Renal Impairment, Tuberculosis
Conditions
Keywords
Open-Label, Pretomanid, Renal Pharmacokinetic, Single-Dose
Brief summary
This is a Phase 1, open-label, single-dose, sequential group study to compare the safety and pharmacokinetics (PK) of pretomanid in the following groups of participants: 1) participants with severe renal impairment including those with end stage renal disease (ESRD) not on dialysis, and participants with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) participants with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively. The study will be conducted following a reduced PK study design in Part A. Part A will enroll participants from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 participants with severe renal impairment and ESRD, not on dialysis). A decision to proceed to Part B will be made after the PK of pretomanid, and safety in participants enrolled in Part A have been reviewed. If Part A demonstrates at least a 50% increase in pretomanid area under the plasma concentration-time curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched participants with normal renal function), then the reduced PK study will extend to the full PK study to enroll participants into Part B (i.e., to investigate mild and moderate renal impairment). All Part B groups (1B, 1C, 3, and 4) will be enrolled concurrently. If the reduced PK study shows at least a 50% increase in AUC in patients with severe renal impairment and patients with ESRD not yet on dialysis relative to the matched healthy controls, a full PK renal impairment study in patients with all intermediate levels of renal function impairment should be conducted. Otherwise, no further study is recommended. The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in participants with renal impairment compared to matched healthy controls.
Detailed description
This is a Phase 1, open-label, single-dose, sequential group study to compare the safety and pharmacokinetics (PK) of pretomanid in the following groups of participants: 1) participants with severe renal impairment including those with end stage renal disease (ESRD) not on dialysis, and participants with mild or moderate renal impairment, designated as Groups 2, 3, and 4, respectively; and 2) participants with normal renal function matched to the above renal impairment groups, designated as Groups 1A, 1B, and 1C, respectively. The study will be conducted following a reduced PK study design in Part A. Part A will enroll participants from Group 1A (i.e., 6 healthy matched controls) and Group 2 (i.e., 6 participants with severe renal impairment and ESRD, not on dialysis). A decision to proceed to Part B will be made after the PK of pretomanid, and safety in participants enrolled in Part A have been reviewed. If Part A demonstrates at least a 50% increase in pretomanid area under the plasma concentration-time curve (AUC) in Group 2 (severe renal impairments and ESRD, not on dialysis) relative to the exposures in Group 1A (matched participants with normal renal function), then the reduced PK study will extend to the full PK study to enroll participants into Part B (i.e., to investigate mild and moderate renal impairment). All Part B groups (1B, 1C, 3, and 4) will be enrolled concurrently. If the reduced PK study shows at least a 50% increase in AUC in patients with severe renal impairment and patients with ESRD not yet on dialysis relative to the matched healthy controls, a full PK renal impairment study in patients with all intermediate levels of renal function impairment should be conducted. Otherwise, no further study is recommended. The approximate patient involvement will be 3 months. The primary objective is to evaluate the PK profiles of pretomanid in plasma and urine after a single oral dose of 200 mg in participants with renal impairment compared to matched healthy controls. The secondary objectives are 1) to assess the safety profile of a single oral dose of 200 mg pretomanid in renally impaired participants to matched healthy controls; and 2) to evaluate the PK profiles or representative pretomanid metabolites (M19 and M50) in plasma and urine.
Interventions
DRUGPA-824
PA-824, a nitroimidazooxazine, used in prior studies of pretomanid is a novel TB treatment that is being investigated for use with other TB drugs to shorten and/or simplify regimens to treat either drug susceptible or resistant disease. After fasting for a minimum of 8 hours, subjects will receive one dose of 200 mg of pretomanid orally under direct supervision with 240 mL of water and a mouth check will be done.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
Yes
Inclusion criteria
Participant Inclusion Criteria for Patients with Renal Impairment (Groups 2-4) 1. Have the ability to understand the requirements of the study and have provided written informed consent\* before any study-related procedure is performed. \*As evidence by signature on an informed consent document approved by the Institutional Review Board 2. Agree to abide by the study restrictions. 3. Are between the ages of 18 and 85 years, inclusive, at the time of enrollment. 4. Must have mild, moderate, or severe renal impairment or end stage renal disease (ESRD), but are not on dialysis. 5. Have no history of chronic tobacco/nicotine usage (i.e., \>10 cigarettes per day for 3 months minimum prior to admission). 6. Have corrected QT interval by Fridericia (QTcF) \<460 msec on Electrocardiogram (ECG). 7. Have a Body Mass Index (BMI) of 18 to 40 kg/m\^2 at enrollment. 8. Women of childbearing potential\*\* must use an acceptable contraception method\*\*\* for the duration of the study. \*\*Not sterilized via tubal ligation, bilateral oophorectomy, bilateral salpingectomy, hysterectomy, implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \<1 year has passed since the last menses if menopausal. \*\*\*Includes, non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the participant receiving study product, barrier methods such as condoms with spermicide or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives (the pill). 