 Ratio (%) |
| Panel 2: Pretomanid After Fast | Food Effect - Ratio of AUC 0-inf Fed Vs Fasted | 187.54 Ratio (%) |
| Treatment C Fed and Fasted | Food Effect - Ratio of AUC 0-inf Fed Vs Fasted | 113.58 Ratio (%) |
| Treatment D Fed and Fasted | Food Effect - Ratio of AUC 0-inf Fed Vs Fasted | 81.57 Ratio (%) |
Secondary
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.
Time frame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Population: Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref). Quantifiable predose concentrations that were below 5% of the respective Cmax values were included in the pharmacokinetic analyses without adjustment. Data for subjects with quantifiable predose concentrations that were above 5% of the respective Cmax values were excluded from concentration-time descriptive statistics and mean concentration-time profiles
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panel 1: Pretomanid After Meal | Food Effect - Ratio of AUC 0-t Fed Vs Fasted | 167.96 Ratio (%) |
| Panel 2: Pretomanid After Fast | Food Effect - Ratio of AUC 0-t Fed Vs Fasted | 188.36 Ratio (%) |
| Treatment C Fed and Fasted | Food Effect - Ratio of AUC 0-t Fed Vs Fasted | 114.09 Ratio (%) |
| Treatment D Fed and Fasted | Food Effect - Ratio of AUC 0-t Fed Vs Fasted | 81.74 Ratio (%) |
Secondary
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)
Time frame: intake (pre-dose), and at 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, and 96 hours post dose
Population: Ratio(%) = Geometric Mean (Test)/Geometric Mean (Ref). Quantifiable predose concentrations that were below 5% of the respective Cmax values were included in the pharmacokinetic analyses without adjustment. Data for subjects with quantifiable predose concentrations that were above 5% of the respective Cmax values were excluded from concentration-time descriptive statistics and mean concentration-time profiles
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panel 1: Pretomanid After Meal | Food Effect - Ratio of Cmax Fed Vs Fasted | 187.65 Ratio (%) |
| Panel 2: Pretomanid After Fast | Food Effect - Ratio of Cmax Fed Vs Fasted | 173.24 Ratio (%) |
| Treatment C Fed and Fasted | Food Effect - Ratio of Cmax Fed Vs Fasted | 93.25 Ratio (%) |
| Treatment D Fed and Fasted | Food Effect - Ratio of Cmax Fed Vs Fasted | 69.38 Ratio (%) |