9. If participant is male and capable of reproduction, agrees to avoid fathering a child for the duration of the study by using an acceptable method of birth control\*\*\*\*. \*\*\*\*In addition to the use of a barrier method (condom) unless vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #8, and/or abstinence from sexual intercourse with women. 10. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product. Participant Inclusion Criteria for Healthy Participants (Groups 1A-1C) 1. Have the ability to understand the requirements of the study and have provided written informed consent\* before any study-related procedure is performed. \*As evidence by signature on an informed consent document approved by the Institutional Review Board (IRB). 2. Agree to abide by the study restrictions. 3. Are healthy male or non-pregnant female, between the ages of 18 and 85 years, inclusive, with normal GFR \>90 at screening. 4. Have no history of chronic tobacco/nicotine usage (i.e., \>10 cigarettes per day for 3 months minimum prior to admission). 5. Have a normal corrected QT interval by Fridericia (QTcF) \<460 msec on ECG. 6. Have a Body Mass Index of 18 to 40 kg/m\^2 at enrollment. 7. Women of childbearing potential\*\* must use an acceptable contraception method\*\*\* for the duration of the study. \*\*Not sterilized via tubal ligation, bilateral oophorectomy, bilateral salpingectomy, hysterectomy, implanted contraceptive device placement (permanent, non-surgical, non-hormonal sterilization) with documented radiological confirmation test at least 90 days after the procedure, and still menstruating or \<1 year has passed since the last menses if menopausal. \*\*\*Includes non-male sexual relationships, abstinence from sexual intercourse with a male partner, monogamous relationship with vasectomized partner who has been vasectomized for 180 days or more prior to the participant receiving study product, barrier methods such as condoms with spermicide or diaphragms/cervical caps with spermicide, effective intrauterine devices, NuvaRing(R), and licensed hormonal methods such as implants, injectables, or oral contraceptives (the pill). 8. If participant is male and capable of reproduction, agrees to avoid fathering a child for the duration of the study by using an acceptable method of birth control\*\*\*\*. \*\*\*\*In addition to the use of a barrier method (condom) unless vasectomized, acceptable methods of birth control are restricted to a monogamous relationship with a woman who agrees to use acceptable contraception as outlined in inclusion criterion #7, and/or abstinence from sexual intercourse with women. 9. Women of childbearing potential must have a negative urine pregnancy test within 24 hours prior to receipt of study product.
Exclusion criteria
Participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | The mean fold change of AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site. |
| Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | The mean fold change of AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Maximum M19 and M50 concentrations is the maximum observed drug concentration in blood plasma at specified pre-dose and post-dose timepoints. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Apparent terminal half-life of M19 and M50 at specified pre-dose and post-dose timepoints was estimated by ln(2)/Lambda\_z, where Lambda\_z is the elimination rate constant. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Renal clearance (CLr) of M19 and M50 calculated as the amount excreted in urine to time t in urine divided by the plasma AUC from 0 to time t. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Amount of M19 and M50 excreted in Urine \[Ae(0-t)\] is the sum of the amount of M19 and M50 recovered in urine during the collection window. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Apparent Volume of Distribution at specified pre-dose and post-dose timepoints is the volume that the total amount of administered drug would occupy to provide the same concentration as it currently is in blood plasma divided by the bioavailability. It is calculated by Dose/\[Lambda\_z x AUC(0-infinity)\]. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Time of maximum M19 and M50 concentration (Tmax) at specified pre-dose and post-dose timepoints. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | Apparent oral clearance was calculated by noncompartmental analysis using the formula Dose/AUC(0-infinity). M19 and M50 are the two primary representative metabolites of pretomanid. |
| Number of Participants With and Severity of Adverse Events | Day 1 to Day 85 | An Adverse Event (AE) was defined as any unfavorable or unintended medical occurrence temporally associated with the use of a study drug, device, other medical product, or procedure whether or not it is considered related to the product itself. |
| Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant. M19 and M50 are the two primary representative metabolites of pretomanid. |
| Mean Change From Baseline in Hemoglobin (Hgb) | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Magnesium | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Serum Potassium | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Total Bilirubin | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change in Oral Temperature From Baseline | Days 1, 2, 3, 4, 5, and 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change in Pulse From Baseline | Days 1, 2, 3, 4, 5, and 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change in Sitting Systolic Blood Pressure From Baseline | Days 1, 2, 3, 4, 5, and 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change in Sitting Diastolic Blood Pressure From Baseline | Days 1, 2, 3, 4, 5, and 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change in the Electrocardiogram (ECG) Corrected QT Interval by Fridericia (QTcF) Interval From Baseline | Day 5 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Mean Change From Baseline in Creatinine | Day 5 and Day 12 | The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration. |
| Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose. | AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method. M19 and M50 are the two primary representative metabolites of pretomanid. |
Countries
United States
Participant flow
Recruitment details
The study population was represented by participants of varying degrees of renal disease, recruited from the community at large. Participants were between 18 and 85 years, inclusive at the time of enrollment. Enrollment occurred from 17APR2024 to 05AUG2024.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Matched Controls Healthy participants with normal renal function received a single oral dose of 200 mg pretomanid | 6 |
| ESRD Not on Dialysis Participants with End Stage Renal Disease (ESRD) not on dialysis received a single oral dose of 200 mg pretomanid | 1 |
| Severe Renal Impairment Participants with severe renal impairment received a single oral dose of 200 mg pretomanid | 5 |
| Total | 12 |
Baseline characteristics
| Characteristic | Severe Renal Impairment | ESRD Not on Dialysis | Total | Healthy Matched Controls |
|---|---|---|---|---|
| Age, Continuous | 62.0 years STANDARD_DEVIATION 10 | 40.0 years | 56.3 years STANDARD_DEVIATION 12.3 | 54.3 years STANDARD_DEVIATION 12.8 |
| BMI | 36.02 kg/m^2 STANDARD_DEVIATION 3.42 | 40.0 kg/m^2 | 34.43 kg/m^2 STANDARD_DEVIATION 3.83 | 32.17 kg/m^2 STANDARD_DEVIATION 2.84 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 7 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 0 Participants | 5 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Height | 167.42 cm STANDARD_DEVIATION 3.61 | 155.00 cm | 164.45 cm STANDARD_DEVIATION 7.27 | 163.55 cm STANDARD_DEVIATION 8.85 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 1 Participants | 10 Participants | 5 Participants |
| Region of Enrollment United States | 5 participants | 1 participants | 12 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 6 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 0 Participants | 6 Participants | 3 Participants |
| Weight | 101.12 kg STANDARD_DEVIATION 11.53 | 96.00 kg | 93.44 kg STANDARD_DEVIATION 14.34 | 86.62 kg STANDARD_DEVIATION 15.15 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 1 | 0 / 5 |
| other Total, other adverse events | 0 / 6 | 0 / 1 | 3 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 1 | 0 / 5 |
Outcome results
Primary
Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls
The mean fold change of AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Matched Controls | Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls | 88650 ng*h/mL |
| ESRD Not on Dialysis | Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls | 76400 ng*h/mL |
| Severe Renal Impairment | Fold Change in Pretomanid AUC(0-infinity) in Participants With Renal Impairment as Compared to Matched Healthy Controls | 76740 ng*h/mL |
Comparison: No formal hypothesis testing was conducted. Assuming a 20% coefficient of variation for the AUC(0-infinity) of both groups, the probability of observing at least a 50% increase in the geometric mean ratio of AUCs given a true 100% increase is \>99%. The probability of the lower bound of the 90% CI for the geometric mean ratio of AUCs being at least 1.5 in this scenario is approximately 70%90% CI: [0.54, 1.39]Regression, Linear
Comparison: No formal hypothesis testing was conducted. Assuming a 20% coefficient of variation for the AUC(0-infinity) of both groups, the probability of observing at least a 50% increase in the geometric mean ratio of AUCs given a true 100% increase is \>99%. The probability of the lower bound of the 90% CI for the geometric mean ratio of AUCs being at least 1.5 in this scenario is approximately 70%90% CI: [0.71, 1.28]Regression, Linear
Primary
Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls
The mean fold change of AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method. The mean fold change of each enrolled renal impairment arm as compared to the Healthy Matched Control arm was calculated by a linear regression model controlling for site.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Healthy Matched Controls | Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls | 77130 ng*h/mL |
| ESRD Not on Dialysis | Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls | 63600 ng*h/mL |
| Severe Renal Impairment | Fold Change in Pretomanid AUC(0-last) in Participants With Renal Impairment as Compared to Matched Healthy Controls | 62660 ng*h/mL |
Comparison: No formal hypothesis testing was conducted. Assuming a 20% coefficient of variation for the AUC(0-last) of both groups, the probability of observing at least a 50% increase in the geometric mean ratio of AUCs given a true 100% increase is \>99%. The probability of the lower bound of the 90% CI for the geometric mean ratio of AUCs being at least 1.5 in this scenario is approximately 70%.90% CI: [0.54, 1.26]Regression, Linear
Comparison: No formal hypothesis testing was conducted. Assuming a 20% coefficient of variation for the AUC(0-last) of both groups, the probability of observing at least a 50% increase in the geometric mean ratio of AUCs given a true 100% increase is \>99%. The probability of the lower bound of the 90% CI for the geometric mean ratio of AUCs being at least 1.5 in this scenario is approximately 70%90% CI: [0.67, 1.14]Regression, Linear
Secondary
Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points
Amount of M19 and M50 excreted in Urine \[Ae(0-t)\] is the sum of the amount of M19 and M50 recovered in urine during the collection window. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK urine analysis subset will consist of all participants with sufficient urine PK data available to estimate the urine PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | M19 | 678.3 ug | Standard Deviation 314 |
| Healthy Matched Controls | Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | M50 | 3302 ug | Standard Deviation 2420 |
| ESRD Not on Dialysis | Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | M19 | 715.0 ug | — |
| ESRD Not on Dialysis | Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | M50 | 585.0 ug | — |
| Severe Renal Impairment | Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | M50 | 548.0 ug | Standard Deviation 143.4 |
| Severe Renal Impairment | Amount of M19 and M50 Excreted in Urine at Specified Pre-dose and Post-dose Time Points | M19 | 1637 ug | Standard Deviation 1894 |
Secondary
Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points
Apparent oral clearance was calculated by noncompartmental analysis using the formula Dose/AUC(0-infinity). M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | M19 | 59.73 L/h | Standard Deviation 24.27 |
| Healthy Matched Controls | Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | M50 | 318.8 L/h | Standard Deviation 116.5 |
| ESRD Not on Dialysis | Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | M19 | 33.40 L/h | — |
| ESRD Not on Dialysis | Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | M50 | 272.0 L/h | — |
| Severe Renal Impairment | Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | M19 | 36.50 L/h | Standard Deviation 24.1 |
| Severe Renal Impairment | Apparent Oral Clearance of M19 and M50 From Dose/AUC(0-infinity) at Specified Pre-dose and Post-dose Time Points | M50 | 200.5 L/h | Standard Deviation 62.07 |
Secondary
Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points
Apparent terminal half-life of M19 and M50 at specified pre-dose and post-dose timepoints was estimated by ln(2)/Lambda\_z, where Lambda\_z is the elimination rate constant. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 31.58 Hours | Standard Deviation 8.06 |
| Healthy Matched Controls | Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 31.12 Hours | Standard Deviation 7.13 |
| ESRD Not on Dialysis | Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 48.80 Hours | — |
| ESRD Not on Dialysis | Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 31.0 Hours | — |
| Severe Renal Impairment | Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 53.68 Hours | Standard Deviation 14.29 |
| Severe Renal Impairment | Apparent Terminal Elimination Half-life of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 35.68 Hours | Standard Deviation 5.97 |
Secondary
Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points
Apparent Volume of Distribution at specified pre-dose and post-dose timepoints is the volume that the total amount of administered drug would occupy to provide the same concentration as it currently is in blood plasma divided by the bioavailability. It is calculated by Dose/\[Lambda\_z x AUC(0-infinity)\]. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 2793 L | Standard Deviation 1414 |
| Healthy Matched Controls | Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 13570 L | Standard Deviation 3050 |
| ESRD Not on Dialysis | Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 2350 L | — |
| ESRD Not on Dialysis | Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 12100 L | — |
| Severe Renal Impairment | Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 3106 L | Standard Deviation 2543 |
| Severe Renal Impairment | Apparent Volume of Distribution of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 10540 L | Standard Deviation 4333 |
Secondary
Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points
AUC(0-infinity) was calculated by noncompartmental analysis using the linear up log down method with the area extrapolated to infinity as Clast/Lambda\_z where Clast was the last observed concentration and Lambda\_z is the elimination rate constant. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | M19 | 4013 ng*h/mL | Standard Deviation 2021 |
| Healthy Matched Controls | Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | M50 | 700.7 ng*h/mL | Standard Deviation 251.3 |
| ESRD Not on Dialysis | Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | M19 | 5980 ng*h/mL | — |
| ESRD Not on Dialysis | Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | M50 | 737.0 ng*h/mL | — |
| Severe Renal Impairment | Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | M19 | 7458 ng*h/mL | Standard Deviation 4410 |
| Severe Renal Impairment | Area Under the M19 and M50 Concentration Time-curve Extrapolated to Infinity at Specified Pre-dose and Post-dose Time Points | M50 | 1132 ng*h/mL | Standard Deviation 547.1 |
Secondary
Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points
AUC(0-last) Area under the concentration time-curve to the last concentration above the lower limit of quantitation at specified pre-dose and post-dose time points was calculated by noncompartmental analysis using the linear up log down method. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | M19 | 3503 ng*h/mL | Standard Deviation 1852 |
| Healthy Matched Controls | Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | M50 | 585.0 ng*h/mL | Standard Deviation 202.5 |
| ESRD Not on Dialysis | Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | M19 | 4150 ng*h/mL | — |
| ESRD Not on Dialysis | Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | M50 | 631.0 ng*h/mL | — |
| Severe Renal Impairment | Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | M19 | 4746 ng*h/mL | Standard Deviation 3064 |
| Severe Renal Impairment | Area Under the M19 and M50 Concentration Time-curve to the Last Concentration Above the Lower Limit of Quantitation at Specified Pre-dose and Post-dose Time Points | M50 | 932.8 ng*h/mL | Standard Deviation 479.7 |
Secondary
Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points
Maximum M19 and M50 concentrations is the maximum observed drug concentration in blood plasma at specified pre-dose and post-dose timepoints. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | M19 | 82.05 ng/mL | Standard Deviation 33.34 |
| Healthy Matched Controls | Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | M50 | 15.05 ng/mL | Standard Deviation 3.603 |
| ESRD Not on Dialysis | Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | M19 | 81.30 ng/mL | — |
| ESRD Not on Dialysis | Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | M50 | 12.60 ng/mL | — |
| Severe Renal Impairment | Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | M19 | 73.66 ng/mL | Standard Deviation 48.38 |
| Severe Renal Impairment | Maximum M19 and M50 Concentrations at Specified Pre-dose and Post-dose Time Points | M50 | 16.28 ng/mL | Standard Deviation 8.149 |
Secondary
Mean Change From Baseline in Alanine Aminotransferase (ALT)
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 5 | 0.0 U/L | Standard Deviation 5.5 |
| Healthy Matched Controls | Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 12 | 1.2 U/L | Standard Deviation 6.1 |
| ESRD Not on Dialysis | Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 5 | 2.0 U/L | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 12 | 1.0 U/L | — |
| Severe Renal Impairment | Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 5 | 2.0 U/L | Standard Deviation 8.2 |
| Severe Renal Impairment | Mean Change From Baseline in Alanine Aminotransferase (ALT) | Day 12 | 4.0 U/L | Standard Deviation 7.6 |
Secondary
Mean Change From Baseline in Aspartate Aminotransferase (AST)
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 5 | -2.3 U/L | Standard Deviation 4.6 |
| Healthy Matched Controls | Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 12 | 0.5 U/L | Standard Deviation 3.3 |
| ESRD Not on Dialysis | Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 5 | 1.0 U/L | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 12 | -2.0 U/L | — |
| Severe Renal Impairment | Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 5 | 0.4 U/L | Standard Deviation 1.5 |
| Severe Renal Impairment | Mean Change From Baseline in Aspartate Aminotransferase (AST) | Day 12 | 0.8 U/L | Standard Deviation 2.5 |
Secondary
Mean Change From Baseline in Blood Urea Nitrogen (BUN)
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 5 | -1.5 mg/dL | Standard Deviation 4.5 |
| Healthy Matched Controls | Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 12 | -1.2 mg/dL | Standard Deviation 2.5 |
| ESRD Not on Dialysis | Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 5 | 2.0 mg/dL | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 12 | -9.0 mg/dL | — |
| Severe Renal Impairment | Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 5 | 6.6 mg/dL | Standard Deviation 19.6 |
| Severe Renal Impairment | Mean Change From Baseline in Blood Urea Nitrogen (BUN) | Day 12 | 3.0 mg/dL | Standard Deviation 23 |
Secondary
Mean Change From Baseline in Creatinine
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Creatinine | Day 5 | 0.032 mg/dL | Standard Deviation 0.097 |
| Healthy Matched Controls | Mean Change From Baseline in Creatinine | Day 12 | -0.017 mg/dL | Standard Deviation 0.108 |
| ESRD Not on Dialysis | Mean Change From Baseline in Creatinine | Day 5 | -0.520 mg/dL | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Creatinine | Day 12 | -0.400 mg/dL | — |
| Severe Renal Impairment | Mean Change From Baseline in Creatinine | Day 5 | 0.330 mg/dL | Standard Deviation 0.738 |
| Severe Renal Impairment | Mean Change From Baseline in Creatinine | Day 12 | 0.028 mg/dL | Standard Deviation 0.448 |
Secondary
Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR)
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 5 | -6.0 mL/min/1.73m^2 | Standard Deviation 19.9 |
| Healthy Matched Controls | Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 12 | 3.2 mL/min/1.73m^2 | Standard Deviation 20.4 |
| ESRD Not on Dialysis | Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 5 | 4.0 mL/min/1.73m^2 | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 12 | 1.0 mL/min/1.73m^2 | — |
| Severe Renal Impairment | Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 5 | -2.6 mL/min/1.73m^2 | Standard Deviation 5.5 |
| Severe Renal Impairment | Mean Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) | Day 12 | 0.6 mL/min/1.73m^2 | Standard Deviation 2.6 |
Secondary
Mean Change From Baseline in Hemoglobin (Hgb)
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Hemoglobin (Hgb) | Day 5 | 0.52 g/dL | Standard Deviation 0.83 |
| Healthy Matched Controls | Mean Change From Baseline in Hemoglobin (Hgb) | Day 12 | -0.37 g/dL | Standard Deviation 0.67 |
| ESRD Not on Dialysis | Mean Change From Baseline in Hemoglobin (Hgb) | Day 5 | -0.60 g/dL | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Hemoglobin (Hgb) | Day 12 | 0.00 g/dL | — |
| Severe Renal Impairment | Mean Change From Baseline in Hemoglobin (Hgb) | Day 5 | -0.66 g/dL | Standard Deviation 0.85 |
| Severe Renal Impairment | Mean Change From Baseline in Hemoglobin (Hgb) | Day 12 | -1.26 g/dL | Standard Deviation 0.65 |
Secondary
Mean Change From Baseline in Magnesium
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Magnesium | Day 5 | -0.12 mg/dL | Standard Deviation 0.2 |
| Healthy Matched Controls | Mean Change From Baseline in Magnesium | Day 12 | 0.00 mg/dL | Standard Deviation 0.14 |
| ESRD Not on Dialysis | Mean Change From Baseline in Magnesium | Day 5 | -0.20 mg/dL | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Magnesium | Day 12 | -0.20 mg/dL | — |
| Severe Renal Impairment | Mean Change From Baseline in Magnesium | Day 5 | -0.10 mg/dL | Standard Deviation 0.22 |
| Severe Renal Impairment | Mean Change From Baseline in Magnesium | Day 12 | -0.04 mg/dL | Standard Deviation 0.23 |
Secondary
Mean Change From Baseline in Serum Potassium
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Serum Potassium | Day 5 | 0.27 mmol/L | Standard Deviation 0.46 |
| Healthy Matched Controls | Mean Change From Baseline in Serum Potassium | Day 12 | 0.12 mmol/L | Standard Deviation 0.29 |
| ESRD Not on Dialysis | Mean Change From Baseline in Serum Potassium | Day 5 | 0.60 mmol/L | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Serum Potassium | Day 12 | 0.10 mmol/L | — |
| Severe Renal Impairment | Mean Change From Baseline in Serum Potassium | Day 5 | 0.18 mmol/L | Standard Deviation 0.42 |
| Severe Renal Impairment | Mean Change From Baseline in Serum Potassium | Day 12 | 0.14 mmol/L | Standard Deviation 0.71 |
Secondary
Mean Change From Baseline in Total Bilirubin
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5 and Day 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change From Baseline in Total Bilirubin | Day 5 | 0.03 mg/dL | Standard Deviation 0.27 |
| Healthy Matched Controls | Mean Change From Baseline in Total Bilirubin | Day 12 | 0.10 mg/dL | Standard Deviation 0.31 |
| ESRD Not on Dialysis | Mean Change From Baseline in Total Bilirubin | Day 5 | 0.00 mg/dL | — |
| ESRD Not on Dialysis | Mean Change From Baseline in Total Bilirubin | Day 12 | 0.00 mg/dL | — |
| Severe Renal Impairment | Mean Change From Baseline in Total Bilirubin | Day 5 | -0.02 mg/dL | Standard Deviation 0.25 |
| Severe Renal Impairment | Mean Change From Baseline in Total Bilirubin | Day 12 | -0.02 mg/dL | Standard Deviation 0.15 |
Secondary
Mean Change in Oral Temperature From Baseline
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Days 1, 2, 3, 4, 5, and 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change in Oral Temperature From Baseline | Day 1 (12 hours post-dose) | -0.07 degrees Fahrenheit | Standard Deviation 0.31 |
| Healthy Matched Controls | Mean Change in Oral Temperature From Baseline | Day 2 (24 hours post-dose) | -0.12 degrees Fahrenheit | Standard Deviation 0.15 |
| Healthy Matched Controls | Mean Change in Oral Temperature From Baseline | Day 3 (48 hours post-dose) | -0.10 degrees Fahrenheit | Standard Deviation 0.26 |
| Healthy Matched Controls | Mean Change in Oral Temperature From Baseline | Day 4 (72 hours post-dose) | -0.22 degrees Fahrenheit | Standard Deviation 0.31 |
| Healthy Matched Controls | Mean Change in Oral Temperature From Baseline | Day 5 (96 hours post-dose) | -0.28 degrees Fahrenheit | Standard Deviation 0.42 |
| Healthy Matched Controls | Mean Change in Oral Temperature From Baseline | Day 12 | -0.22 degrees Fahrenheit | Standard Deviation 0.29 |
| ESRD Not on Dialysis | Mean Change in Oral Temperature From Baseline | Day 12 | -1.20 degrees Fahrenheit | — |
| ESRD Not on Dialysis | Mean Change in Oral Temperature From Baseline | Day 1 (12 hours post-dose) | -0.90 degrees Fahrenheit | — |
| ESRD Not on Dialysis | Mean Change in Oral Temperature From Baseline | Day 4 (72 hours post-dose) | -0.20 degrees Fahrenheit | — |
| ESRD Not on Dialysis | Mean Change in Oral Temperature From Baseline | Day 5 (96 hours post-dose) | -0.70 degrees Fahrenheit | — |
| ESRD Not on Dialysis | Mean Change in Oral Temperature From Baseline | Day 2 (24 hours post-dose) | -0.50 degrees Fahrenheit | — |
| ESRD Not on Dialysis | Mean Change in Oral Temperature From Baseline | Day 3 (48 hours post-dose) | -0.20 degrees Fahrenheit | — |
| Severe Renal Impairment | Mean Change in Oral Temperature From Baseline | Day 2 (24 hours post-dose) | -0.22 degrees Fahrenheit | Standard Deviation 0.24 |
| Severe Renal Impairment | Mean Change in Oral Temperature From Baseline | Day 3 (48 hours post-dose) | 0.20 degrees Fahrenheit | Standard Deviation 0.53 |
| Severe Renal Impairment | Mean Change in Oral Temperature From Baseline | Day 12 | 0.02 degrees Fahrenheit | Standard Deviation 0.16 |
| Severe Renal Impairment | Mean Change in Oral Temperature From Baseline | Day 4 (72 hours post-dose) | -0.24 degrees Fahrenheit | Standard Deviation 0.34 |
| Severe Renal Impairment | Mean Change in Oral Temperature From Baseline | Day 1 (12 hours post-dose) | 0.14 degrees Fahrenheit | Standard Deviation 0.54 |
| Severe Renal Impairment | Mean Change in Oral Temperature From Baseline | Day 5 (96 hours post-dose) | -0.06 degrees Fahrenheit | Standard Deviation 0.21 |
Secondary
Mean Change in Pulse From Baseline
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Days 1, 2, 3, 4, 5, and 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change in Pulse From Baseline | Day 12 | 5.3 bpm | Standard Deviation 5.6 |
| Healthy Matched Controls | Mean Change in Pulse From Baseline | Day 3 (48 hours post-dose) | 3.5 bpm | Standard Deviation 3.3 |
| Healthy Matched Controls | Mean Change in Pulse From Baseline | Day 5 (96 hours post-dose) | 2.0 bpm | Standard Deviation 7.6 |
| Healthy Matched Controls | Mean Change in Pulse From Baseline | Day 1 (12 hours post-dose) | -0.3 bpm | Standard Deviation 8.3 |
| Healthy Matched Controls | Mean Change in Pulse From Baseline | Day 4 (72 hours post-dose) | 5.7 bpm | Standard Deviation 7.9 |
| Healthy Matched Controls | Mean Change in Pulse From Baseline | Day 2 (24 hours post-dose) | 3.7 bpm | Standard Deviation 6.7 |
| ESRD Not on Dialysis | Mean Change in Pulse From Baseline | Day 4 (72 hours post-dose) | -18.0 bpm | — |
| ESRD Not on Dialysis | Mean Change in Pulse From Baseline | Day 5 (96 hours post-dose) | -18.0 bpm | — |
| ESRD Not on Dialysis | Mean Change in Pulse From Baseline | Day 2 (24 hours post-dose) | -3.0 bpm | — |
| ESRD Not on Dialysis | Mean Change in Pulse From Baseline | Day 12 | -4.0 bpm | — |
| ESRD Not on Dialysis | Mean Change in Pulse From Baseline | Day 1 (12 hours post-dose) | -8.0 bpm | — |
| ESRD Not on Dialysis | Mean Change in Pulse From Baseline | Day 3 (48 hours post-dose) | -6.0 bpm | — |
| Severe Renal Impairment | Mean Change in Pulse From Baseline | Day 12 | -6.8 bpm | Standard Deviation 6.1 |
| Severe Renal Impairment | Mean Change in Pulse From Baseline | Day 1 (12 hours post-dose) | 0.4 bpm | Standard Deviation 5 |
| Severe Renal Impairment | Mean Change in Pulse From Baseline | Day 2 (24 hours post-dose) | -0.2 bpm | Standard Deviation 5.2 |
| Severe Renal Impairment | Mean Change in Pulse From Baseline | Day 3 (48 hours post-dose) | -1.4 bpm | Standard Deviation 6.5 |
| Severe Renal Impairment | Mean Change in Pulse From Baseline | Day 4 (72 hours post-dose) | -4.2 bpm | Standard Deviation 3.8 |
| Severe Renal Impairment | Mean Change in Pulse From Baseline | Day 5 (96 hours post-dose) | -1.8 bpm | Standard Deviation 4.8 |
Secondary
Mean Change in Sitting Diastolic Blood Pressure From Baseline
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Days 1, 2, 3, 4, 5, and 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 5 (96 hours post-dose) | -0.5 mmHg | Standard Deviation 5.7 |
| Healthy Matched Controls | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 3 (48 hours post-dose) | -0.5 mmHg | Standard Deviation 6.7 |
| Healthy Matched Controls | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 12 | -1.5 mmHg | Standard Deviation 6 |
| Healthy Matched Controls | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 1 (12 hours post-dose) | 1.3 mmHg | Standard Deviation 2.5 |
| Healthy Matched Controls | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 4 (72 hours post-dose) | 1.2 mmHg | Standard Deviation 3.9 |
| Healthy Matched Controls | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 2 (24 hours post-dose) | -3.7 mmHg | Standard Deviation 6.3 |
| ESRD Not on Dialysis | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 4 (72 hours post-dose) | -6.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 5 (96 hours post-dose) | -4.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 2 (24 hours post-dose) | -6.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 12 | -1.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 1 (12 hours post-dose) | 3.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 3 (48 hours post-dose) | -7.0 mmHg | — |
| Severe Renal Impairment | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 12 | -1.4 mmHg | Standard Deviation 10.3 |
| Severe Renal Impairment | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 1 (12 hours post-dose) | 2.0 mmHg | Standard Deviation 9.8 |
| Severe Renal Impairment | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 2 (24 hours post-dose) | -2.4 mmHg | Standard Deviation 7 |
| Severe Renal Impairment | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 3 (48 hours post-dose) | -2.2 mmHg | Standard Deviation 7.3 |
| Severe Renal Impairment | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 4 (72 hours post-dose) | 1.0 mmHg | Standard Deviation 11.2 |
| Severe Renal Impairment | Mean Change in Sitting Diastolic Blood Pressure From Baseline | Day 5 (96 hours post-dose) | -2.4 mmHg | Standard Deviation 13.8 |
Secondary
Mean Change in Sitting Systolic Blood Pressure From Baseline
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Days 1, 2, 3, 4, 5, and 12
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 1 (12 hours post-dose) | 0.8 mmHg | Standard Deviation 4.4 |
| Healthy Matched Controls | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 2 (24 hours post-dose) | -6.5 mmHg | Standard Deviation 7.5 |
| Healthy Matched Controls | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 3 (48 hours post-dose) | 0.3 mmHg | Standard Deviation 10.1 |
| Healthy Matched Controls | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 4 (72 hours post-dose) | 0.8 mmHg | Standard Deviation 8.1 |
| Healthy Matched Controls | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 5 (96 hours post-dose) | 0.5 mmHg | Standard Deviation 6.9 |
| Healthy Matched Controls | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 12 | 0.8 mmHg | Standard Deviation 4.8 |
| ESRD Not on Dialysis | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 12 | -13.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 1 (12 hours post-dose) | -4.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 4 (72 hours post-dose) | -20.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 5 (96 hours post-dose) | -17.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 2 (24 hours post-dose) | -16.0 mmHg | — |
| ESRD Not on Dialysis | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 3 (48 hours post-dose) | -23.0 mmHg | — |
| Severe Renal Impairment | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 2 (24 hours post-dose) | -15.0 mmHg | Standard Deviation 14.9 |
| Severe Renal Impairment | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 3 (48 hours post-dose) | -11.2 mmHg | Standard Deviation 14 |
| Severe Renal Impairment | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 12 | -5.4 mmHg | Standard Deviation 20.2 |
| Severe Renal Impairment | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 4 (72 hours post-dose) | -3.4 mmHg | Standard Deviation 17.7 |
| Severe Renal Impairment | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 1 (12 hours post-dose) | 2.0 mmHg | Standard Deviation 19.2 |
| Severe Renal Impairment | Mean Change in Sitting Systolic Blood Pressure From Baseline | Day 5 (96 hours post-dose) | -3.8 mmHg | Standard Deviation 13.5 |
Secondary
Mean Change in the Electrocardiogram (ECG) Corrected QT Interval by Fridericia (QTcF) Interval From Baseline
The mean change from baseline was calculated by taking the mean of each participant value at the specified day minus the value last recorded prior to drug administration.
Time frame: Day 5
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy Matched Controls | Mean Change in the Electrocardiogram (ECG) Corrected QT Interval by Fridericia (QTcF) Interval From Baseline | 5.3 ms | Standard Deviation 13.3 |
| ESRD Not on Dialysis | Mean Change in the Electrocardiogram (ECG) Corrected QT Interval by Fridericia (QTcF) Interval From Baseline | 25.0 ms | — |
| Severe Renal Impairment | Mean Change in the Electrocardiogram (ECG) Corrected QT Interval by Fridericia (QTcF) Interval From Baseline | -10.0 ms | Standard Deviation 10.9 |
Secondary
Number of Participants With and Severity of Adverse Events
An Adverse Event (AE) was defined as any unfavorable or unintended medical occurrence temporally associated with the use of a study drug, device, other medical product, or procedure whether or not it is considered related to the product itself.
Time frame: Day 1 to Day 85
Population: The safety analysis population set included all participants who receive any amount of study product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Healthy Matched Controls | Number of Participants With and Severity of Adverse Events | Mild Related Unsolicited Treatment Emergent AEs | 0 Participants |
| Healthy Matched Controls | Number of Participants With and Severity of Adverse Events | Unsolicited AEs | 0 Participants |
| Healthy Matched Controls | Number of Participants With and Severity of Adverse Events | Lab finding of Mild or Worse Severity Through Day 12 | 0 Participants |
| Healthy Matched Controls | Number of Participants With and Severity of Adverse Events | Unsolicited Treatment Emergent AEs | 0 Participants |
| Healthy Matched Controls | Number of Participants With and Severity of Adverse Events | Moderate Related Unsolicited Treatment Emergent AEs | 0 Participants |
| ESRD Not on Dialysis | Number of Participants With and Severity of Adverse Events | Unsolicited Treatment Emergent AEs | 0 Participants |
| ESRD Not on Dialysis | Number of Participants With and Severity of Adverse Events | Mild Related Unsolicited Treatment Emergent AEs | 0 Participants |
| ESRD Not on Dialysis | Number of Participants With and Severity of Adverse Events | Moderate Related Unsolicited Treatment Emergent AEs | 0 Participants |
| ESRD Not on Dialysis | Number of Participants With and Severity of Adverse Events | Lab finding of Mild or Worse Severity Through Day 12 | 1 Participants |
| ESRD Not on Dialysis | Number of Participants With and Severity of Adverse Events | Unsolicited AEs | 0 Participants |
| Severe Renal Impairment | Number of Participants With and Severity of Adverse Events | Moderate Related Unsolicited Treatment Emergent AEs | 1 Participants |
| Severe Renal Impairment | Number of Participants With and Severity of Adverse Events | Unsolicited Treatment Emergent AEs | 3 Participants |
| Severe Renal Impairment | Number of Participants With and Severity of Adverse Events | Unsolicited AEs | 3 Participants |
| Severe Renal Impairment | Number of Participants With and Severity of Adverse Events | Mild Related Unsolicited Treatment Emergent AEs | 2 Participants |
| Severe Renal Impairment | Number of Participants With and Severity of Adverse Events | Lab finding of Mild or Worse Severity Through Day 12 | 5 Participants |
Secondary
Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points
Renal clearance (CLr) of M19 and M50 calculated as the amount excreted in urine to time t in urine divided by the plasma AUC from 0 to time t. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK urine analysis subset will consist of all participants with sufficient urine PK data available to estimate the urine PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 0.222 L/h | Standard Deviation 0.134 |
| Healthy Matched Controls | Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 5.935 L/h | Standard Deviation 3.857 |
| ESRD Not on Dialysis | Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 0.170 L/h | — |
| ESRD Not on Dialysis | Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 0.930 L/h | — |
| Severe Renal Impairment | Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M19 | 0.440 L/h | Standard Deviation 0.567 |
| Severe Renal Impairment | Renal Clearance of M19 and M50 at Specified Pre-dose and Post-dose Time Points | M50 | 0.634 L/h | Standard Deviation 0.139 |
Secondary
Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points
Time of maximum M19 and M50 concentration (Tmax) at specified pre-dose and post-dose timepoints. M19 and M50 are the two primary representative metabolites of pretomanid.
Time frame: Day 1 at 1, 2, 4, 5, 6, 8, 12, 16 hours post dose; Day 2 at 24 and 36 hours post dose; Day 3 at 48 hours post dose; Day 4 at 72 hours post dose; and Day 5 at 96 hours post dose.
Population: The PK plasma analysis subset consisted of all participants with sufficient plasma PK data available to estimate the plasma PK parameters using noncompartmental methods.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Healthy Matched Controls | Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | M19 | 10.67 Hours | Standard Deviation 7.45 |
| Healthy Matched Controls | Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | M50 | 7.50 Hours | Standard Deviation 3.78 |
| ESRD Not on Dialysis | Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | M19 | 24.00 Hours | — |
| ESRD Not on Dialysis | Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | M50 | 16.00 Hours | — |
| Severe Renal Impairment | Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | M19 | 22.42 Hours | Standard Deviation 15.43 |
| Severe Renal Impairment | Time of Maximum M19 and M50 Concentration at Specified Pre-dose and Post-dose Time Points | M50 | 13.60 Hours | Standard Deviation 2.19 |